VANCOUVER—Among patients with secondary progressive multiple sclerosis (MS), natalizumab does not delay progression of ambulatory disability, according to phase III trial results presented at the 68th Annual Meeting of the American Academy of Neurology. The drug may slow progression of upper-extremity disability, however, researchers said.

Natalizumab, a recombinant humanized monoclonal antibody against alpha-4 beta-1 integrin, reduces inflammation by inhibiting the transmigration of leukocytes into the brain. It is FDA-approved to treat relapsing-remitting MS, and data have suggested that the drug also may benefit patients with progressive forms of MS.

To investigate whether natalizumab slows disability progression unrelated to relapses in patients with secondary progressive MS, Deborah Steiner, MD, Medical Director at Biogen, and colleagues conducted ASCEND, a multicenter, double-blind, placebo-controlled, randomized trial.

The primary end point was the proportion of participants with confirmed disability progression on the EDSS, Nine-Hole Peg Test, or Timed 25-Foot Walk at six months and at the end of the trial. On the EDSS, progression was defined as an increase of at least 1.0 from a baseline EDSS score of 5.5 or less, or an increase of at least 0.5 from a baseline EDSS score of 6 or more. On the Timed 25-Foot Walk, progression was defined as an increase of 20% or more from baseline. On the Nine-Hole Peg Test, progression was defined as an increase of 20% or more on either hand.

ASCEND did not meet its primary end point. The proportion of progressors was higher in the placebo-treated group (48%) than in the natalizumab-treated group (44%), but the difference was not statistically significant.

Natalizumab treatment was, how­ever, associated with a statistically significant reduction of upper-extremity disability progression, as measured by the Nine-Hole Peg Test. Fifteen percent of participants who received natalizumab had confirmed disability progression on the Nine-Hole Peg Test, compared with 23% of participants who received placebo (odds ratio, 0.56). Dr. Steiner noted that ABILHAND, a patient-reported upper-extremity outcome, clearly differentiated Nine-Hole Peg Test progressors from nonprogressors. This finding “confirms the meaningfulness” of the treatment’s effect on upper extremity disability, the researchers said.

On the Nine-Hole Peg Test, estimated probabilities of confirmed progression over two years showed increased separation over time between the natalizumab and placebo arms. “In contrast, no significant separation over time was observed between natalizumab- and placebo-treated patients on the Timed 25-Foot Walk (38.3% vs 39.2%) or EDSS (17.4% vs 16.7%) components of the primary end point,” the researchers said.

“There’s a striking contrast between the lack of effect on ambulatory function … and the effect on upper-extremity function,” Dr. Steiner said.

Natalizumab was generally well tolerated, with adverse events consistent with its known safety profile.

The study was supported by Biogen in Cambridge, Massachusetts.

—Jake Remaly

VANCOUVER—Among patients with secondary progressive multiple sclerosis (MS), natalizumab does not delay progression of ambulatory disability, according to phase III trial results presented at the 68th Annual Meeting of the American Academy of Neurology. The drug may slow progression of upper-extremity disability, however, researchers said.

Natalizumab, a recombinant humanized monoclonal antibody against alpha-4 beta-1 integrin, reduces inflammation by inhibiting the transmigration of leukocytes into the brain. It is FDA-approved to treat relapsing-remitting MS, and data have suggested that the drug also may benefit patients with progressive forms of MS.

To investigate whether natalizumab slows disability progression unrelated to relapses in patients with secondary progressive MS, Deborah Steiner, MD, Medical Director at Biogen, and colleagues conducted ASCEND, a multicenter, double-blind, placebo-controlled, randomized trial.

The primary end point was the proportion of participants with confirmed disability progression on the EDSS, Nine-Hole Peg Test, or Timed 25-Foot Walk at six months and at the end of the trial. On the EDSS, progression was defined as an increase of at least 1.0 from a baseline EDSS score of 5.5 or less, or an increase of at least 0.5 from a baseline EDSS score of 6 or more. On the Timed 25-Foot Walk, progression was defined as an increase of 20% or more from baseline. On the Nine-Hole Peg Test, progression was defined as an increase of 20% or more on either hand.

ASCEND did not meet its primary end point. The proportion of progressors was higher in the placebo-treated group (48%) than in the natalizumab-treated group (44%), but the difference was not statistically significant.

Natalizumab treatment was, how­ever, associated with a statistically significant reduction of upper-extremity disability progression, as measured by the Nine-Hole Peg Test. Fifteen percent of participants who received natalizumab had confirmed disability progression on the Nine-Hole Peg Test, compared with 23% of participants who received placebo (odds ratio, 0.56). Dr. Steiner noted that ABILHAND, a patient-reported upper-extremity outcome, clearly differentiated Nine-Hole Peg Test progressors from nonprogressors. This finding “confirms the meaningfulness” of the treatment’s effect on upper extremity disability, the researchers said.

On the Nine-Hole Peg Test, estimated probabilities of confirmed progression over two years showed increased separation over time between the natalizumab and placebo arms. “In contrast, no significant separation over time was observed between natalizumab- and placebo-treated patients on the Timed 25-Foot Walk (38.3% vs 39.2%) or EDSS (17.4% vs 16.7%) components of the primary end point,” the researchers said.

“There’s a striking contrast between the lack of effect on ambulatory function … and the effect on upper-extremity function,” Dr. Steiner said.

Natalizumab was generally well tolerated, with adverse events consistent with its known safety profile.

The study was supported by Biogen in Cambridge, Massachusetts.

—Jake Remaly

VANCOUVER—Among patients with secondary progressive multiple sclerosis (MS), natalizumab does not delay progression of ambulatory disability, according to phase III trial results presented at the 68th Annual Meeting of the American Academy of Neurology. The drug may slow progression of upper-extremity disability, however, researchers said.

Natalizumab, a recombinant humanized monoclonal antibody against alpha-4 beta-1 integrin, reduces inflammation by inhibiting the transmigration of leukocytes into the brain. It is FDA-approved to treat relapsing-remitting MS, and data have suggested that the drug also may benefit patients with progressive forms of MS.

To investigate whether natalizumab slows disability progression unrelated to relapses in patients with secondary progressive MS, Deborah Steiner, MD, Medical Director at Biogen, and colleagues conducted ASCEND, a multicenter, double-blind, placebo-controlled, randomized trial.

The primary end point was the proportion of participants with confirmed disability progression on the EDSS, Nine-Hole Peg Test, or Timed 25-Foot Walk at six months and at the end of the trial. On the EDSS, progression was defined as an increase of at least 1.0 from a baseline EDSS score of 5.5 or less, or an increase of at least 0.5 from a baseline EDSS score of 6 or more. On the Timed 25-Foot Walk, progression was defined as an increase of 20% or more from baseline. On the Nine-Hole Peg Test, progression was defined as an increase of 20% or more on either hand.

ASCEND did not meet its primary end point. The proportion of progressors was higher in the placebo-treated group (48%) than in the natalizumab-treated group (44%), but the difference was not statistically significant.

Natalizumab treatment was, how­ever, associated with a statistically significant reduction of upper-extremity disability progression, as measured by the Nine-Hole Peg Test. Fifteen percent of participants who received natalizumab had confirmed disability progression on the Nine-Hole Peg Test, compared with 23% of participants who received placebo (odds ratio, 0.56). Dr. Steiner noted that ABILHAND, a patient-reported upper-extremity outcome, clearly differentiated Nine-Hole Peg Test progressors from nonprogressors. This finding “confirms the meaningfulness” of the treatment’s effect on upper extremity disability, the researchers said.

On the Nine-Hole Peg Test, estimated probabilities of confirmed progression over two years showed increased separation over time between the natalizumab and placebo arms. “In contrast, no significant separation over time was observed between natalizumab- and placebo-treated patients on the Timed 25-Foot Walk (38.3% vs 39.2%) or EDSS (17.4% vs 16.7%) components of the primary end point,” the researchers said.

“There’s a striking contrast between the lack of effect on ambulatory function … and the effect on upper-extremity function,” Dr. Steiner said.

Natalizumab was generally well tolerated, with adverse events consistent with its known safety profile.

The study was supported by Biogen in Cambridge, Massachusetts.

—Jake Remaly

What if this increase had occurred in cardiovascular disease or cancer (both on the decline, in fact, thanks to the intense attention they receive)? I think there would have been a public outcry, followed by demands by Congress that the National Institutes of Health and the CDC address this catastrophic rise immediately. And billions of dollars would then be earmarked to prevent these 2 diseases. 

How sad that society has “forgotten” that mental illness has deadly consequences, often leading to suicide (42,773 deaths in 2014 alone²—the second most common cause among people age 15 to 25³)! Hundreds of thousands of people attempt suicide every year, and those who do not lose their life often end up injured or maimed. Millions who suffer depression, bipolar disorder, schizophrenia, anxiety, posttraumatic stress disorder, or a substance use disorder are at high risk of suicide, and many never receive the timely intervention that might save their life.

Our national blind spot
It is poignant that the CDC report was released in spring: The rate of suicide is highest in April and May, when the light-dark cycle is reversed. This springtime peak runs contrary to the common belief that the rate of suicide is highest during winter months. The Annual Meeting of the American Psychiatric Association convenes in May, such that, ironically, thousands of psychiatrists are away from their office exactly when their patients might need them most

Lack of attention to the high risk of suicide among all ages and both sexes is emblematic of society’s inexplicable neglect of the needs of the mentally ill. That neglect is fueled, and exacerbated, by the destructive stigma attached to brain disorders that display psychiatric symptoms. As a neuropsychiatrist, I label this neglect societal anosognosia—the same as the lack of insight seen in patients with acute schizophrenia, who are unaware of how impaired they are and insist that they are not sick. (Anosognosia also occurs in stroke patients who deny that their limb is paralyzed and insist that all is well.)

Loss of insight can have serious consequences for patients who lose the ability to monitor and evaluate their physical and mental health. Just as patients with anosognosia think they do not need help, a society that fails to attend to the mental illness of its citizens endangers their overall health and welfare.

From neglect of mental illness many hazards arise
Tens of millions of Americans suffer from mental illness, according to the National Institute of Mental Health-sponsored Epidemiologic Catchment Area Study.⁴ The last thing these people can afford is societal anosognosia, which deprives them of necessary and timely access to psychiatric care.

Societal anosognosia is associated with numerous hazards for persons with mental illness, including:

• Lack of compassion, which is readily available for people with a medical ailment (broken bones, cardiovascular disease, cancer).
• Lack of adequate, affordable health insurance and financial support, compared with what is available for non-psychiatric disorders.
• Shortage of publicly funded programs and mental health practitioners to provide prevention and intervention for those who consider ending their life during an episode of depression, psychosis, stress, or a panic attack.
• Allowing the stigma to continue unabated. Why are there strict laws about hate crimes, but not about stigma? Why does society continue to portray depression and anxiety as a personal weakness or failure, while patients with Parkinson’s disease or multiple sclerosis who have motor weakness are not stigmatized for their physical deficits?
• Transforming the seriously mentally ill into felons by arresting and jailing them because of erratic behavior—instead of hospitalizing them for the medical care they need. The trans­institutionalization of the mentally ill—from state hospitals to prisons—is one of the most shameful consequences of societal anosognosia, burdening our patients with the dual stigma of being a criminal and mentally ill.
• Turning a blind eye to abuses by insurance companies. More appalling is the perpetuation of restricted health coverage despite the passage of parity laws! Why are sensory and motor disorders of brain lesions covered fully, while the thought, emotional, and behavior disorders of the brain covered only partially?
• Consent laws that restrict psychiatrists from medicating acutely psychotic or depressed patients unless they consent—but no laws that restrict a cardiologist from immediately treating an unconscious heart attack patient who cannot consent, or an obtunded stroke patient who cannot communicate? The duration of untreated psychosis or depression has been shown repeatedly to have deleterious effects on brain tissue and functional outcomes, yet treatment of an acutely ill psychiatric patient is often delayed until a court order is obtained. When was the last time a court order was needed to treat an acute myocardial infarction?
• Failure to recognize that premature mortality (by approximately 25 years) is a devastating consequence of mental illness, whether from suicide or cardiometabolic risk factors due to smoking, substance use (often used to self-medicate because proper treatment is lacking), poor diet, and sedentary living.
• Failure to provide basic primary care to people with severe mental illness, and the much lower use of life-saving diagnostic and treatment procedures offered to these patients, compared with non-psychiatric patients.
• Inadequate funding for research on psychiatric disorders, compared with other medical disorders—even though direct and indirect costs of mental illness to society (hundreds of billions of dollars a year) far exceed costs of most medical disorders.
• Severe shortage of rehabilitation programs for the mentally ill, compared with many other medical disorders. Why does paralysis of the mind receive far less support than paralysis of the legs or arms? 

The rising suicide rate reflects poorly on us
Societal anosognosia is a global scourge, affecting many underdeveloped countries. Why do developed nations, like ours, have the same blind spot for mental illness? Might ignorance and discrimination be universal?

The tragic rise in the rate of death by suicide in men and women, among all age groups, year after year, is stunningly incongruent when juxtaposed against the elimination of smallpox and other communicable diseases through a concerted societal effort to support scientific advances in vaccine development. Societal anosognosia appears to be selective: We have comprehensive insight about diseases of the body but not diseases of the mind.

The essence and soul of a society are the collective minds of its citizens, not their bodies. Societal anosognosia is a serious dysfunction of its mind, and a rising suicide rate is a symptom of that pathological dysfunction.

What if this increase had occurred in cardiovascular disease or cancer (both on the decline, in fact, thanks to the intense attention they receive)? I think there would have been a public outcry, followed by demands by Congress that the National Institutes of Health and the CDC address this catastrophic rise immediately. And billions of dollars would then be earmarked to prevent these 2 diseases. 

How sad that society has “forgotten” that mental illness has deadly consequences, often leading to suicide (42,773 deaths in 2014 alone²—the second most common cause among people age 15 to 25³)! Hundreds of thousands of people attempt suicide every year, and those who do not lose their life often end up injured or maimed. Millions who suffer depression, bipolar disorder, schizophrenia, anxiety, posttraumatic stress disorder, or a substance use disorder are at high risk of suicide, and many never receive the timely intervention that might save their life.

Our national blind spot
It is poignant that the CDC report was released in spring: The rate of suicide is highest in April and May, when the light-dark cycle is reversed. This springtime peak runs contrary to the common belief that the rate of suicide is highest during winter months. The Annual Meeting of the American Psychiatric Association convenes in May, such that, ironically, thousands of psychiatrists are away from their office exactly when their patients might need them most

Lack of attention to the high risk of suicide among all ages and both sexes is emblematic of society’s inexplicable neglect of the needs of the mentally ill. That neglect is fueled, and exacerbated, by the destructive stigma attached to brain disorders that display psychiatric symptoms. As a neuropsychiatrist, I label this neglect societal anosognosia—the same as the lack of insight seen in patients with acute schizophrenia, who are unaware of how impaired they are and insist that they are not sick. (Anosognosia also occurs in stroke patients who deny that their limb is paralyzed and insist that all is well.)

Loss of insight can have serious consequences for patients who lose the ability to monitor and evaluate their physical and mental health. Just as patients with anosognosia think they do not need help, a society that fails to attend to the mental illness of its citizens endangers their overall health and welfare.

From neglect of mental illness many hazards arise
Tens of millions of Americans suffer from mental illness, according to the National Institute of Mental Health-sponsored Epidemiologic Catchment Area Study.⁴ The last thing these people can afford is societal anosognosia, which deprives them of necessary and timely access to psychiatric care.

Societal anosognosia is associated with numerous hazards for persons with mental illness, including:

• Lack of compassion, which is readily available for people with a medical ailment (broken bones, cardiovascular disease, cancer).
• Lack of adequate, affordable health insurance and financial support, compared with what is available for non-psychiatric disorders.
• Shortage of publicly funded programs and mental health practitioners to provide prevention and intervention for those who consider ending their life during an episode of depression, psychosis, stress, or a panic attack.
• Allowing the stigma to continue unabated. Why are there strict laws about hate crimes, but not about stigma? Why does society continue to portray depression and anxiety as a personal weakness or failure, while patients with Parkinson’s disease or multiple sclerosis who have motor weakness are not stigmatized for their physical deficits?
• Transforming the seriously mentally ill into felons by arresting and jailing them because of erratic behavior—instead of hospitalizing them for the medical care they need. The trans­institutionalization of the mentally ill—from state hospitals to prisons—is one of the most shameful consequences of societal anosognosia, burdening our patients with the dual stigma of being a criminal and mentally ill.
• Turning a blind eye to abuses by insurance companies. More appalling is the perpetuation of restricted health coverage despite the passage of parity laws! Why are sensory and motor disorders of brain lesions covered fully, while the thought, emotional, and behavior disorders of the brain covered only partially?
• Consent laws that restrict psychiatrists from medicating acutely psychotic or depressed patients unless they consent—but no laws that restrict a cardiologist from immediately treating an unconscious heart attack patient who cannot consent, or an obtunded stroke patient who cannot communicate? The duration of untreated psychosis or depression has been shown repeatedly to have deleterious effects on brain tissue and functional outcomes, yet treatment of an acutely ill psychiatric patient is often delayed until a court order is obtained. When was the last time a court order was needed to treat an acute myocardial infarction?
• Failure to recognize that premature mortality (by approximately 25 years) is a devastating consequence of mental illness, whether from suicide or cardiometabolic risk factors due to smoking, substance use (often used to self-medicate because proper treatment is lacking), poor diet, and sedentary living.
• Failure to provide basic primary care to people with severe mental illness, and the much lower use of life-saving diagnostic and treatment procedures offered to these patients, compared with non-psychiatric patients.
• Inadequate funding for research on psychiatric disorders, compared with other medical disorders—even though direct and indirect costs of mental illness to society (hundreds of billions of dollars a year) far exceed costs of most medical disorders.
• Severe shortage of rehabilitation programs for the mentally ill, compared with many other medical disorders. Why does paralysis of the mind receive far less support than paralysis of the legs or arms? 

The rising suicide rate reflects poorly on us
Societal anosognosia is a global scourge, affecting many underdeveloped countries. Why do developed nations, like ours, have the same blind spot for mental illness? Might ignorance and discrimination be universal?

The tragic rise in the rate of death by suicide in men and women, among all age groups, year after year, is stunningly incongruent when juxtaposed against the elimination of smallpox and other communicable diseases through a concerted societal effort to support scientific advances in vaccine development. Societal anosognosia appears to be selective: We have comprehensive insight about diseases of the body but not diseases of the mind.

The essence and soul of a society are the collective minds of its citizens, not their bodies. Societal anosognosia is a serious dysfunction of its mind, and a rising suicide rate is a symptom of that pathological dysfunction.

What if this increase had occurred in cardiovascular disease or cancer (both on the decline, in fact, thanks to the intense attention they receive)? I think there would have been a public outcry, followed by demands by Congress that the National Institutes of Health and the CDC address this catastrophic rise immediately. And billions of dollars would then be earmarked to prevent these 2 diseases. 

How sad that society has “forgotten” that mental illness has deadly consequences, often leading to suicide (42,773 deaths in 2014 alone²—the second most common cause among people age 15 to 25³)! Hundreds of thousands of people attempt suicide every year, and those who do not lose their life often end up injured or maimed. Millions who suffer depression, bipolar disorder, schizophrenia, anxiety, posttraumatic stress disorder, or a substance use disorder are at high risk of suicide, and many never receive the timely intervention that might save their life.

Our national blind spot
It is poignant that the CDC report was released in spring: The rate of suicide is highest in April and May, when the light-dark cycle is reversed. This springtime peak runs contrary to the common belief that the rate of suicide is highest during winter months. The Annual Meeting of the American Psychiatric Association convenes in May, such that, ironically, thousands of psychiatrists are away from their office exactly when their patients might need them most

Lack of attention to the high risk of suicide among all ages and both sexes is emblematic of society’s inexplicable neglect of the needs of the mentally ill. That neglect is fueled, and exacerbated, by the destructive stigma attached to brain disorders that display psychiatric symptoms. As a neuropsychiatrist, I label this neglect societal anosognosia—the same as the lack of insight seen in patients with acute schizophrenia, who are unaware of how impaired they are and insist that they are not sick. (Anosognosia also occurs in stroke patients who deny that their limb is paralyzed and insist that all is well.)

Loss of insight can have serious consequences for patients who lose the ability to monitor and evaluate their physical and mental health. Just as patients with anosognosia think they do not need help, a society that fails to attend to the mental illness of its citizens endangers their overall health and welfare.

From neglect of mental illness many hazards arise
Tens of millions of Americans suffer from mental illness, according to the National Institute of Mental Health-sponsored Epidemiologic Catchment Area Study.⁴ The last thing these people can afford is societal anosognosia, which deprives them of necessary and timely access to psychiatric care.

Societal anosognosia is associated with numerous hazards for persons with mental illness, including:

• Lack of compassion, which is readily available for people with a medical ailment (broken bones, cardiovascular disease, cancer).
• Lack of adequate, affordable health insurance and financial support, compared with what is available for non-psychiatric disorders.
• Shortage of publicly funded programs and mental health practitioners to provide prevention and intervention for those who consider ending their life during an episode of depression, psychosis, stress, or a panic attack.
• Allowing the stigma to continue unabated. Why are there strict laws about hate crimes, but not about stigma? Why does society continue to portray depression and anxiety as a personal weakness or failure, while patients with Parkinson’s disease or multiple sclerosis who have motor weakness are not stigmatized for their physical deficits?
• Transforming the seriously mentally ill into felons by arresting and jailing them because of erratic behavior—instead of hospitalizing them for the medical care they need. The trans­institutionalization of the mentally ill—from state hospitals to prisons—is one of the most shameful consequences of societal anosognosia, burdening our patients with the dual stigma of being a criminal and mentally ill.
• Turning a blind eye to abuses by insurance companies. More appalling is the perpetuation of restricted health coverage despite the passage of parity laws! Why are sensory and motor disorders of brain lesions covered fully, while the thought, emotional, and behavior disorders of the brain covered only partially?
• Consent laws that restrict psychiatrists from medicating acutely psychotic or depressed patients unless they consent—but no laws that restrict a cardiologist from immediately treating an unconscious heart attack patient who cannot consent, or an obtunded stroke patient who cannot communicate? The duration of untreated psychosis or depression has been shown repeatedly to have deleterious effects on brain tissue and functional outcomes, yet treatment of an acutely ill psychiatric patient is often delayed until a court order is obtained. When was the last time a court order was needed to treat an acute myocardial infarction?
• Failure to recognize that premature mortality (by approximately 25 years) is a devastating consequence of mental illness, whether from suicide or cardiometabolic risk factors due to smoking, substance use (often used to self-medicate because proper treatment is lacking), poor diet, and sedentary living.
• Failure to provide basic primary care to people with severe mental illness, and the much lower use of life-saving diagnostic and treatment procedures offered to these patients, compared with non-psychiatric patients.
• Inadequate funding for research on psychiatric disorders, compared with other medical disorders—even though direct and indirect costs of mental illness to society (hundreds of billions of dollars a year) far exceed costs of most medical disorders.
• Severe shortage of rehabilitation programs for the mentally ill, compared with many other medical disorders. Why does paralysis of the mind receive far less support than paralysis of the legs or arms? 

The rising suicide rate reflects poorly on us
Societal anosognosia is a global scourge, affecting many underdeveloped countries. Why do developed nations, like ours, have the same blind spot for mental illness? Might ignorance and discrimination be universal?

The tragic rise in the rate of death by suicide in men and women, among all age groups, year after year, is stunningly incongruent when juxtaposed against the elimination of smallpox and other communicable diseases through a concerted societal effort to support scientific advances in vaccine development. Societal anosognosia appears to be selective: We have comprehensive insight about diseases of the body but not diseases of the mind.

The essence and soul of a society are the collective minds of its citizens, not their bodies. Societal anosognosia is a serious dysfunction of its mind, and a rising suicide rate is a symptom of that pathological dysfunction.

Pooja Patel, MD

Selim Benbadis, MD

Dr. Patel is a fourth year neurology resident at the University of South Florida and will begin an epilepsy fellowship at the University of South Florida in July. 

Dr. Benbadis is Professor and Director of the Comprehensive Epilepsy Program at the University of South Florida and Tampa General Hospital in Tampa, Florida.

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with intractable epilepsy. SUDEP accounts for 7.5% to 17% of all deaths related to epilepsy and has an annual incidence of 3 to 9 per 1000 in the general epilepsy population. Even with such a high prevalence, epilepsy patients, their families, and even many physicians are unaware of the mortality and risk of SUDEP. SUDEP has recently received significant attention in the scientific literature due to its high prevalence and lack of well-defined mechanisms. Understanding the modifiable risk factors and pathophysiology of SUDEP is critically important to help delineate preventive strategies.

Several mechanisms have been proposed to play a role in the pathophysiology of SUDEP. Recent literature have included new insights derived from combined data from older and newer studies where clues were obtained from witnessed SUDEP cases, Epilepsy Monitoring Unit observation of SUDEP cases, physiological data obtained from nonfatal seizures, and animal models. Based on many cohort studies, the initial mechanism is thought to be due to hypoventilation or apnea resulting from the seizure itself. The prone position is thought to contribute to prolonged oxygen desaturation by causing loss of arousal and inability to sense increased carbon dioxide levels. This in turn can cause secondary cardiac arrhythmias that are fatal. The other proposed mechanism is primary cardiac arrhythmia resulting from autonomic dysfunction before, during, or after a seizure. Additionally, serotonergic neurons might contribute as well by causing combination of hypoventilation and seizure. Experts also have suggested that genetic mutations cause primary dysfunction leading to fatal seizures; however, this requires further research.

Based on recent findings about the pathophysiology of SUDEP, several preventive measures have been suggested. The critical preventive measure is still believed to be good control of seizures, as uncontrolled generalized tonic-clonic seizures continue to be the biggest risk factor of SUDEP. Good control of seizures can be difficult in chronic refractory epilepsy and early referral should be made to an epilepsy center. Several studies evaluating patients after epilepsy surgery have discovered that surgery reduces patients’ likelihood of SUDEP. A study done in 2000 evaluated vagus nerve stimulation (VNS) implantation and SUDEP risk, and concluded that during the first 2 years the risk of SUDEP was higher than isolated use of some of the antiepileptics. However, after a 2-year follow-up, the risk of SUDEP was remarkably lower. The initial higher rate was likely due to the fact that VNS was implanted in refractory patients who had failed antiepileptics and were candidates for surgery. Experts believe that VNS is likely protective toward SUDEP as it reduces the amount of generalized tonic-clonic seizures.

Sleep is considered to be high risk for SUDEP because of the higher number of seizures occurring in sleep and hormonal and autonomic changes occurring at nighttime, which increase SUDEP risk. Use of a bed where the head can be adjusted to be higher than the feet, a supine sleep position, a special pillow to prevent suffocation, and even supervision at night has been recommended to reduce the risk of SUDEP. Supervision at night, which includes a supervising person sharing the same bedroom, special precautions such as regular checks throughout the night, or use of a monitoring device, was associated with a decreased risk of SUDEP in a recent study. Medications such as alpha-blockers and beta-blockers might be considered as they can reduce sympathetic discharge and prevent cardiac arrhythmias. Selective serotonin reuptake inhibitors can also reduce ictal hypoxemia and can help prevent a potential mechanism leading to SUDEP.

SUDEP is a significant burden in the field of epilepsy because of its mortality, but it is a subject that is not known well among patients, family, and providers. A recent Australian study reported that only a minority of adult patients with epilepsy had heard about SUDEP from their neurologists. Due to limited experience and knowledge of SUDEP, some neurologists may be unable to provide the appropriate education to patients and their families. The first qualitative study to explore opinions of bereaved relatives on whether to discuss SUDEP with patients was recently performed in the United States. The study showed that 91% of parents of epilepsy patients and 89.5% of adults with epilepsy would have preferred to have information about SUDEP. These respondents would have liked their neurologists in particular to discuss SUDEP so that they could have focused on preventive techniques. Study results suggest a lack of knowledge and the need for more awareness of SUDEP among the epilepsy population. It should be the neurologists’ responsibility to discuss and inform patients and their families about SUDEP at an appropriate time based on their diagnosis.

Resources such as the SUDEP-7 inventory can be used to help physicians identify patients with refractory epilepsy at risk for SUDEP. In 2011, the first SUDEP-7 inventory was found to be associated to two biomarkers: vagus-mediated heart rate variability and post-ictal generalized electroencephalogram suppression. In 2015, this inventory was modified to the revised SUDEP-7 inventory, which re-evaluated the association with heart rate. Results indicated that older age, longer duration of epilepsy, and presence of developmental disability had direct influence on vagus-mediated heart rate variability and thus increased SUDEP risk. The higher the SUDEP-7 inventory score, the higher the risk of SUDEP. SUDEP-7 inventory and other similar inventories can be a valuable tool for risk stratification and in turn can be used when deciding whether or not to have discussion of SUDEP with patients and families.

In conclusion, SUDEP continues to be a growing concern of mortality in the epilepsy population. Recent research has shed light on its pathophysiologic mechanism, which will in turn help us determine preventive techniques for vulnerable patients. Hopefully, increased SUDEP awareness will help physicians be more knowledgeable and comfortable in leading the discussion of SUDEP. Further research is still needed to uncover the role of genetics using animal and human models.

Sources

Annegers JF, Coan SP, Hauser WA, Leestma J. Epilepsy, vagal nerve stimulation by the NCP system, all-cause mortality and sudden, unexpected, unexplained death. Epilepsia. 2000;41(5):549-553.

Dlouhy BJ, Gehlbach BK, Richerson GB. Sudden unexpected death in epilepsy: basic mechanisms and clinical implications for prevention. J Neurol Neurosurg Psychiatry. 2016;87(4):402-413. 

Morse AM, Kothare SV. Pediatric sudden unexpected death in epilepsy. Pediatr Neurol. 2016;57:7-16.

Novak JL, Miller PR, Markovic D, Meymandi SK, DeGiorgio CM. Risk assessment for sudden death in epilepsy: the SUDEP-7 inventory. Front Neurol. 2015;6:252.

Pansani AP, Colugnati DB, Scorza CA, de Almeida AC, Cavalheiro EA, Scorza FA. Furthering our understanding of SUDEP: the role of animal models. Expert Rev Neurother. 2016;16(5):561-572.

RamachandranNair R, Jack SM, Strohm S. SUDEP: to discuss or not? recommendations from bereaved relatives. Epilepsy Behav. 2016;56:20-25.      

Pooja Patel, MD

Selim Benbadis, MD

Dr. Patel is a fourth year neurology resident at the University of South Florida and will begin an epilepsy fellowship at the University of South Florida in July. 

Dr. Benbadis is Professor and Director of the Comprehensive Epilepsy Program at the University of South Florida and Tampa General Hospital in Tampa, Florida.

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with intractable epilepsy. SUDEP accounts for 7.5% to 17% of all deaths related to epilepsy and has an annual incidence of 3 to 9 per 1000 in the general epilepsy population. Even with such a high prevalence, epilepsy patients, their families, and even many physicians are unaware of the mortality and risk of SUDEP. SUDEP has recently received significant attention in the scientific literature due to its high prevalence and lack of well-defined mechanisms. Understanding the modifiable risk factors and pathophysiology of SUDEP is critically important to help delineate preventive strategies.

Several mechanisms have been proposed to play a role in the pathophysiology of SUDEP. Recent literature have included new insights derived from combined data from older and newer studies where clues were obtained from witnessed SUDEP cases, Epilepsy Monitoring Unit observation of SUDEP cases, physiological data obtained from nonfatal seizures, and animal models. Based on many cohort studies, the initial mechanism is thought to be due to hypoventilation or apnea resulting from the seizure itself. The prone position is thought to contribute to prolonged oxygen desaturation by causing loss of arousal and inability to sense increased carbon dioxide levels. This in turn can cause secondary cardiac arrhythmias that are fatal. The other proposed mechanism is primary cardiac arrhythmia resulting from autonomic dysfunction before, during, or after a seizure. Additionally, serotonergic neurons might contribute as well by causing combination of hypoventilation and seizure. Experts also have suggested that genetic mutations cause primary dysfunction leading to fatal seizures; however, this requires further research.

Based on recent findings about the pathophysiology of SUDEP, several preventive measures have been suggested. The critical preventive measure is still believed to be good control of seizures, as uncontrolled generalized tonic-clonic seizures continue to be the biggest risk factor of SUDEP. Good control of seizures can be difficult in chronic refractory epilepsy and early referral should be made to an epilepsy center. Several studies evaluating patients after epilepsy surgery have discovered that surgery reduces patients’ likelihood of SUDEP. A study done in 2000 evaluated vagus nerve stimulation (VNS) implantation and SUDEP risk, and concluded that during the first 2 years the risk of SUDEP was higher than isolated use of some of the antiepileptics. However, after a 2-year follow-up, the risk of SUDEP was remarkably lower. The initial higher rate was likely due to the fact that VNS was implanted in refractory patients who had failed antiepileptics and were candidates for surgery. Experts believe that VNS is likely protective toward SUDEP as it reduces the amount of generalized tonic-clonic seizures.

Sleep is considered to be high risk for SUDEP because of the higher number of seizures occurring in sleep and hormonal and autonomic changes occurring at nighttime, which increase SUDEP risk. Use of a bed where the head can be adjusted to be higher than the feet, a supine sleep position, a special pillow to prevent suffocation, and even supervision at night has been recommended to reduce the risk of SUDEP. Supervision at night, which includes a supervising person sharing the same bedroom, special precautions such as regular checks throughout the night, or use of a monitoring device, was associated with a decreased risk of SUDEP in a recent study. Medications such as alpha-blockers and beta-blockers might be considered as they can reduce sympathetic discharge and prevent cardiac arrhythmias. Selective serotonin reuptake inhibitors can also reduce ictal hypoxemia and can help prevent a potential mechanism leading to SUDEP.

SUDEP is a significant burden in the field of epilepsy because of its mortality, but it is a subject that is not known well among patients, family, and providers. A recent Australian study reported that only a minority of adult patients with epilepsy had heard about SUDEP from their neurologists. Due to limited experience and knowledge of SUDEP, some neurologists may be unable to provide the appropriate education to patients and their families. The first qualitative study to explore opinions of bereaved relatives on whether to discuss SUDEP with patients was recently performed in the United States. The study showed that 91% of parents of epilepsy patients and 89.5% of adults with epilepsy would have preferred to have information about SUDEP. These respondents would have liked their neurologists in particular to discuss SUDEP so that they could have focused on preventive techniques. Study results suggest a lack of knowledge and the need for more awareness of SUDEP among the epilepsy population. It should be the neurologists’ responsibility to discuss and inform patients and their families about SUDEP at an appropriate time based on their diagnosis.

Resources such as the SUDEP-7 inventory can be used to help physicians identify patients with refractory epilepsy at risk for SUDEP. In 2011, the first SUDEP-7 inventory was found to be associated to two biomarkers: vagus-mediated heart rate variability and post-ictal generalized electroencephalogram suppression. In 2015, this inventory was modified to the revised SUDEP-7 inventory, which re-evaluated the association with heart rate. Results indicated that older age, longer duration of epilepsy, and presence of developmental disability had direct influence on vagus-mediated heart rate variability and thus increased SUDEP risk. The higher the SUDEP-7 inventory score, the higher the risk of SUDEP. SUDEP-7 inventory and other similar inventories can be a valuable tool for risk stratification and in turn can be used when deciding whether or not to have discussion of SUDEP with patients and families.

In conclusion, SUDEP continues to be a growing concern of mortality in the epilepsy population. Recent research has shed light on its pathophysiologic mechanism, which will in turn help us determine preventive techniques for vulnerable patients. Hopefully, increased SUDEP awareness will help physicians be more knowledgeable and comfortable in leading the discussion of SUDEP. Further research is still needed to uncover the role of genetics using animal and human models.

Sources

Annegers JF, Coan SP, Hauser WA, Leestma J. Epilepsy, vagal nerve stimulation by the NCP system, all-cause mortality and sudden, unexpected, unexplained death. Epilepsia. 2000;41(5):549-553.

Dlouhy BJ, Gehlbach BK, Richerson GB. Sudden unexpected death in epilepsy: basic mechanisms and clinical implications for prevention. J Neurol Neurosurg Psychiatry. 2016;87(4):402-413. 

Morse AM, Kothare SV. Pediatric sudden unexpected death in epilepsy. Pediatr Neurol. 2016;57:7-16.

Novak JL, Miller PR, Markovic D, Meymandi SK, DeGiorgio CM. Risk assessment for sudden death in epilepsy: the SUDEP-7 inventory. Front Neurol. 2015;6:252.

Pansani AP, Colugnati DB, Scorza CA, de Almeida AC, Cavalheiro EA, Scorza FA. Furthering our understanding of SUDEP: the role of animal models. Expert Rev Neurother. 2016;16(5):561-572.

RamachandranNair R, Jack SM, Strohm S. SUDEP: to discuss or not? recommendations from bereaved relatives. Epilepsy Behav. 2016;56:20-25.      

Pooja Patel, MD

Selim Benbadis, MD

Dr. Patel is a fourth year neurology resident at the University of South Florida and will begin an epilepsy fellowship at the University of South Florida in July. 

Dr. Benbadis is Professor and Director of the Comprehensive Epilepsy Program at the University of South Florida and Tampa General Hospital in Tampa, Florida.

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with intractable epilepsy. SUDEP accounts for 7.5% to 17% of all deaths related to epilepsy and has an annual incidence of 3 to 9 per 1000 in the general epilepsy population. Even with such a high prevalence, epilepsy patients, their families, and even many physicians are unaware of the mortality and risk of SUDEP. SUDEP has recently received significant attention in the scientific literature due to its high prevalence and lack of well-defined mechanisms. Understanding the modifiable risk factors and pathophysiology of SUDEP is critically important to help delineate preventive strategies.

Several mechanisms have been proposed to play a role in the pathophysiology of SUDEP. Recent literature have included new insights derived from combined data from older and newer studies where clues were obtained from witnessed SUDEP cases, Epilepsy Monitoring Unit observation of SUDEP cases, physiological data obtained from nonfatal seizures, and animal models. Based on many cohort studies, the initial mechanism is thought to be due to hypoventilation or apnea resulting from the seizure itself. The prone position is thought to contribute to prolonged oxygen desaturation by causing loss of arousal and inability to sense increased carbon dioxide levels. This in turn can cause secondary cardiac arrhythmias that are fatal. The other proposed mechanism is primary cardiac arrhythmia resulting from autonomic dysfunction before, during, or after a seizure. Additionally, serotonergic neurons might contribute as well by causing combination of hypoventilation and seizure. Experts also have suggested that genetic mutations cause primary dysfunction leading to fatal seizures; however, this requires further research.

Based on recent findings about the pathophysiology of SUDEP, several preventive measures have been suggested. The critical preventive measure is still believed to be good control of seizures, as uncontrolled generalized tonic-clonic seizures continue to be the biggest risk factor of SUDEP. Good control of seizures can be difficult in chronic refractory epilepsy and early referral should be made to an epilepsy center. Several studies evaluating patients after epilepsy surgery have discovered that surgery reduces patients’ likelihood of SUDEP. A study done in 2000 evaluated vagus nerve stimulation (VNS) implantation and SUDEP risk, and concluded that during the first 2 years the risk of SUDEP was higher than isolated use of some of the antiepileptics. However, after a 2-year follow-up, the risk of SUDEP was remarkably lower. The initial higher rate was likely due to the fact that VNS was implanted in refractory patients who had failed antiepileptics and were candidates for surgery. Experts believe that VNS is likely protective toward SUDEP as it reduces the amount of generalized tonic-clonic seizures.

Sleep is considered to be high risk for SUDEP because of the higher number of seizures occurring in sleep and hormonal and autonomic changes occurring at nighttime, which increase SUDEP risk. Use of a bed where the head can be adjusted to be higher than the feet, a supine sleep position, a special pillow to prevent suffocation, and even supervision at night has been recommended to reduce the risk of SUDEP. Supervision at night, which includes a supervising person sharing the same bedroom, special precautions such as regular checks throughout the night, or use of a monitoring device, was associated with a decreased risk of SUDEP in a recent study. Medications such as alpha-blockers and beta-blockers might be considered as they can reduce sympathetic discharge and prevent cardiac arrhythmias. Selective serotonin reuptake inhibitors can also reduce ictal hypoxemia and can help prevent a potential mechanism leading to SUDEP.

SUDEP is a significant burden in the field of epilepsy because of its mortality, but it is a subject that is not known well among patients, family, and providers. A recent Australian study reported that only a minority of adult patients with epilepsy had heard about SUDEP from their neurologists. Due to limited experience and knowledge of SUDEP, some neurologists may be unable to provide the appropriate education to patients and their families. The first qualitative study to explore opinions of bereaved relatives on whether to discuss SUDEP with patients was recently performed in the United States. The study showed that 91% of parents of epilepsy patients and 89.5% of adults with epilepsy would have preferred to have information about SUDEP. These respondents would have liked their neurologists in particular to discuss SUDEP so that they could have focused on preventive techniques. Study results suggest a lack of knowledge and the need for more awareness of SUDEP among the epilepsy population. It should be the neurologists’ responsibility to discuss and inform patients and their families about SUDEP at an appropriate time based on their diagnosis.

Resources such as the SUDEP-7 inventory can be used to help physicians identify patients with refractory epilepsy at risk for SUDEP. In 2011, the first SUDEP-7 inventory was found to be associated to two biomarkers: vagus-mediated heart rate variability and post-ictal generalized electroencephalogram suppression. In 2015, this inventory was modified to the revised SUDEP-7 inventory, which re-evaluated the association with heart rate. Results indicated that older age, longer duration of epilepsy, and presence of developmental disability had direct influence on vagus-mediated heart rate variability and thus increased SUDEP risk. The higher the SUDEP-7 inventory score, the higher the risk of SUDEP. SUDEP-7 inventory and other similar inventories can be a valuable tool for risk stratification and in turn can be used when deciding whether or not to have discussion of SUDEP with patients and families.

In conclusion, SUDEP continues to be a growing concern of mortality in the epilepsy population. Recent research has shed light on its pathophysiologic mechanism, which will in turn help us determine preventive techniques for vulnerable patients. Hopefully, increased SUDEP awareness will help physicians be more knowledgeable and comfortable in leading the discussion of SUDEP. Further research is still needed to uncover the role of genetics using animal and human models.

Sources

Annegers JF, Coan SP, Hauser WA, Leestma J. Epilepsy, vagal nerve stimulation by the NCP system, all-cause mortality and sudden, unexpected, unexplained death. Epilepsia. 2000;41(5):549-553.

Dlouhy BJ, Gehlbach BK, Richerson GB. Sudden unexpected death in epilepsy: basic mechanisms and clinical implications for prevention. J Neurol Neurosurg Psychiatry. 2016;87(4):402-413. 

Morse AM, Kothare SV. Pediatric sudden unexpected death in epilepsy. Pediatr Neurol. 2016;57:7-16.

Novak JL, Miller PR, Markovic D, Meymandi SK, DeGiorgio CM. Risk assessment for sudden death in epilepsy: the SUDEP-7 inventory. Front Neurol. 2015;6:252.

Pansani AP, Colugnati DB, Scorza CA, de Almeida AC, Cavalheiro EA, Scorza FA. Furthering our understanding of SUDEP: the role of animal models. Expert Rev Neurother. 2016;16(5):561-572.

RamachandranNair R, Jack SM, Strohm S. SUDEP: to discuss or not? recommendations from bereaved relatives. Epilepsy Behav. 2016;56:20-25.      

Trajectories of blood pressure in mid to late life are associated with incident stroke and mortality, according to research published online ahead of print May 9 in Hypertension.

Most associations between blood pressure—a major modifiable risk factor for stroke—and incident stroke have been based on blood pressure measurements taken at a single time point.

Although long-term trajectories of blood pressure can vary considerably in the elderly, studies have not looked at the long-term blood pressure trajectories in mid to late life or at whether such trajectories relate to stroke, said M. Arfan Ikram, MD, PhD, senior study author and Associate Professor of Neuroepidemiology at Erasmus University Medical Center in Rotterdam, the Netherlands.

M. Arfan Ikram, MD, PhD

To identify long-term trajectories of blood pressure in a population-based study and examine the risk of stroke within those trajectories, Dr. Ikram and colleagues evaluated the course of systolic blood pressure in 6,745 participants within the Rotterdam Study.

Participants resided in Ommoord, a suburb of Rotterdam, and received baseline examinations starting in 1990. The investigators used data from five follow-up visits, which occurred every three to four years from 1990 to 2011. During each follow-up visit, blood pressure was measured twice in the right arm, in sitting position, after a resting period of five minutes. Researchers used the average of the two measurements. The investigators focused on systolic blood pressure because it is the best predictor of cardiovascular events.

Participants’ ages ranged from 55 to 106, and 60% were women. Participants had a mean follow-up of 13.5 years.

Four Trajectories

The investigators jointly modeled participants’ risk of stroke and competing causes of death using joint latent class mixed modeling. When assessing blood pressure trajectories, the researchers found that the joint latent class model with four trajectory classes had the best fit.

Class 1, the largest class, included 4,938 participants. It was characterized by a gradually increasing blood pressure, starting at an average of 120 mm Hg at age 55 and increasing to an average of 160 mm Hg at age 95. Class 2, with 822 participants, was characterized by a similar blood pressure at age 55, but a much steeper increase in blood pressure, to an average of 200 mm Hg. The two other classes were characterized by a relatively higher baseline blood pressure. In class 3 (870 participants), the average baseline blood pressure of 140 mm Hg had modest variation over time. In class 4 (115 patients), the average baseline blood pressure of 160 mm Hg decreased after age 65.

People in class 4 were more frequently men. Use of blood pressure-lowering medication was similar between classes at baseline. At the end of follow-up, classes 3 and 4 had higher proportions of blood pressure-lowering medication users. Frequency of current smokers varied between classes, with particularly higher frequencies in classes 2 and 4.

Groups’ Risk Varied

During the study period, 1,053 participants had a stroke. Researchers also studied the number of deaths that occurred from nonstroke health events. They adjusted for sex and baseline blood-pressure lowering medication.

Classes 2, 3, and 4 had a significantly and substantially higher risk of stroke, compared with class 1 (ie, 4.7% to 13.6% vs 0.7%). Classes 2 and 4 had the highest risk of dying of other causes. The risk of dying of other causes in class 3 was similar to that of class 1. The risk of stroke in class 3, however, continued to increase until older age and was highest overall.

In all, 2,546 people (51.5%) in class 1, 575 (70.0%) people in class 2, 288 (33.1%) people in class 3, and 87 (75.7%) people in class 4 died due to a nonstroke-related cause. Between 25% and 38% of nonstroke deaths were due to cardiovascular events.

In multivariable-adjusted models that controlled for cholesterol, lipid-lowering medication, BMI, smoking, alcohol use, diabetes mellitus type 2, and antithrombotic medication, the results were relatively similar, the researchers said. The risk of stroke in classes 2 and 4 was attenuated by data adjustment, whereas the risk increased in class 3.

“Assessing trajectories of blood pressure provides a more nuanced understanding of the associations between blood pressure, stroke, and mortality,” the authors said.

The researchers noted that people in class 2 with steep increases in blood pressure might not receive effective treatment in time under current guidelines, and future studies could determine whether this class can be a target for prevention.

Effect of Slope

Prior studies that examined blood pressure trajectories in young to middle-aged people identified several parallel trajectories and found that long-term higher blood pressure related to more cardiovascular pathology.

“In our older population, we also observed that the class with a high mid-life blood pressure had the highest risk of stroke and death, compared to the class with the lowest blood pressure,” Dr. Ikram and colleagues said. “However, a novel finding of our study is that the slope of increase was associated with an increasing risk of stroke and competing causes of death. Namely, we identified two classes characterized by equally low baseline blood pressure and increasing trajectories, but only the class characterized by steep increases had a high risk of stroke and death. Of note, the risks in that class were even similar to the class with a high mid-life blood pressure.”

The large study population, the use of repeated measures of blood pressure over a long follow-up, and thorough collection of stroke assessments were among the study’s strengths. The study was not large enough to examine stroke subtypes, the authors said. In addition, the study’s population was geographically limited and mostly white, although the findings likely apply to people from other communities, Dr. Ikram said.

“Blood pressure should be measured regularly because it can change markedly over the course of a couple years and put you at high risk for an adverse event,” said Dr. Ikram. “Since the risks of stroke and death differ across these trajectory paths, they are potentially important for preventive strategies.”

—Jake Remaly

Trajectories of blood pressure in mid to late life are associated with incident stroke and mortality, according to research published online ahead of print May 9 in Hypertension.

Most associations between blood pressure—a major modifiable risk factor for stroke—and incident stroke have been based on blood pressure measurements taken at a single time point.

Although long-term trajectories of blood pressure can vary considerably in the elderly, studies have not looked at the long-term blood pressure trajectories in mid to late life or at whether such trajectories relate to stroke, said M. Arfan Ikram, MD, PhD, senior study author and Associate Professor of Neuroepidemiology at Erasmus University Medical Center in Rotterdam, the Netherlands.

M. Arfan Ikram, MD, PhD

To identify long-term trajectories of blood pressure in a population-based study and examine the risk of stroke within those trajectories, Dr. Ikram and colleagues evaluated the course of systolic blood pressure in 6,745 participants within the Rotterdam Study.

Participants resided in Ommoord, a suburb of Rotterdam, and received baseline examinations starting in 1990. The investigators used data from five follow-up visits, which occurred every three to four years from 1990 to 2011. During each follow-up visit, blood pressure was measured twice in the right arm, in sitting position, after a resting period of five minutes. Researchers used the average of the two measurements. The investigators focused on systolic blood pressure because it is the best predictor of cardiovascular events.

Participants’ ages ranged from 55 to 106, and 60% were women. Participants had a mean follow-up of 13.5 years.

Four Trajectories

The investigators jointly modeled participants’ risk of stroke and competing causes of death using joint latent class mixed modeling. When assessing blood pressure trajectories, the researchers found that the joint latent class model with four trajectory classes had the best fit.

Class 1, the largest class, included 4,938 participants. It was characterized by a gradually increasing blood pressure, starting at an average of 120 mm Hg at age 55 and increasing to an average of 160 mm Hg at age 95. Class 2, with 822 participants, was characterized by a similar blood pressure at age 55, but a much steeper increase in blood pressure, to an average of 200 mm Hg. The two other classes were characterized by a relatively higher baseline blood pressure. In class 3 (870 participants), the average baseline blood pressure of 140 mm Hg had modest variation over time. In class 4 (115 patients), the average baseline blood pressure of 160 mm Hg decreased after age 65.

People in class 4 were more frequently men. Use of blood pressure-lowering medication was similar between classes at baseline. At the end of follow-up, classes 3 and 4 had higher proportions of blood pressure-lowering medication users. Frequency of current smokers varied between classes, with particularly higher frequencies in classes 2 and 4.

Groups’ Risk Varied

During the study period, 1,053 participants had a stroke. Researchers also studied the number of deaths that occurred from nonstroke health events. They adjusted for sex and baseline blood-pressure lowering medication.

Classes 2, 3, and 4 had a significantly and substantially higher risk of stroke, compared with class 1 (ie, 4.7% to 13.6% vs 0.7%). Classes 2 and 4 had the highest risk of dying of other causes. The risk of dying of other causes in class 3 was similar to that of class 1. The risk of stroke in class 3, however, continued to increase until older age and was highest overall.

In all, 2,546 people (51.5%) in class 1, 575 (70.0%) people in class 2, 288 (33.1%) people in class 3, and 87 (75.7%) people in class 4 died due to a nonstroke-related cause. Between 25% and 38% of nonstroke deaths were due to cardiovascular events.

In multivariable-adjusted models that controlled for cholesterol, lipid-lowering medication, BMI, smoking, alcohol use, diabetes mellitus type 2, and antithrombotic medication, the results were relatively similar, the researchers said. The risk of stroke in classes 2 and 4 was attenuated by data adjustment, whereas the risk increased in class 3.

“Assessing trajectories of blood pressure provides a more nuanced understanding of the associations between blood pressure, stroke, and mortality,” the authors said.

The researchers noted that people in class 2 with steep increases in blood pressure might not receive effective treatment in time under current guidelines, and future studies could determine whether this class can be a target for prevention.

Effect of Slope

Prior studies that examined blood pressure trajectories in young to middle-aged people identified several parallel trajectories and found that long-term higher blood pressure related to more cardiovascular pathology.

“In our older population, we also observed that the class with a high mid-life blood pressure had the highest risk of stroke and death, compared to the class with the lowest blood pressure,” Dr. Ikram and colleagues said. “However, a novel finding of our study is that the slope of increase was associated with an increasing risk of stroke and competing causes of death. Namely, we identified two classes characterized by equally low baseline blood pressure and increasing trajectories, but only the class characterized by steep increases had a high risk of stroke and death. Of note, the risks in that class were even similar to the class with a high mid-life blood pressure.”

The large study population, the use of repeated measures of blood pressure over a long follow-up, and thorough collection of stroke assessments were among the study’s strengths. The study was not large enough to examine stroke subtypes, the authors said. In addition, the study’s population was geographically limited and mostly white, although the findings likely apply to people from other communities, Dr. Ikram said.

“Blood pressure should be measured regularly because it can change markedly over the course of a couple years and put you at high risk for an adverse event,” said Dr. Ikram. “Since the risks of stroke and death differ across these trajectory paths, they are potentially important for preventive strategies.”

—Jake Remaly

Trajectories of blood pressure in mid to late life are associated with incident stroke and mortality, according to research published online ahead of print May 9 in Hypertension.

Most associations between blood pressure—a major modifiable risk factor for stroke—and incident stroke have been based on blood pressure measurements taken at a single time point.

Although long-term trajectories of blood pressure can vary considerably in the elderly, studies have not looked at the long-term blood pressure trajectories in mid to late life or at whether such trajectories relate to stroke, said M. Arfan Ikram, MD, PhD, senior study author and Associate Professor of Neuroepidemiology at Erasmus University Medical Center in Rotterdam, the Netherlands.

M. Arfan Ikram, MD, PhD

To identify long-term trajectories of blood pressure in a population-based study and examine the risk of stroke within those trajectories, Dr. Ikram and colleagues evaluated the course of systolic blood pressure in 6,745 participants within the Rotterdam Study.

Participants resided in Ommoord, a suburb of Rotterdam, and received baseline examinations starting in 1990. The investigators used data from five follow-up visits, which occurred every three to four years from 1990 to 2011. During each follow-up visit, blood pressure was measured twice in the right arm, in sitting position, after a resting period of five minutes. Researchers used the average of the two measurements. The investigators focused on systolic blood pressure because it is the best predictor of cardiovascular events.

Participants’ ages ranged from 55 to 106, and 60% were women. Participants had a mean follow-up of 13.5 years.

Four Trajectories

The investigators jointly modeled participants’ risk of stroke and competing causes of death using joint latent class mixed modeling. When assessing blood pressure trajectories, the researchers found that the joint latent class model with four trajectory classes had the best fit.

Class 1, the largest class, included 4,938 participants. It was characterized by a gradually increasing blood pressure, starting at an average of 120 mm Hg at age 55 and increasing to an average of 160 mm Hg at age 95. Class 2, with 822 participants, was characterized by a similar blood pressure at age 55, but a much steeper increase in blood pressure, to an average of 200 mm Hg. The two other classes were characterized by a relatively higher baseline blood pressure. In class 3 (870 participants), the average baseline blood pressure of 140 mm Hg had modest variation over time. In class 4 (115 patients), the average baseline blood pressure of 160 mm Hg decreased after age 65.

People in class 4 were more frequently men. Use of blood pressure-lowering medication was similar between classes at baseline. At the end of follow-up, classes 3 and 4 had higher proportions of blood pressure-lowering medication users. Frequency of current smokers varied between classes, with particularly higher frequencies in classes 2 and 4.

Groups’ Risk Varied

During the study period, 1,053 participants had a stroke. Researchers also studied the number of deaths that occurred from nonstroke health events. They adjusted for sex and baseline blood-pressure lowering medication.

Classes 2, 3, and 4 had a significantly and substantially higher risk of stroke, compared with class 1 (ie, 4.7% to 13.6% vs 0.7%). Classes 2 and 4 had the highest risk of dying of other causes. The risk of dying of other causes in class 3 was similar to that of class 1. The risk of stroke in class 3, however, continued to increase until older age and was highest overall.

In all, 2,546 people (51.5%) in class 1, 575 (70.0%) people in class 2, 288 (33.1%) people in class 3, and 87 (75.7%) people in class 4 died due to a nonstroke-related cause. Between 25% and 38% of nonstroke deaths were due to cardiovascular events.

In multivariable-adjusted models that controlled for cholesterol, lipid-lowering medication, BMI, smoking, alcohol use, diabetes mellitus type 2, and antithrombotic medication, the results were relatively similar, the researchers said. The risk of stroke in classes 2 and 4 was attenuated by data adjustment, whereas the risk increased in class 3.

“Assessing trajectories of blood pressure provides a more nuanced understanding of the associations between blood pressure, stroke, and mortality,” the authors said.

The researchers noted that people in class 2 with steep increases in blood pressure might not receive effective treatment in time under current guidelines, and future studies could determine whether this class can be a target for prevention.

Effect of Slope

Prior studies that examined blood pressure trajectories in young to middle-aged people identified several parallel trajectories and found that long-term higher blood pressure related to more cardiovascular pathology.

“In our older population, we also observed that the class with a high mid-life blood pressure had the highest risk of stroke and death, compared to the class with the lowest blood pressure,” Dr. Ikram and colleagues said. “However, a novel finding of our study is that the slope of increase was associated with an increasing risk of stroke and competing causes of death. Namely, we identified two classes characterized by equally low baseline blood pressure and increasing trajectories, but only the class characterized by steep increases had a high risk of stroke and death. Of note, the risks in that class were even similar to the class with a high mid-life blood pressure.”

The large study population, the use of repeated measures of blood pressure over a long follow-up, and thorough collection of stroke assessments were among the study’s strengths. The study was not large enough to examine stroke subtypes, the authors said. In addition, the study’s population was geographically limited and mostly white, although the findings likely apply to people from other communities, Dr. Ikram said.

“Blood pressure should be measured regularly because it can change markedly over the course of a couple years and put you at high risk for an adverse event,” said Dr. Ikram. “Since the risks of stroke and death differ across these trajectory paths, they are potentially important for preventive strategies.”

—Jake Remaly

VANCOUVER – The risk of dimethyl fumarate lymphopenia – and perhaps progressive multifocal leukoencephalopathy – is greatest in patients 60 years or older and those with baseline absolute lymphocyte counts below 2 x 109/L, according to a review of 206 patients with relapsing-remitting or progressive multiple sclerosis from the University of Rochester (N.Y.).

A total of 87 patients (42%), all of whom were on dimethyl fumarate (DMF; Tecfidera) for at least 3 months, developed lymphopenia with an absolute lymphocyte count (ALC) below 0.91 x 10⁹/L. That’s not a surprise; lymphopenia is a well-known side effect of the drug, and the rates in Rochester were similar to what was reported in clinical trials. The greatest concern with DMF lymphopenia is subsequent progressive multifocal leukoencephalopathy (PML); a handful of cases have been reported in lymphopenic patients, none in the University of Rochester review.

What was surprising was that in the 34 patients aged 60 years or older, 24 (71%) developed lymphopenia, versus 62 (36%) of the 172 under 60 years old (P = .0005). Meanwhile, of 93 patients with baseline ALCs below 2 x 10⁹/L, 49 (53%) became lymphopenic, versus 34 of 104 patients (33%) who started DMF with higher lymphocyte counts (P = .0006). A total of nine patients in the study did not have a baseline ALC available.

M. Alexander Otto/Frontline Medical News

“If I had a patient who was 70 years old with a low baseline lymphocyte count, [these findings] would weigh into my decisions about choosing” this medication. “Age and baseline ALC may guide future selection of patients for DMF therapy,” neurologist and investigator Dr. Jessica Robb said at the annual meeting of the American Academy of Neurology.

Also, because higher grade lymphopenia didn’t resolve in most cases until the drug was stopped, “if I had a patient who developed more severe grade 3 or 4 lymphopenia, I would probably have a lower threshold for” discontinuation. “I would probably think about changing medication more quickly rather than leaving them on [DMF] and hoping that their lymphopenia resolves,” Dr. Robb said.

The Rochester findings are in line with a 2015 report from Washington University, St. Louis, that also indicated a higher risk of moderate to severe lymphopenia in older patients and those with lower baseline ALCs, as well as recent natalizumab (Tysabri) users. Grade 2 or worse lymphopenia “is unlikely to resolve while on the drug,” the St. Louis investigators concluded (Mult Scler J Exp Transl Clin. 2015 Jan-Dec;1:2055217315596994).

Taken together, the two studies are important because there’s otherwise not much else in the medical literature identifying DMF lymphopenia risk factors. Lymphopenia and PML are also concerns with other multiple sclerosis (MS) agents.

“The increased prevalence of lymphopenia in older patients and in patients with a lower baseline ALC suggests a failure of lymphopoiesis triggered by DMF therapy. Indeed, lymphopoiesis declines with age due to thymic involution and decreased production of naive lymphocytes. ... Whether these consequences of normal aging could be amplified by DMF is an avenue for future study,” the St. Louis team said.

“The significance of increased risk for lymphopenia in patients recently exposed to natalizumab is not immediately obvious. ... Natalizumab is known to expand circulating leukocytes, including progenitor cells. If in turn, DMF causes lymphocyte apoptosis or arrest of differentiation, then patients sequentially exposed to natalizumab and DMF might have a larger number of circulating lymphocytes vulnerable to DMF effects than other patients,” they said.

Food and Drug Administration labeling for DMF recommends lymphocyte counts at baseline, 6 months, and every 6-12 months thereafter. However, European regulators recently recommended lymphocyte counts at baseline and every 3 months to catch problems early, as well as baseline MRIs as references for possible PML.

Standard, 240-mg twice-daily dosing was used at the University of Rochester, and the mean age in the study was 49 years. The majority of patients were women, and the mean duration of MS was 11 years. Almost three-quarters of the patients were new to immunosuppression, and none of the patients developed serious infections.

The University of Rochester team noted a higher rate of grade 1 lymphopenia than reported in clinical trials (18% vs. 10%). Twelve patients (6%) discontinued DMF because of lymphopenia.

Dr. Robb and the other investigators had no relevant disclosures.

[email protected]

VANCOUVER – The risk of dimethyl fumarate lymphopenia – and perhaps progressive multifocal leukoencephalopathy – is greatest in patients 60 years or older and those with baseline absolute lymphocyte counts below 2 x 109/L, according to a review of 206 patients with relapsing-remitting or progressive multiple sclerosis from the University of Rochester (N.Y.).

A total of 87 patients (42%), all of whom were on dimethyl fumarate (DMF; Tecfidera) for at least 3 months, developed lymphopenia with an absolute lymphocyte count (ALC) below 0.91 x 10⁹/L. That’s not a surprise; lymphopenia is a well-known side effect of the drug, and the rates in Rochester were similar to what was reported in clinical trials. The greatest concern with DMF lymphopenia is subsequent progressive multifocal leukoencephalopathy (PML); a handful of cases have been reported in lymphopenic patients, none in the University of Rochester review.

What was surprising was that in the 34 patients aged 60 years or older, 24 (71%) developed lymphopenia, versus 62 (36%) of the 172 under 60 years old (P = .0005). Meanwhile, of 93 patients with baseline ALCs below 2 x 10⁹/L, 49 (53%) became lymphopenic, versus 34 of 104 patients (33%) who started DMF with higher lymphocyte counts (P = .0006). A total of nine patients in the study did not have a baseline ALC available.

M. Alexander Otto/Frontline Medical News

“If I had a patient who was 70 years old with a low baseline lymphocyte count, [these findings] would weigh into my decisions about choosing” this medication. “Age and baseline ALC may guide future selection of patients for DMF therapy,” neurologist and investigator Dr. Jessica Robb said at the annual meeting of the American Academy of Neurology.

Also, because higher grade lymphopenia didn’t resolve in most cases until the drug was stopped, “if I had a patient who developed more severe grade 3 or 4 lymphopenia, I would probably have a lower threshold for” discontinuation. “I would probably think about changing medication more quickly rather than leaving them on [DMF] and hoping that their lymphopenia resolves,” Dr. Robb said.

The Rochester findings are in line with a 2015 report from Washington University, St. Louis, that also indicated a higher risk of moderate to severe lymphopenia in older patients and those with lower baseline ALCs, as well as recent natalizumab (Tysabri) users. Grade 2 or worse lymphopenia “is unlikely to resolve while on the drug,” the St. Louis investigators concluded (Mult Scler J Exp Transl Clin. 2015 Jan-Dec;1:2055217315596994).

Taken together, the two studies are important because there’s otherwise not much else in the medical literature identifying DMF lymphopenia risk factors. Lymphopenia and PML are also concerns with other multiple sclerosis (MS) agents.

“The increased prevalence of lymphopenia in older patients and in patients with a lower baseline ALC suggests a failure of lymphopoiesis triggered by DMF therapy. Indeed, lymphopoiesis declines with age due to thymic involution and decreased production of naive lymphocytes. ... Whether these consequences of normal aging could be amplified by DMF is an avenue for future study,” the St. Louis team said.

“The significance of increased risk for lymphopenia in patients recently exposed to natalizumab is not immediately obvious. ... Natalizumab is known to expand circulating leukocytes, including progenitor cells. If in turn, DMF causes lymphocyte apoptosis or arrest of differentiation, then patients sequentially exposed to natalizumab and DMF might have a larger number of circulating lymphocytes vulnerable to DMF effects than other patients,” they said.

Food and Drug Administration labeling for DMF recommends lymphocyte counts at baseline, 6 months, and every 6-12 months thereafter. However, European regulators recently recommended lymphocyte counts at baseline and every 3 months to catch problems early, as well as baseline MRIs as references for possible PML.

Standard, 240-mg twice-daily dosing was used at the University of Rochester, and the mean age in the study was 49 years. The majority of patients were women, and the mean duration of MS was 11 years. Almost three-quarters of the patients were new to immunosuppression, and none of the patients developed serious infections.

The University of Rochester team noted a higher rate of grade 1 lymphopenia than reported in clinical trials (18% vs. 10%). Twelve patients (6%) discontinued DMF because of lymphopenia.

Dr. Robb and the other investigators had no relevant disclosures.

[email protected]

VANCOUVER – The risk of dimethyl fumarate lymphopenia – and perhaps progressive multifocal leukoencephalopathy – is greatest in patients 60 years or older and those with baseline absolute lymphocyte counts below 2 x 109/L, according to a review of 206 patients with relapsing-remitting or progressive multiple sclerosis from the University of Rochester (N.Y.).

A total of 87 patients (42%), all of whom were on dimethyl fumarate (DMF; Tecfidera) for at least 3 months, developed lymphopenia with an absolute lymphocyte count (ALC) below 0.91 x 10⁹/L. That’s not a surprise; lymphopenia is a well-known side effect of the drug, and the rates in Rochester were similar to what was reported in clinical trials. The greatest concern with DMF lymphopenia is subsequent progressive multifocal leukoencephalopathy (PML); a handful of cases have been reported in lymphopenic patients, none in the University of Rochester review.

What was surprising was that in the 34 patients aged 60 years or older, 24 (71%) developed lymphopenia, versus 62 (36%) of the 172 under 60 years old (P = .0005). Meanwhile, of 93 patients with baseline ALCs below 2 x 10⁹/L, 49 (53%) became lymphopenic, versus 34 of 104 patients (33%) who started DMF with higher lymphocyte counts (P = .0006). A total of nine patients in the study did not have a baseline ALC available.

M. Alexander Otto/Frontline Medical News

“If I had a patient who was 70 years old with a low baseline lymphocyte count, [these findings] would weigh into my decisions about choosing” this medication. “Age and baseline ALC may guide future selection of patients for DMF therapy,” neurologist and investigator Dr. Jessica Robb said at the annual meeting of the American Academy of Neurology.

Also, because higher grade lymphopenia didn’t resolve in most cases until the drug was stopped, “if I had a patient who developed more severe grade 3 or 4 lymphopenia, I would probably have a lower threshold for” discontinuation. “I would probably think about changing medication more quickly rather than leaving them on [DMF] and hoping that their lymphopenia resolves,” Dr. Robb said.

The Rochester findings are in line with a 2015 report from Washington University, St. Louis, that also indicated a higher risk of moderate to severe lymphopenia in older patients and those with lower baseline ALCs, as well as recent natalizumab (Tysabri) users. Grade 2 or worse lymphopenia “is unlikely to resolve while on the drug,” the St. Louis investigators concluded (Mult Scler J Exp Transl Clin. 2015 Jan-Dec;1:2055217315596994).

Taken together, the two studies are important because there’s otherwise not much else in the medical literature identifying DMF lymphopenia risk factors. Lymphopenia and PML are also concerns with other multiple sclerosis (MS) agents.

“The increased prevalence of lymphopenia in older patients and in patients with a lower baseline ALC suggests a failure of lymphopoiesis triggered by DMF therapy. Indeed, lymphopoiesis declines with age due to thymic involution and decreased production of naive lymphocytes. ... Whether these consequences of normal aging could be amplified by DMF is an avenue for future study,” the St. Louis team said.

“The significance of increased risk for lymphopenia in patients recently exposed to natalizumab is not immediately obvious. ... Natalizumab is known to expand circulating leukocytes, including progenitor cells. If in turn, DMF causes lymphocyte apoptosis or arrest of differentiation, then patients sequentially exposed to natalizumab and DMF might have a larger number of circulating lymphocytes vulnerable to DMF effects than other patients,” they said.

Food and Drug Administration labeling for DMF recommends lymphocyte counts at baseline, 6 months, and every 6-12 months thereafter. However, European regulators recently recommended lymphocyte counts at baseline and every 3 months to catch problems early, as well as baseline MRIs as references for possible PML.

Standard, 240-mg twice-daily dosing was used at the University of Rochester, and the mean age in the study was 49 years. The majority of patients were women, and the mean duration of MS was 11 years. Almost three-quarters of the patients were new to immunosuppression, and none of the patients developed serious infections.

The University of Rochester team noted a higher rate of grade 1 lymphopenia than reported in clinical trials (18% vs. 10%). Twelve patients (6%) discontinued DMF because of lymphopenia.

Dr. Robb and the other investigators had no relevant disclosures.

[email protected]

1. Enroll in the Focused Practice in Hospital Medicine MOC program by August 1 at www.abim.org.
2. Schedule a seat for the exam before August 15 at www.abim.org.
3. Order SHM SPARK, the missing piece of the MOC exam-prep puzzle.

SHM recently developed the only MOC exam-preparation tool by hospitalists for hospitalists, SHM SPARK. It complements tools already on the market and will help hospitalists succeed on the upcoming exam. SHM SPARK delivers 175 vignette-style multiple-choice questions that bridge the primary knowledge gaps found within existing MOC exam-preparation products and provides in-depth review on:

• Palliative care, ethics, and decision making
• Patient safety
• Perioperative care and consultative co-management
• Quality, cost, and clinical reasoning

SHM SPARK offers detailed learning objectives and discussion points and allows users to define individual areas of strengths and weaknesses. Users can claim 58 ABIM MOC Medical Knowledge points upon completion of all four modules with a minimum passing score of 80%. After successful completion of all four modules, participants may claim up to 10.5 AMA PRA Category 1 credits.

1. Enroll in the Focused Practice in Hospital Medicine MOC program by August 1 at www.abim.org.
2. Schedule a seat for the exam before August 15 at www.abim.org.
3. Order SHM SPARK, the missing piece of the MOC exam-prep puzzle.

SHM recently developed the only MOC exam-preparation tool by hospitalists for hospitalists, SHM SPARK. It complements tools already on the market and will help hospitalists succeed on the upcoming exam. SHM SPARK delivers 175 vignette-style multiple-choice questions that bridge the primary knowledge gaps found within existing MOC exam-preparation products and provides in-depth review on:

• Palliative care, ethics, and decision making
• Patient safety
• Perioperative care and consultative co-management
• Quality, cost, and clinical reasoning

SHM SPARK offers detailed learning objectives and discussion points and allows users to define individual areas of strengths and weaknesses. Users can claim 58 ABIM MOC Medical Knowledge points upon completion of all four modules with a minimum passing score of 80%. After successful completion of all four modules, participants may claim up to 10.5 AMA PRA Category 1 credits.

1. Enroll in the Focused Practice in Hospital Medicine MOC program by August 1 at www.abim.org.
2. Schedule a seat for the exam before August 15 at www.abim.org.
3. Order SHM SPARK, the missing piece of the MOC exam-prep puzzle.

SHM recently developed the only MOC exam-preparation tool by hospitalists for hospitalists, SHM SPARK. It complements tools already on the market and will help hospitalists succeed on the upcoming exam. SHM SPARK delivers 175 vignette-style multiple-choice questions that bridge the primary knowledge gaps found within existing MOC exam-preparation products and provides in-depth review on:

• Palliative care, ethics, and decision making
• Patient safety
• Perioperative care and consultative co-management
• Quality, cost, and clinical reasoning

SHM SPARK offers detailed learning objectives and discussion points and allows users to define individual areas of strengths and weaknesses. Users can claim 58 ABIM MOC Medical Knowledge points upon completion of all four modules with a minimum passing score of 80%. After successful completion of all four modules, participants may claim up to 10.5 AMA PRA Category 1 credits.

In 2014, the Society of Hospital Medicine endorsed the Interstate Medical Licensure Compact as a way to address divergent physician licensing requirements among states. The thrust of SHM’s reasoning was that differing licensing policies across state lines not only hinder the ability of hospitalists to quickly adjust staffing to meet the needs of hospitals and patients but also create extensive, costly, and often redundant administrative hurdles for individual hospitalists and hospital medicine groups. For hospitalists looking to relocate to another state, practice in multiple states, provide telemedicine services, or even take on some per diem work, the Interstate Medical Licensure Compact should be of great help.

To briefly summarize, states participating in the compact agree to share information with one another and work together in streamlining the licensing process. For example, the compact aims to reduce redundant licensing requirements by creating one place where physicians submit basic information such as their education credentials. The compact does not establish a national license; a license to practice medicine will still be issued by individual state medical boards. Physicians will still need to be licensed in the state where the patient is located, but the difference is that the process of obtaining a license will be streamlined significantly.

To join the Interstate Medical Licensure Compact, state legislatures must enact the compact into state law. Two years in, the compact is now being implemented in 12 states: Alabama, Idaho, Illinois, Iowa, Minnesota, Montana, Nevada, South Dakota, Utah, West Virginia, Wisconsin, and Wyoming. States where it has been introduced but not yet adopted include Alaska, Arizona, Colorado, Kansas, Maryland, Michigan, Mississippi, Nebraska, New Hampshire, Oklahoma, Pennsylvania, Rhode Island, Vermont, and Washington.

Licenses via the compact process are not currently being issued, but representatives from the 12 participating states have begun to formally meet and are working out the administrative procedures needed to begin expedited licensure processes. With a core group of states adopting and implementing the compact, it will be important for state officials to hear why adoption of the compact is important to physicians.

This presents an opportunity for hospitalists residing in holdout states to participate in some advocacy work at the state level—on their own, as a group, or even within one of SHM’s many state chapters. To find your local chapter and get involved, visit www.hospitalmedicine.org/chapters.

To assist, detailed information on the Interstate Medical Licensure Compact can be found at www.licenseportability.org, and SHM advocacy staff is available to address questions members may have about getting started. You can reach them via email at [email protected]. TH

Josh Boswell is SHM’s director of government affairs.

In 2014, the Society of Hospital Medicine endorsed the Interstate Medical Licensure Compact as a way to address divergent physician licensing requirements among states. The thrust of SHM’s reasoning was that differing licensing policies across state lines not only hinder the ability of hospitalists to quickly adjust staffing to meet the needs of hospitals and patients but also create extensive, costly, and often redundant administrative hurdles for individual hospitalists and hospital medicine groups. For hospitalists looking to relocate to another state, practice in multiple states, provide telemedicine services, or even take on some per diem work, the Interstate Medical Licensure Compact should be of great help.

To briefly summarize, states participating in the compact agree to share information with one another and work together in streamlining the licensing process. For example, the compact aims to reduce redundant licensing requirements by creating one place where physicians submit basic information such as their education credentials. The compact does not establish a national license; a license to practice medicine will still be issued by individual state medical boards. Physicians will still need to be licensed in the state where the patient is located, but the difference is that the process of obtaining a license will be streamlined significantly.

To join the Interstate Medical Licensure Compact, state legislatures must enact the compact into state law. Two years in, the compact is now being implemented in 12 states: Alabama, Idaho, Illinois, Iowa, Minnesota, Montana, Nevada, South Dakota, Utah, West Virginia, Wisconsin, and Wyoming. States where it has been introduced but not yet adopted include Alaska, Arizona, Colorado, Kansas, Maryland, Michigan, Mississippi, Nebraska, New Hampshire, Oklahoma, Pennsylvania, Rhode Island, Vermont, and Washington.

Licenses via the compact process are not currently being issued, but representatives from the 12 participating states have begun to formally meet and are working out the administrative procedures needed to begin expedited licensure processes. With a core group of states adopting and implementing the compact, it will be important for state officials to hear why adoption of the compact is important to physicians.

This presents an opportunity for hospitalists residing in holdout states to participate in some advocacy work at the state level—on their own, as a group, or even within one of SHM’s many state chapters. To find your local chapter and get involved, visit www.hospitalmedicine.org/chapters.

To assist, detailed information on the Interstate Medical Licensure Compact can be found at www.licenseportability.org, and SHM advocacy staff is available to address questions members may have about getting started. You can reach them via email at [email protected]. TH

Josh Boswell is SHM’s director of government affairs.

In 2014, the Society of Hospital Medicine endorsed the Interstate Medical Licensure Compact as a way to address divergent physician licensing requirements among states. The thrust of SHM’s reasoning was that differing licensing policies across state lines not only hinder the ability of hospitalists to quickly adjust staffing to meet the needs of hospitals and patients but also create extensive, costly, and often redundant administrative hurdles for individual hospitalists and hospital medicine groups. For hospitalists looking to relocate to another state, practice in multiple states, provide telemedicine services, or even take on some per diem work, the Interstate Medical Licensure Compact should be of great help.

To briefly summarize, states participating in the compact agree to share information with one another and work together in streamlining the licensing process. For example, the compact aims to reduce redundant licensing requirements by creating one place where physicians submit basic information such as their education credentials. The compact does not establish a national license; a license to practice medicine will still be issued by individual state medical boards. Physicians will still need to be licensed in the state where the patient is located, but the difference is that the process of obtaining a license will be streamlined significantly.

To join the Interstate Medical Licensure Compact, state legislatures must enact the compact into state law. Two years in, the compact is now being implemented in 12 states: Alabama, Idaho, Illinois, Iowa, Minnesota, Montana, Nevada, South Dakota, Utah, West Virginia, Wisconsin, and Wyoming. States where it has been introduced but not yet adopted include Alaska, Arizona, Colorado, Kansas, Maryland, Michigan, Mississippi, Nebraska, New Hampshire, Oklahoma, Pennsylvania, Rhode Island, Vermont, and Washington.

Licenses via the compact process are not currently being issued, but representatives from the 12 participating states have begun to formally meet and are working out the administrative procedures needed to begin expedited licensure processes. With a core group of states adopting and implementing the compact, it will be important for state officials to hear why adoption of the compact is important to physicians.

This presents an opportunity for hospitalists residing in holdout states to participate in some advocacy work at the state level—on their own, as a group, or even within one of SHM’s many state chapters. To find your local chapter and get involved, visit www.hospitalmedicine.org/chapters.

To assist, detailed information on the Interstate Medical Licensure Compact can be found at www.licenseportability.org, and SHM advocacy staff is available to address questions members may have about getting started. You can reach them via email at [email protected]. TH

Josh Boswell is SHM’s director of government affairs.

CMV infection

The US Food and Drug Administration (FDA) has approved the first cytomegalovirus (CMV) test for use in hematopoietic stem cell transplant (HSCT) recipients.

With this approval, the COBAS® AmpliPrep/COBAS® TaqMan® CMV Test is available for monitoring CMV treatment in all types of transplant patients in the US.

The test, which was developed by Roche, is an in vitro nucleic acid amplification test that quantitates CMV DNA in human plasma.

It is intended to aid the management of HSCT recipients and solid-organ transplant recipients who are undergoing anti-CMV therapy.

In this population, serial DNA measurements can be used to assess virological response to antiviral treatment. The results from the test must be interpreted within the context of all relevant clinical and laboratory findings.

The COBAS® AmpliPrep/COBAS® TaqMan® CMV Test is not intended for use as a screening test for the presence of CMV DNA in blood or blood products.

The test is designed for use on the automated COBAS® AmpliPrep/COBAS® TaqMan® System, an established platform for viral load monitoring of multiple infectious diseases.

The system combines the COBAS® AmpliPrep Instrument for automated sample preparation and the COBAS® TaqMan® Analyzer or the smaller COBAS® TaqMan® 48 Analyzer for automated real-time PCR amplification and detection.

The COBAS® AmpliPrep/COBAS® TaqMan® System has parallel processing with other molecular diagnostics assays targeting other diseases. Roche’s AmpErase enzyme is also included in each test and is designed to prevent cross-contamination of samples and labs.

CMV infection

The US Food and Drug Administration (FDA) has approved the first cytomegalovirus (CMV) test for use in hematopoietic stem cell transplant (HSCT) recipients.

With this approval, the COBAS® AmpliPrep/COBAS® TaqMan® CMV Test is available for monitoring CMV treatment in all types of transplant patients in the US.

The test, which was developed by Roche, is an in vitro nucleic acid amplification test that quantitates CMV DNA in human plasma.

It is intended to aid the management of HSCT recipients and solid-organ transplant recipients who are undergoing anti-CMV therapy.

In this population, serial DNA measurements can be used to assess virological response to antiviral treatment. The results from the test must be interpreted within the context of all relevant clinical and laboratory findings.

The COBAS® AmpliPrep/COBAS® TaqMan® CMV Test is not intended for use as a screening test for the presence of CMV DNA in blood or blood products.

The test is designed for use on the automated COBAS® AmpliPrep/COBAS® TaqMan® System, an established platform for viral load monitoring of multiple infectious diseases.

The system combines the COBAS® AmpliPrep Instrument for automated sample preparation and the COBAS® TaqMan® Analyzer or the smaller COBAS® TaqMan® 48 Analyzer for automated real-time PCR amplification and detection.

The COBAS® AmpliPrep/COBAS® TaqMan® System has parallel processing with other molecular diagnostics assays targeting other diseases. Roche’s AmpErase enzyme is also included in each test and is designed to prevent cross-contamination of samples and labs.

CMV infection

The US Food and Drug Administration (FDA) has approved the first cytomegalovirus (CMV) test for use in hematopoietic stem cell transplant (HSCT) recipients.

With this approval, the COBAS® AmpliPrep/COBAS® TaqMan® CMV Test is available for monitoring CMV treatment in all types of transplant patients in the US.

The test, which was developed by Roche, is an in vitro nucleic acid amplification test that quantitates CMV DNA in human plasma.

It is intended to aid the management of HSCT recipients and solid-organ transplant recipients who are undergoing anti-CMV therapy.

In this population, serial DNA measurements can be used to assess virological response to antiviral treatment. The results from the test must be interpreted within the context of all relevant clinical and laboratory findings.

The COBAS® AmpliPrep/COBAS® TaqMan® CMV Test is not intended for use as a screening test for the presence of CMV DNA in blood or blood products.

The test is designed for use on the automated COBAS® AmpliPrep/COBAS® TaqMan® System, an established platform for viral load monitoring of multiple infectious diseases.

The system combines the COBAS® AmpliPrep Instrument for automated sample preparation and the COBAS® TaqMan® Analyzer or the smaller COBAS® TaqMan® 48 Analyzer for automated real-time PCR amplification and detection.

The COBAS® AmpliPrep/COBAS® TaqMan® System has parallel processing with other molecular diagnostics assays targeting other diseases. Roche’s AmpErase enzyme is also included in each test and is designed to prevent cross-contamination of samples and labs.

Doctor and patient

Photo courtesy of NIH

Worrying about wasting their doctor’s time is stopping people from reporting symptoms that might be related to cancer, according to a small study published in the British Journal of General Practice.

The goal of the study was to determine why some people are more likely than others to worry about wasting a general practitioner’s (GP’s) time and delay reporting possible cancer symptoms.

“People worrying about wasting their doctor’s time is one of the challenges we need to tackle when thinking about trying to diagnose cancer earlier,” said study author Katriina Whitaker, PhD, of the University of Surrey in the UK.

“We need to get to the root of the problem and find out why people are feeling worried. Not a lot of work has been done on this so far. Our study draws attention to some reasons patients put off going to their GP to check out possible cancer symptoms.”

For this study, Dr Whitaker and her colleagues conducted interviews with subjects in London, South East England, and North West England.

The subjects were recruited from a sample of 2042 adults, age 50 and older, who completed a survey that included a list of “cancer alarm symptoms.”

Ultimately, the researchers interviewed 62 subjects who had reported symptoms at baseline, were still present at the 3-month follow-up, and had agreed to be contacted.

The interviews revealed a few reasons why subjects were hesitant to report symptoms to their GP.

Some subjects felt that long waiting times for appointments indicated GPs were very busy, so they shouldn’t bother making an appointment unless symptoms seemed very serious.

Other subjects felt that seeking help when their symptoms did not seem serious—ie, persistent, worsening, or life-threatening—was a waste of a doctor’s time.

Still other subjects were hesitant to seek help because their doctors had been dismissive about symptoms in the past.

On the other hand, subjects who reported positive interactions with GPs or good relationships with them were less worried about time-wasting.

And other subjects weren’t worried about wasting their doctor’s time because they think of GPs as fulfilling a service financed by taxpayers.

“We’ve all had times where we’ve wondered if we should go to see a GP, but getting unusual or persistent changes checked out is really important,” said Julie Sharp, head of health and patient information at Cancer Research UK, which funded this study.

“Worrying about wasting a GP’s time should not put people off. Doctors are there to help spot cancer symptoms early when treatment is more likely to be successful, and delaying a visit could save up bigger problems for later. So if you’ve noticed anything that isn’t normal for you, make an appointment to see your doctor.”

Doctor and patient

Photo courtesy of NIH

Worrying about wasting their doctor’s time is stopping people from reporting symptoms that might be related to cancer, according to a small study published in the British Journal of General Practice.

The goal of the study was to determine why some people are more likely than others to worry about wasting a general practitioner’s (GP’s) time and delay reporting possible cancer symptoms.

“People worrying about wasting their doctor’s time is one of the challenges we need to tackle when thinking about trying to diagnose cancer earlier,” said study author Katriina Whitaker, PhD, of the University of Surrey in the UK.

“We need to get to the root of the problem and find out why people are feeling worried. Not a lot of work has been done on this so far. Our study draws attention to some reasons patients put off going to their GP to check out possible cancer symptoms.”

For this study, Dr Whitaker and her colleagues conducted interviews with subjects in London, South East England, and North West England.

The subjects were recruited from a sample of 2042 adults, age 50 and older, who completed a survey that included a list of “cancer alarm symptoms.”

Ultimately, the researchers interviewed 62 subjects who had reported symptoms at baseline, were still present at the 3-month follow-up, and had agreed to be contacted.

The interviews revealed a few reasons why subjects were hesitant to report symptoms to their GP.

Some subjects felt that long waiting times for appointments indicated GPs were very busy, so they shouldn’t bother making an appointment unless symptoms seemed very serious.

Other subjects felt that seeking help when their symptoms did not seem serious—ie, persistent, worsening, or life-threatening—was a waste of a doctor’s time.

Still other subjects were hesitant to seek help because their doctors had been dismissive about symptoms in the past.

On the other hand, subjects who reported positive interactions with GPs or good relationships with them were less worried about time-wasting.

And other subjects weren’t worried about wasting their doctor’s time because they think of GPs as fulfilling a service financed by taxpayers.

“We’ve all had times where we’ve wondered if we should go to see a GP, but getting unusual or persistent changes checked out is really important,” said Julie Sharp, head of health and patient information at Cancer Research UK, which funded this study.

“Worrying about wasting a GP’s time should not put people off. Doctors are there to help spot cancer symptoms early when treatment is more likely to be successful, and delaying a visit could save up bigger problems for later. So if you’ve noticed anything that isn’t normal for you, make an appointment to see your doctor.”

Doctor and patient

Photo courtesy of NIH

Worrying about wasting their doctor’s time is stopping people from reporting symptoms that might be related to cancer, according to a small study published in the British Journal of General Practice.

The goal of the study was to determine why some people are more likely than others to worry about wasting a general practitioner’s (GP’s) time and delay reporting possible cancer symptoms.

“People worrying about wasting their doctor’s time is one of the challenges we need to tackle when thinking about trying to diagnose cancer earlier,” said study author Katriina Whitaker, PhD, of the University of Surrey in the UK.

“We need to get to the root of the problem and find out why people are feeling worried. Not a lot of work has been done on this so far. Our study draws attention to some reasons patients put off going to their GP to check out possible cancer symptoms.”

For this study, Dr Whitaker and her colleagues conducted interviews with subjects in London, South East England, and North West England.

The subjects were recruited from a sample of 2042 adults, age 50 and older, who completed a survey that included a list of “cancer alarm symptoms.”

Ultimately, the researchers interviewed 62 subjects who had reported symptoms at baseline, were still present at the 3-month follow-up, and had agreed to be contacted.

The interviews revealed a few reasons why subjects were hesitant to report symptoms to their GP.

Some subjects felt that long waiting times for appointments indicated GPs were very busy, so they shouldn’t bother making an appointment unless symptoms seemed very serious.

Other subjects felt that seeking help when their symptoms did not seem serious—ie, persistent, worsening, or life-threatening—was a waste of a doctor’s time.

Still other subjects were hesitant to seek help because their doctors had been dismissive about symptoms in the past.

On the other hand, subjects who reported positive interactions with GPs or good relationships with them were less worried about time-wasting.

And other subjects weren’t worried about wasting their doctor’s time because they think of GPs as fulfilling a service financed by taxpayers.

“We’ve all had times where we’ve wondered if we should go to see a GP, but getting unusual or persistent changes checked out is really important,” said Julie Sharp, head of health and patient information at Cancer Research UK, which funded this study.

“Worrying about wasting a GP’s time should not put people off. Doctors are there to help spot cancer symptoms early when treatment is more likely to be successful, and delaying a visit could save up bigger problems for later. So if you’ve noticed anything that isn’t normal for you, make an appointment to see your doctor.”

Red blood cells

Recent studies have suggested that roughly half of patients hospitalized with traumatic brain injuries (TBIs) are anemic, but it hasn’t been clear how the anemia affects patients’ recovery.

Now, researchers have found evidence suggesting that low hemoglobin levels can negatively influence the outcomes of patients with TBIs.

The team detailed this evidence in a paper published in World Neurosurgery.

“More research is needed to develop treatment protocols for anemic patients with traumatic brain injuries,” said study author N. Scott Litofsky, MD, of the University of Missouri School of Medicine in Columbia.

“There has been a lack of consensus among physicians regarding the relationship of anemia and traumatic brain injuries on a patient’s health. Because of this uncertainty, treatment protocols are unclear and inconsistent. Our observational study found that a patient’s outcome is worse when he or she is anemic.”

The researchers studied 939 TBI patients with anemia who were admitted to a Level I trauma center.

The team assessed the relationships between patients’ initial hemoglobin level and lowest hemoglobin level during hospitalization at threshold values of ≤7, ≤8, ≤9, and ≤10 g/dL relative to their Glasgow Outcome Score within a year of surgery.

The data suggested that both initial hemoglobin levels and lowest hemoglobin levels were independent predictors of poor outcome (P<0.0001).

For each increase in initial hemoglobin level of 1 g/dL, the odds of a patient achieving a good outcome increased by 32%. For each increase in lowest hemoglobin level of 1 g/dL, the probability of a good outcome increased by 35.6%.

Female patients had worse outcomes than male patients if their initial hemoglobin levels were between 7 g/dL and 8 g/dL (P<0.05).

And receiving a blood transfusion was associated with poorer outcomes at hemoglobin levels ≤9 g/dL and ≤10 g/dL (P<0.05) but not at the lower hemoglobin thresholds.

The researchers said these data suggest clinicians may want to consider giving blood transfusions in TBI patients with hemoglobin levels of 8 g/dL or lower.

However, Dr Litofsky noted that the purpose of this study was not to propose transfusion guidelines. It was to determine the effects of anemia on TBI outcomes.

“Now that we have shown that anemia affects a patient’s recovery, further studies are needed to determine the best way to correct it,” he said. “The ultimate goal of this research is to help patients recover more quickly from traumatic brain injuries.”

Red blood cells

Recent studies have suggested that roughly half of patients hospitalized with traumatic brain injuries (TBIs) are anemic, but it hasn’t been clear how the anemia affects patients’ recovery.

Now, researchers have found evidence suggesting that low hemoglobin levels can negatively influence the outcomes of patients with TBIs.

The team detailed this evidence in a paper published in World Neurosurgery.

“More research is needed to develop treatment protocols for anemic patients with traumatic brain injuries,” said study author N. Scott Litofsky, MD, of the University of Missouri School of Medicine in Columbia.

“There has been a lack of consensus among physicians regarding the relationship of anemia and traumatic brain injuries on a patient’s health. Because of this uncertainty, treatment protocols are unclear and inconsistent. Our observational study found that a patient’s outcome is worse when he or she is anemic.”

The researchers studied 939 TBI patients with anemia who were admitted to a Level I trauma center.

The team assessed the relationships between patients’ initial hemoglobin level and lowest hemoglobin level during hospitalization at threshold values of ≤7, ≤8, ≤9, and ≤10 g/dL relative to their Glasgow Outcome Score within a year of surgery.

The data suggested that both initial hemoglobin levels and lowest hemoglobin levels were independent predictors of poor outcome (P<0.0001).

For each increase in initial hemoglobin level of 1 g/dL, the odds of a patient achieving a good outcome increased by 32%. For each increase in lowest hemoglobin level of 1 g/dL, the probability of a good outcome increased by 35.6%.

Female patients had worse outcomes than male patients if their initial hemoglobin levels were between 7 g/dL and 8 g/dL (P<0.05).

And receiving a blood transfusion was associated with poorer outcomes at hemoglobin levels ≤9 g/dL and ≤10 g/dL (P<0.05) but not at the lower hemoglobin thresholds.

The researchers said these data suggest clinicians may want to consider giving blood transfusions in TBI patients with hemoglobin levels of 8 g/dL or lower.

However, Dr Litofsky noted that the purpose of this study was not to propose transfusion guidelines. It was to determine the effects of anemia on TBI outcomes.

“Now that we have shown that anemia affects a patient’s recovery, further studies are needed to determine the best way to correct it,” he said. “The ultimate goal of this research is to help patients recover more quickly from traumatic brain injuries.”

Red blood cells

Recent studies have suggested that roughly half of patients hospitalized with traumatic brain injuries (TBIs) are anemic, but it hasn’t been clear how the anemia affects patients’ recovery.

Now, researchers have found evidence suggesting that low hemoglobin levels can negatively influence the outcomes of patients with TBIs.

The team detailed this evidence in a paper published in World Neurosurgery.

“More research is needed to develop treatment protocols for anemic patients with traumatic brain injuries,” said study author N. Scott Litofsky, MD, of the University of Missouri School of Medicine in Columbia.

“There has been a lack of consensus among physicians regarding the relationship of anemia and traumatic brain injuries on a patient’s health. Because of this uncertainty, treatment protocols are unclear and inconsistent. Our observational study found that a patient’s outcome is worse when he or she is anemic.”

The researchers studied 939 TBI patients with anemia who were admitted to a Level I trauma center.

The team assessed the relationships between patients’ initial hemoglobin level and lowest hemoglobin level during hospitalization at threshold values of ≤7, ≤8, ≤9, and ≤10 g/dL relative to their Glasgow Outcome Score within a year of surgery.

The data suggested that both initial hemoglobin levels and lowest hemoglobin levels were independent predictors of poor outcome (P<0.0001).

For each increase in initial hemoglobin level of 1 g/dL, the odds of a patient achieving a good outcome increased by 32%. For each increase in lowest hemoglobin level of 1 g/dL, the probability of a good outcome increased by 35.6%.

Female patients had worse outcomes than male patients if their initial hemoglobin levels were between 7 g/dL and 8 g/dL (P<0.05).

And receiving a blood transfusion was associated with poorer outcomes at hemoglobin levels ≤9 g/dL and ≤10 g/dL (P<0.05) but not at the lower hemoglobin thresholds.

The researchers said these data suggest clinicians may want to consider giving blood transfusions in TBI patients with hemoglobin levels of 8 g/dL or lower.

However, Dr Litofsky noted that the purpose of this study was not to propose transfusion guidelines. It was to determine the effects of anemia on TBI outcomes.

“Now that we have shown that anemia affects a patient’s recovery, further studies are needed to determine the best way to correct it,” he said. “The ultimate goal of this research is to help patients recover more quickly from traumatic brain injuries.”