Erik Greb

Almost half of Americans report feeling daytime sleepiness on at least 3 days per week. For most patients, this sleepiness results from insufficient nighttime sleep. But a minority of these patients have narcolepsy, a chronic neurologic disorder that impairs the brain’s control of sleep-wake cycles. This disorder often goes undiagnosed, but neurologists can make a significant difference by learning how to recognize and treat it.

Thorpy_Michael_Bronx_web.jpg

What is narcolepsy?

Narcolepsy is characterized by excessive daytime sleepiness (EDS) and sudden attacks of sleep. Patients have difficulty staying awake for long periods of time, and the disorder can make performing daily tasks difficult. Problems with concentration and alertness are common.

Narcolepsy is considered to have two subtypes. Patients with narcolepsy type 1 also have cataplexy, a sudden loss of muscle tone. Attacks of cataplexy are triggered by strong, usually positive, emotions. These attacks have manifestations ranging from slurred speech to complete weakness of most muscles. Patients with narcolepsy type 2, however, do not have cataplexy.

Dysregulation of rapid eye movement (REM) sleep, which is when most dreaming occurs, is another symptom of narcolepsy. The transition to REM sleep is quicker in patients with narcolepsy and usually occurs within 15 minutes of sleep onset. A related symptom is sleep paralysis, an inability to move while falling asleep or waking up. This symptom resembles a state that normally occurs during REM sleep.

Scammell_Thomas_Boston_web.jpg

Criteria and diagnosis

To receive a diagnosis of narcolepsy type 1, a patient must have EDS that persists for at least 3 months and at least one of the following two features: cataplexy and objective evidence of quick sleep onset and early start of REM sleep or low cerebrospinal fluid (CSF) levels (that is, less than 110 pg/mL) of hypocretin. Hypocretin, also known as orexin, is a neuropeptide that regulates wakefulness and arousal.

Maski_Kiran_Boston_web.jpg

Patients must meet five criteria to receive a diagnosis of narcolepsy type 2. They must have EDS that persists for at least 3 months. They must have test results that show quick sleep onset and early start of REM sleep. They must have no cataplexy. Their CSF levels of hypocretin must be normal or unknown. Finally, they must have no other conditions that provide a better explanation for their symptoms and test results.

“The diagnosis of narcolepsy is made primarily by history on the clinical features of the disorder,” said Michael J. Thorpy, MB, ChB, professor of neurology at Albert Einstein College of Medicine and director of the Sleep–Wake Disorders Center at Montefiore Medical Center in New York. When narcolepsy is suspected, testing is required to confirm the diagnosis. The patient should undergo all-night polysomnographic (PSG) testing, followed by a daytime multiple sleep latency test (MSLT). Measurement of CSF hypocretin can be diagnostic but is performed mainly in the research setting and is not common in the clinical setting, said Dr. Thorpy.

Patients with narcolepsy typically fall asleep in an average of less than 8 minutes during the nap opportunities of the MSLT. They also have at least two sleep-onset REM periods. “A new change in the diagnostic classification is that a sleep-onset REM period on the preceding night’s PSG can count as one of the two sleep-onset REM periods required for diagnosis,” said Dr. Thorpy.

“In the case of type 1 narcolepsy, the history is usually pretty clear, and the MSLT is usually positive, in the sense that it is consistent with a narcolepsy pattern,” said Thomas E. Scammell, MD, professor of neurology at Harvard Medical School and Beth Israel Deaconess Medical Center in Boston. “The PSG is also important, because other factors that disrupt the patient’s nighttime sleep (such as obstructive sleep apnea and periodic limb movements) must be ruled out, especially in type 2 narcolepsy,” said Dr. Scammell.

Early sleep onset, late diagnosis

Diagnostic delay is a common problem for patients with narcolepsy. Although the median age of onset is 16 years, a patient typically does not receive the appropriate diagnosis until adulthood. “It takes, on average, somewhere between 8 and 12 years for a patient to get a diagnosis of narcolepsy,” said Dr. Thorpy. Growing awareness and an increase in the number of sleep disorder centers have reduced but not eliminated the diagnostic delay.

Children with narcolepsy are often misdiagnosed. “One of the most common misdiagnoses in childhood is ADHD, because sleepiness in children differs from that in adults,” said Dr. Thorpy. Sleepy children often become hyperactive and display increased impulsivity, he explained. Stimulants prescribed for ADHD tend to mask the symptoms of narcolepsy and delay the correct diagnosis. Mood disorders, behavioral disorders, and psychogenic disorders are other common misdiagnoses for children with narcolepsy.

But when it comes to adults, sometimes patients themselves contribute to the diagnostic delay. EDS is “such a pervasive feeling that I think a lot of people just don’t make much of it,” said Dr. Scammell. The symptom is easily ascribed to insufficient sleep or a difficult work schedule. “It may take them months to get to see a doctor,” said Dr. Scammell.

Behavioral treatments

Nonpharmacologic treatments are one component of care for patients with narcolepsy. Patients must maintain a regular sleep-wake schedule and ensure that they are in bed for no less than 8 hours per night, said Dr. Thorpy. Taking no more than two daytime naps of less than 20 minutes each can help relieve some of the sleepiness, he added.

In addition to ensuring an adequate amount of sleep, it is important to promote good quality sleep, said Dr. Scammell. To do this, clinicians should address any conditions such as sleep apnea that disrupt patients’ sleep, he added.

Patients also tend to avoid situations that are likely to entail the emotional stimuli that could precipitate cataplexy. Some avoid laughter or try to suppress their emotions. “That’s not good,” said Kiran Maski, MD, MPH, assistant professor of neurology at Harvard Medical School and neurologist and sleep physician at Boston Children’s Hospital. “We worry that that might be a risk factor for depression or social isolation.” Cognitive-behavioral therapy can help patients with narcolepsy gradually increase their comfort with and exposure to social situations.

Although behavioral treatments are helpful, they are not sufficient to control all the symptoms of narcolepsy. Most patients require pharmacologic treatments, which are the most effective treatments for narcolepsy, said Dr. Thorpy.

Pharmacologic treatments

Previously, neurologists relied on the stimulants methylphenidate and amphetamine, which primarily treated patients’ EDS. But the field is moving away from these drugs because of their tendency to induce side effects and their potential for abuse, said Dr. Thorpy. In this context, modafinil and armodafinil became the mainstay for promoting alertness in patients with narcolepsy.

In recent years, newer medications have emerged that have slightly greater efficacy and better safety profiles than modafinil and armodafinil. Solriamfetol (Sunosi, Jazz Pharmaceuticals), for example, is effective for EDS but does not affect cataplexy. Pitolisant (Wakix, Harmony Biosciences), on the other hand, effectively treats EDS and cataplexy.

Sodium oxybate (Xyrem, Jazz Pharmaceuticals) is the only medication that treats all the symptoms of narcolepsy, said Dr. Thorpy. “That treats the sleepiness, the cataplexy, and the disturbed nocturnal sleep,” he added. Sodium oxybate also appears to reduce sleep paralysis, hallucinations, and disturbed dreams.

A potential concern about sodium oxybate, which has been used since approximately 2000, is its high sodium load. A new formulation called low-sodium oxybate (Xywav, Jazz Pharmaceuticals) “has a slightly better safety profile, particularly in people who have cardiovascular or renal disease,” said Dr. Thorpy. “This is tending to take over the role of regular sodium oxybate.”

Many clinicians who treat patients with narcolepsy develop their own approaches, but the choice of treatment generally depends on the patient’s symptoms, said Dr. Scammell. Modafinil is a good first choice for patients with mild to moderate sleepiness, he added. Pitolisant is another good choice for these patients but is more expensive. Both drugs are well tolerated.

Clinicians can consider solriamfetol and amphetamine for patients with moderate to severe sleepiness. “I generally consider the oxybates to be a second line,” said Dr. Scammell. Although these drugs may be the most effective, and they do help patients a great deal, they have a higher prevalence of side effects and are more expensive, he added. “If we can get good results with something gentle and simple like modafinil, that would be great.”

“There are differences of opinion as to what the first-line treatments are,” said Dr. Thorpy. Some patients prefer to use the traditional stimulants as first-line treatments, but others prefer to avoid them because of their adverse effects. They favor the newer, and unfortunately more expensive, medications instead. But there is no consensus among clinicians about which of the newer medications to use. “There’s no standard treatment, and it’s very hard to develop an algorithm that is acceptable to most physicians treating patients with narcolepsy,” said Dr. Thorpy. Treatment response varies, as well. Some patients respond extremely well to treatment, but clinical trials indicate that even optimal therapy helps patients achieve about 70% of the normal level of alertness. “If they’re sedentary, sitting in a boring meeting or at the computer, they can still fall asleep, even with our current medications,” said Dr. Scammell.

“The hardest symptom of all to treat is the EDS,” agreed Dr. Thorpy. Most patients cannot be treated with one medication alone, and polypharmacy tends to be necessary, he added. Typically, this means the addition of another medication to the regimen to maximize alertness. For other patients, cataplexy is difficult to control, and adding an anticataplectic medication is appropriate. Still, most patients can control their cataplexy with one drug, either oxybate or pitolisant, said Dr. Thorpy.

Investigational treatments

Researchers are trying to develop new medicines with greater potency, and several medications are under investigation. Early studies have shown that reboxetine, an antidepressant medication that affects dopamine and norepinephrine activity, is an effective treatment for EDS and cataplexy. Ongoing phase 3 studies are examining reboxetine for EDS. Another drug known as FT-218 is a once-nightly formulation of sodium oxybate, unlike the twice-nightly formulations of the drug that currently are available. In a phase 3 trial, the drug was associated with significant improvements in wakefulness and reductions in attacks of cataplexy. Avadel, which is developing the drug, submitted it to the U.S. Food and Drug Administration for approval in 2021, but the agency has not yet made a decision about it.

Researchers and patients alike have high hopes for medications that activate the orexin receptors. Orexin stimulates the wake-promoting neurons in the brain. Narcolepsy, and particularly narcolepsy type 1, is characterized by a loss of hypocretin cells in the central nervous system. The loss of these cells promotes sleepiness and disturbed REM sleep. To counteract this loss of cells, several companies are investigating new orexin agonists.

One such medication is TAK-994, which was developed by Takeda. The drug showed great promise for treating EDS and cataplexy, said Dr. Thorpy. But when phase 3 studies suggested that TAK-994 was associated with hepatotoxicity, the company terminated the studies. Nevertheless, other orexin agonists, including Takeda’s TAK-861, are under investigation.

“If we can restore orexin signaling, it could be like giving insulin to type 1 diabetics,” said Dr. Scammell. This class of medications could provide substantial improvements in sleepiness and other symptoms, he added. “I think when orexin agonists become available, it’s going to be quite transformative.” But these drugs are still in early development and will not be available in clinical practice for several years.

Common psychological comorbidities

Certain comorbidities are prevalent among patients with narcolepsy, and psychiatric disorders tend to be the most common. These comorbidities may complicate the management of narcolepsy. Nevertheless, they often are significant enough to require management in their own right, said Dr. Thorpy.

Depression is likely twice as common among patients with narcolepsy than among the general population, said Dr. Scammell. “Whether this is an actual neurobiologic feature of the disease, or whether it is just a reaction to having a challenging disorder isn’t entirely clear,” he added. “But it doesn’t get the attention or treatment that it deserves.”

Partnering with a psychologist or psychiatrist is important because many treatments can exacerbate mood disorders, said Dr. Maski. In general, stimulants, for example, can worsen depression and anxiety and are associated with increased suicide risk. “We oftentimes are using high-dose stimulants in patients, so mood has to be really carefully monitored and managed,” Dr. Maski added.

Cases of depression and suicidal ideation were reported in clinical trials of sodium oxybate. Although these serious adverse events were rare, patients must be monitored very closely even on treatments specifically approved for narcolepsy, said Dr. Maski. Mood disturbances are reported less frequently with modafinil and pitolisant than with stimulants, she noted.

Many times, patients need to take an antidepressant medication, but these drugs could affect the medicines administered for narcolepsy, said Dr. Thorpy. Pitolisant, in particular, may be adversely affected by current antidepressant medications. The only remedies are to change from pitolisant to another narcolepsy medication or to use an antidepressant that does not have histamine 1 receptor antagonism or affect the QTc interval.

Anxiety also is prevalent among patients with narcolepsy, and it can be worsened by traditional stimulants. These drugs also can increase the likelihood of irritability or obsessive-compulsive tendencies. “Traditional stimulants would be best avoided in these patients who have significant anxiety,” said Dr. Thorpy.

The social burden of narcolepsy

The burden of narcolepsy extends beyond psychiatric comorbidities into the social sphere. “Patients with narcolepsy do have greater difficulties in terms of social and interpersonal relationships,” said Dr. Thorpy. The disorder reduces patients’ quality of life, and educational difficulties and job loss are common in this population. “It’s a lifelong, incurable disorder, and these patients suffer an immense burden throughout their life because of the sleepiness that … affects their cognitive abilities,” said Dr. Thorpy.

“There’s an increased reporting of what probably amounts to social isolation,” said Dr. Maski. Patients often report that they must prioritize activities or events because they do not have the energy or alertness to participate in all of them. For instance, adolescents with narcolepsy frequently say that they must forgo after-school extracurricular activities because they need to prioritize studying and getting enough sleep. “Those priorities take away from their normal social life and events that they would like to participate in,” said Dr. Maski.

Another problem is that patients have the impression that others do not understand their condition. They are afraid that they will be perceived as lazy, uninterested, or unmotivated if they fall asleep. “Sometimes they withdraw from social events because they don’t want to be perceived in such a way,” said Dr. Maski. She and her colleagues encourage patients to participate in selected after-school events and to engage in social activities they find meaningful to maintain social networks.

An unpublished study of more than 300 patients with narcolepsy examined the effect of the disorder on patients’ social lives. At the end of the day, many patients “crash and burn,” said Dr. Scammell. Consequently, they do not have as much energy for social activities.

This lack of energy affects patients’ social relationships. The study suggests that patients with narcolepsy do not have as many friends as the general population does. Nevertheless, the frequency of close relationships and marriage was similar between patients with narcolepsy and the general population. “What people are doing is putting their energy into these close relationships, rather than having lots of friends and socializing a lot,” said Dr. Scammell. “I found that heartening, that people were doing their best and developed those close relationships,” which are vitally important for many reasons, he added.

The study, which has been submitted for publication, also asked patients about their sex lives. Many patients reported having had cataplexy during sex, and others reported that their medications caused problems with their sex lives. “Their doctors never ask about these things, and many patients actually would like their doctor to ask about them more,” said Dr. Scammell.

In addition, narcolepsy significantly affects a patient’s ability to drive. Patients with narcolepsy have a three- to fourfold increased risk of car accidents, said Dr. Scammell. This increased risk likely results from patients’ EDS.

But as important as this issue is for patients’ lives, there is no consensus on how to counsel patients about driving, said Dr. Maski. “For instance, it is not really clear if there is value in doing a maintenance of wakefulness test before allowing patients with narcolepsy to drive,” she said. The test is not validated in children or adolescents, which raises questions about how to advise beginning drivers with narcolepsy. “It’s not really clear that passing your maintenance of wakefulness test increases your safety behind the wheel,” said Dr. Maski.

“It’s the rare person with narcolepsy who can easily and safely do a 2-hour drive by themselves,” said Dr. Scammell. Patients must determine what their own limits are, and it is important for clinicians to discuss reasonable limits honestly with their patients. “I almost never would push to have somebody’s license taken away,” said Dr. Scammell. “But there are patients who only can drive around town for short errands, and if it’s anything more than half an hour, they start getting drowsy.”

There is a need for a public awareness campaign about narcolepsy, Dr. Scammell added. Such a campaign was carried out in Italy several years ago, and it included cartoons and TV segments. “It got a lot of people’s attention, and there was a real spike in new and correct diagnoses of narcolepsy,” said Dr. Scammell. But such a broad campaign is expensive, while narcolepsy is rare, and it might not be feasible to reach out to the general population. “But I certainly think it’s worth targeting doctors who are likely to see patients with sleepiness: neurologists, psychiatrists and psychologists, and primary care doctors,” said Dr. Scammell.

Almost half of Americans report feeling daytime sleepiness on at least 3 days per week. For most patients, this sleepiness results from insufficient nighttime sleep. But a minority of these patients have narcolepsy, a chronic neurologic disorder that impairs the brain’s control of sleep-wake cycles. This disorder often goes undiagnosed, but neurologists can make a significant difference by learning how to recognize and treat it.

Thorpy_Michael_Bronx_web.jpg

What is narcolepsy?

Narcolepsy is characterized by excessive daytime sleepiness (EDS) and sudden attacks of sleep. Patients have difficulty staying awake for long periods of time, and the disorder can make performing daily tasks difficult. Problems with concentration and alertness are common.

Narcolepsy is considered to have two subtypes. Patients with narcolepsy type 1 also have cataplexy, a sudden loss of muscle tone. Attacks of cataplexy are triggered by strong, usually positive, emotions. These attacks have manifestations ranging from slurred speech to complete weakness of most muscles. Patients with narcolepsy type 2, however, do not have cataplexy.

Dysregulation of rapid eye movement (REM) sleep, which is when most dreaming occurs, is another symptom of narcolepsy. The transition to REM sleep is quicker in patients with narcolepsy and usually occurs within 15 minutes of sleep onset. A related symptom is sleep paralysis, an inability to move while falling asleep or waking up. This symptom resembles a state that normally occurs during REM sleep.

Scammell_Thomas_Boston_web.jpg

Criteria and diagnosis

To receive a diagnosis of narcolepsy type 1, a patient must have EDS that persists for at least 3 months and at least one of the following two features: cataplexy and objective evidence of quick sleep onset and early start of REM sleep or low cerebrospinal fluid (CSF) levels (that is, less than 110 pg/mL) of hypocretin. Hypocretin, also known as orexin, is a neuropeptide that regulates wakefulness and arousal.

Maski_Kiran_Boston_web.jpg

Patients must meet five criteria to receive a diagnosis of narcolepsy type 2. They must have EDS that persists for at least 3 months. They must have test results that show quick sleep onset and early start of REM sleep. They must have no cataplexy. Their CSF levels of hypocretin must be normal or unknown. Finally, they must have no other conditions that provide a better explanation for their symptoms and test results.

“The diagnosis of narcolepsy is made primarily by history on the clinical features of the disorder,” said Michael J. Thorpy, MB, ChB, professor of neurology at Albert Einstein College of Medicine and director of the Sleep–Wake Disorders Center at Montefiore Medical Center in New York. When narcolepsy is suspected, testing is required to confirm the diagnosis. The patient should undergo all-night polysomnographic (PSG) testing, followed by a daytime multiple sleep latency test (MSLT). Measurement of CSF hypocretin can be diagnostic but is performed mainly in the research setting and is not common in the clinical setting, said Dr. Thorpy.

Patients with narcolepsy typically fall asleep in an average of less than 8 minutes during the nap opportunities of the MSLT. They also have at least two sleep-onset REM periods. “A new change in the diagnostic classification is that a sleep-onset REM period on the preceding night’s PSG can count as one of the two sleep-onset REM periods required for diagnosis,” said Dr. Thorpy.

“In the case of type 1 narcolepsy, the history is usually pretty clear, and the MSLT is usually positive, in the sense that it is consistent with a narcolepsy pattern,” said Thomas E. Scammell, MD, professor of neurology at Harvard Medical School and Beth Israel Deaconess Medical Center in Boston. “The PSG is also important, because other factors that disrupt the patient’s nighttime sleep (such as obstructive sleep apnea and periodic limb movements) must be ruled out, especially in type 2 narcolepsy,” said Dr. Scammell.

Early sleep onset, late diagnosis

Diagnostic delay is a common problem for patients with narcolepsy. Although the median age of onset is 16 years, a patient typically does not receive the appropriate diagnosis until adulthood. “It takes, on average, somewhere between 8 and 12 years for a patient to get a diagnosis of narcolepsy,” said Dr. Thorpy. Growing awareness and an increase in the number of sleep disorder centers have reduced but not eliminated the diagnostic delay.

Children with narcolepsy are often misdiagnosed. “One of the most common misdiagnoses in childhood is ADHD, because sleepiness in children differs from that in adults,” said Dr. Thorpy. Sleepy children often become hyperactive and display increased impulsivity, he explained. Stimulants prescribed for ADHD tend to mask the symptoms of narcolepsy and delay the correct diagnosis. Mood disorders, behavioral disorders, and psychogenic disorders are other common misdiagnoses for children with narcolepsy.

But when it comes to adults, sometimes patients themselves contribute to the diagnostic delay. EDS is “such a pervasive feeling that I think a lot of people just don’t make much of it,” said Dr. Scammell. The symptom is easily ascribed to insufficient sleep or a difficult work schedule. “It may take them months to get to see a doctor,” said Dr. Scammell.

Behavioral treatments

Nonpharmacologic treatments are one component of care for patients with narcolepsy. Patients must maintain a regular sleep-wake schedule and ensure that they are in bed for no less than 8 hours per night, said Dr. Thorpy. Taking no more than two daytime naps of less than 20 minutes each can help relieve some of the sleepiness, he added.

In addition to ensuring an adequate amount of sleep, it is important to promote good quality sleep, said Dr. Scammell. To do this, clinicians should address any conditions such as sleep apnea that disrupt patients’ sleep, he added.

Patients also tend to avoid situations that are likely to entail the emotional stimuli that could precipitate cataplexy. Some avoid laughter or try to suppress their emotions. “That’s not good,” said Kiran Maski, MD, MPH, assistant professor of neurology at Harvard Medical School and neurologist and sleep physician at Boston Children’s Hospital. “We worry that that might be a risk factor for depression or social isolation.” Cognitive-behavioral therapy can help patients with narcolepsy gradually increase their comfort with and exposure to social situations.

Although behavioral treatments are helpful, they are not sufficient to control all the symptoms of narcolepsy. Most patients require pharmacologic treatments, which are the most effective treatments for narcolepsy, said Dr. Thorpy.

Pharmacologic treatments

Previously, neurologists relied on the stimulants methylphenidate and amphetamine, which primarily treated patients’ EDS. But the field is moving away from these drugs because of their tendency to induce side effects and their potential for abuse, said Dr. Thorpy. In this context, modafinil and armodafinil became the mainstay for promoting alertness in patients with narcolepsy.

In recent years, newer medications have emerged that have slightly greater efficacy and better safety profiles than modafinil and armodafinil. Solriamfetol (Sunosi, Jazz Pharmaceuticals), for example, is effective for EDS but does not affect cataplexy. Pitolisant (Wakix, Harmony Biosciences), on the other hand, effectively treats EDS and cataplexy.

Sodium oxybate (Xyrem, Jazz Pharmaceuticals) is the only medication that treats all the symptoms of narcolepsy, said Dr. Thorpy. “That treats the sleepiness, the cataplexy, and the disturbed nocturnal sleep,” he added. Sodium oxybate also appears to reduce sleep paralysis, hallucinations, and disturbed dreams.

A potential concern about sodium oxybate, which has been used since approximately 2000, is its high sodium load. A new formulation called low-sodium oxybate (Xywav, Jazz Pharmaceuticals) “has a slightly better safety profile, particularly in people who have cardiovascular or renal disease,” said Dr. Thorpy. “This is tending to take over the role of regular sodium oxybate.”

Many clinicians who treat patients with narcolepsy develop their own approaches, but the choice of treatment generally depends on the patient’s symptoms, said Dr. Scammell. Modafinil is a good first choice for patients with mild to moderate sleepiness, he added. Pitolisant is another good choice for these patients but is more expensive. Both drugs are well tolerated.

Clinicians can consider solriamfetol and amphetamine for patients with moderate to severe sleepiness. “I generally consider the oxybates to be a second line,” said Dr. Scammell. Although these drugs may be the most effective, and they do help patients a great deal, they have a higher prevalence of side effects and are more expensive, he added. “If we can get good results with something gentle and simple like modafinil, that would be great.”

“There are differences of opinion as to what the first-line treatments are,” said Dr. Thorpy. Some patients prefer to use the traditional stimulants as first-line treatments, but others prefer to avoid them because of their adverse effects. They favor the newer, and unfortunately more expensive, medications instead. But there is no consensus among clinicians about which of the newer medications to use. “There’s no standard treatment, and it’s very hard to develop an algorithm that is acceptable to most physicians treating patients with narcolepsy,” said Dr. Thorpy. Treatment response varies, as well. Some patients respond extremely well to treatment, but clinical trials indicate that even optimal therapy helps patients achieve about 70% of the normal level of alertness. “If they’re sedentary, sitting in a boring meeting or at the computer, they can still fall asleep, even with our current medications,” said Dr. Scammell.

“The hardest symptom of all to treat is the EDS,” agreed Dr. Thorpy. Most patients cannot be treated with one medication alone, and polypharmacy tends to be necessary, he added. Typically, this means the addition of another medication to the regimen to maximize alertness. For other patients, cataplexy is difficult to control, and adding an anticataplectic medication is appropriate. Still, most patients can control their cataplexy with one drug, either oxybate or pitolisant, said Dr. Thorpy.

Investigational treatments

Researchers are trying to develop new medicines with greater potency, and several medications are under investigation. Early studies have shown that reboxetine, an antidepressant medication that affects dopamine and norepinephrine activity, is an effective treatment for EDS and cataplexy. Ongoing phase 3 studies are examining reboxetine for EDS. Another drug known as FT-218 is a once-nightly formulation of sodium oxybate, unlike the twice-nightly formulations of the drug that currently are available. In a phase 3 trial, the drug was associated with significant improvements in wakefulness and reductions in attacks of cataplexy. Avadel, which is developing the drug, submitted it to the U.S. Food and Drug Administration for approval in 2021, but the agency has not yet made a decision about it.

Researchers and patients alike have high hopes for medications that activate the orexin receptors. Orexin stimulates the wake-promoting neurons in the brain. Narcolepsy, and particularly narcolepsy type 1, is characterized by a loss of hypocretin cells in the central nervous system. The loss of these cells promotes sleepiness and disturbed REM sleep. To counteract this loss of cells, several companies are investigating new orexin agonists.

One such medication is TAK-994, which was developed by Takeda. The drug showed great promise for treating EDS and cataplexy, said Dr. Thorpy. But when phase 3 studies suggested that TAK-994 was associated with hepatotoxicity, the company terminated the studies. Nevertheless, other orexin agonists, including Takeda’s TAK-861, are under investigation.

“If we can restore orexin signaling, it could be like giving insulin to type 1 diabetics,” said Dr. Scammell. This class of medications could provide substantial improvements in sleepiness and other symptoms, he added. “I think when orexin agonists become available, it’s going to be quite transformative.” But these drugs are still in early development and will not be available in clinical practice for several years.

Common psychological comorbidities

Certain comorbidities are prevalent among patients with narcolepsy, and psychiatric disorders tend to be the most common. These comorbidities may complicate the management of narcolepsy. Nevertheless, they often are significant enough to require management in their own right, said Dr. Thorpy.

Depression is likely twice as common among patients with narcolepsy than among the general population, said Dr. Scammell. “Whether this is an actual neurobiologic feature of the disease, or whether it is just a reaction to having a challenging disorder isn’t entirely clear,” he added. “But it doesn’t get the attention or treatment that it deserves.”

Partnering with a psychologist or psychiatrist is important because many treatments can exacerbate mood disorders, said Dr. Maski. In general, stimulants, for example, can worsen depression and anxiety and are associated with increased suicide risk. “We oftentimes are using high-dose stimulants in patients, so mood has to be really carefully monitored and managed,” Dr. Maski added.

Cases of depression and suicidal ideation were reported in clinical trials of sodium oxybate. Although these serious adverse events were rare, patients must be monitored very closely even on treatments specifically approved for narcolepsy, said Dr. Maski. Mood disturbances are reported less frequently with modafinil and pitolisant than with stimulants, she noted.

Many times, patients need to take an antidepressant medication, but these drugs could affect the medicines administered for narcolepsy, said Dr. Thorpy. Pitolisant, in particular, may be adversely affected by current antidepressant medications. The only remedies are to change from pitolisant to another narcolepsy medication or to use an antidepressant that does not have histamine 1 receptor antagonism or affect the QTc interval.

Anxiety also is prevalent among patients with narcolepsy, and it can be worsened by traditional stimulants. These drugs also can increase the likelihood of irritability or obsessive-compulsive tendencies. “Traditional stimulants would be best avoided in these patients who have significant anxiety,” said Dr. Thorpy.

The social burden of narcolepsy

The burden of narcolepsy extends beyond psychiatric comorbidities into the social sphere. “Patients with narcolepsy do have greater difficulties in terms of social and interpersonal relationships,” said Dr. Thorpy. The disorder reduces patients’ quality of life, and educational difficulties and job loss are common in this population. “It’s a lifelong, incurable disorder, and these patients suffer an immense burden throughout their life because of the sleepiness that … affects their cognitive abilities,” said Dr. Thorpy.

“There’s an increased reporting of what probably amounts to social isolation,” said Dr. Maski. Patients often report that they must prioritize activities or events because they do not have the energy or alertness to participate in all of them. For instance, adolescents with narcolepsy frequently say that they must forgo after-school extracurricular activities because they need to prioritize studying and getting enough sleep. “Those priorities take away from their normal social life and events that they would like to participate in,” said Dr. Maski.

Another problem is that patients have the impression that others do not understand their condition. They are afraid that they will be perceived as lazy, uninterested, or unmotivated if they fall asleep. “Sometimes they withdraw from social events because they don’t want to be perceived in such a way,” said Dr. Maski. She and her colleagues encourage patients to participate in selected after-school events and to engage in social activities they find meaningful to maintain social networks.

An unpublished study of more than 300 patients with narcolepsy examined the effect of the disorder on patients’ social lives. At the end of the day, many patients “crash and burn,” said Dr. Scammell. Consequently, they do not have as much energy for social activities.

This lack of energy affects patients’ social relationships. The study suggests that patients with narcolepsy do not have as many friends as the general population does. Nevertheless, the frequency of close relationships and marriage was similar between patients with narcolepsy and the general population. “What people are doing is putting their energy into these close relationships, rather than having lots of friends and socializing a lot,” said Dr. Scammell. “I found that heartening, that people were doing their best and developed those close relationships,” which are vitally important for many reasons, he added.

The study, which has been submitted for publication, also asked patients about their sex lives. Many patients reported having had cataplexy during sex, and others reported that their medications caused problems with their sex lives. “Their doctors never ask about these things, and many patients actually would like their doctor to ask about them more,” said Dr. Scammell.

In addition, narcolepsy significantly affects a patient’s ability to drive. Patients with narcolepsy have a three- to fourfold increased risk of car accidents, said Dr. Scammell. This increased risk likely results from patients’ EDS.

But as important as this issue is for patients’ lives, there is no consensus on how to counsel patients about driving, said Dr. Maski. “For instance, it is not really clear if there is value in doing a maintenance of wakefulness test before allowing patients with narcolepsy to drive,” she said. The test is not validated in children or adolescents, which raises questions about how to advise beginning drivers with narcolepsy. “It’s not really clear that passing your maintenance of wakefulness test increases your safety behind the wheel,” said Dr. Maski.

“It’s the rare person with narcolepsy who can easily and safely do a 2-hour drive by themselves,” said Dr. Scammell. Patients must determine what their own limits are, and it is important for clinicians to discuss reasonable limits honestly with their patients. “I almost never would push to have somebody’s license taken away,” said Dr. Scammell. “But there are patients who only can drive around town for short errands, and if it’s anything more than half an hour, they start getting drowsy.”

There is a need for a public awareness campaign about narcolepsy, Dr. Scammell added. Such a campaign was carried out in Italy several years ago, and it included cartoons and TV segments. “It got a lot of people’s attention, and there was a real spike in new and correct diagnoses of narcolepsy,” said Dr. Scammell. But such a broad campaign is expensive, while narcolepsy is rare, and it might not be feasible to reach out to the general population. “But I certainly think it’s worth targeting doctors who are likely to see patients with sleepiness: neurologists, psychiatrists and psychologists, and primary care doctors,” said Dr. Scammell.

Almost half of Americans report feeling daytime sleepiness on at least 3 days per week. For most patients, this sleepiness results from insufficient nighttime sleep. But a minority of these patients have narcolepsy, a chronic neurologic disorder that impairs the brain’s control of sleep-wake cycles. This disorder often goes undiagnosed, but neurologists can make a significant difference by learning how to recognize and treat it.

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What is narcolepsy?

Narcolepsy is characterized by excessive daytime sleepiness (EDS) and sudden attacks of sleep. Patients have difficulty staying awake for long periods of time, and the disorder can make performing daily tasks difficult. Problems with concentration and alertness are common.

Narcolepsy is considered to have two subtypes. Patients with narcolepsy type 1 also have cataplexy, a sudden loss of muscle tone. Attacks of cataplexy are triggered by strong, usually positive, emotions. These attacks have manifestations ranging from slurred speech to complete weakness of most muscles. Patients with narcolepsy type 2, however, do not have cataplexy.

Dysregulation of rapid eye movement (REM) sleep, which is when most dreaming occurs, is another symptom of narcolepsy. The transition to REM sleep is quicker in patients with narcolepsy and usually occurs within 15 minutes of sleep onset. A related symptom is sleep paralysis, an inability to move while falling asleep or waking up. This symptom resembles a state that normally occurs during REM sleep.

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Criteria and diagnosis

To receive a diagnosis of narcolepsy type 1, a patient must have EDS that persists for at least 3 months and at least one of the following two features: cataplexy and objective evidence of quick sleep onset and early start of REM sleep or low cerebrospinal fluid (CSF) levels (that is, less than 110 pg/mL) of hypocretin. Hypocretin, also known as orexin, is a neuropeptide that regulates wakefulness and arousal.

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Patients must meet five criteria to receive a diagnosis of narcolepsy type 2. They must have EDS that persists for at least 3 months. They must have test results that show quick sleep onset and early start of REM sleep. They must have no cataplexy. Their CSF levels of hypocretin must be normal or unknown. Finally, they must have no other conditions that provide a better explanation for their symptoms and test results.

“The diagnosis of narcolepsy is made primarily by history on the clinical features of the disorder,” said Michael J. Thorpy, MB, ChB, professor of neurology at Albert Einstein College of Medicine and director of the Sleep–Wake Disorders Center at Montefiore Medical Center in New York. When narcolepsy is suspected, testing is required to confirm the diagnosis. The patient should undergo all-night polysomnographic (PSG) testing, followed by a daytime multiple sleep latency test (MSLT). Measurement of CSF hypocretin can be diagnostic but is performed mainly in the research setting and is not common in the clinical setting, said Dr. Thorpy.

Patients with narcolepsy typically fall asleep in an average of less than 8 minutes during the nap opportunities of the MSLT. They also have at least two sleep-onset REM periods. “A new change in the diagnostic classification is that a sleep-onset REM period on the preceding night’s PSG can count as one of the two sleep-onset REM periods required for diagnosis,” said Dr. Thorpy.

“In the case of type 1 narcolepsy, the history is usually pretty clear, and the MSLT is usually positive, in the sense that it is consistent with a narcolepsy pattern,” said Thomas E. Scammell, MD, professor of neurology at Harvard Medical School and Beth Israel Deaconess Medical Center in Boston. “The PSG is also important, because other factors that disrupt the patient’s nighttime sleep (such as obstructive sleep apnea and periodic limb movements) must be ruled out, especially in type 2 narcolepsy,” said Dr. Scammell.

Early sleep onset, late diagnosis

Diagnostic delay is a common problem for patients with narcolepsy. Although the median age of onset is 16 years, a patient typically does not receive the appropriate diagnosis until adulthood. “It takes, on average, somewhere between 8 and 12 years for a patient to get a diagnosis of narcolepsy,” said Dr. Thorpy. Growing awareness and an increase in the number of sleep disorder centers have reduced but not eliminated the diagnostic delay.

Children with narcolepsy are often misdiagnosed. “One of the most common misdiagnoses in childhood is ADHD, because sleepiness in children differs from that in adults,” said Dr. Thorpy. Sleepy children often become hyperactive and display increased impulsivity, he explained. Stimulants prescribed for ADHD tend to mask the symptoms of narcolepsy and delay the correct diagnosis. Mood disorders, behavioral disorders, and psychogenic disorders are other common misdiagnoses for children with narcolepsy.

But when it comes to adults, sometimes patients themselves contribute to the diagnostic delay. EDS is “such a pervasive feeling that I think a lot of people just don’t make much of it,” said Dr. Scammell. The symptom is easily ascribed to insufficient sleep or a difficult work schedule. “It may take them months to get to see a doctor,” said Dr. Scammell.

Behavioral treatments

Nonpharmacologic treatments are one component of care for patients with narcolepsy. Patients must maintain a regular sleep-wake schedule and ensure that they are in bed for no less than 8 hours per night, said Dr. Thorpy. Taking no more than two daytime naps of less than 20 minutes each can help relieve some of the sleepiness, he added.

In addition to ensuring an adequate amount of sleep, it is important to promote good quality sleep, said Dr. Scammell. To do this, clinicians should address any conditions such as sleep apnea that disrupt patients’ sleep, he added.

Patients also tend to avoid situations that are likely to entail the emotional stimuli that could precipitate cataplexy. Some avoid laughter or try to suppress their emotions. “That’s not good,” said Kiran Maski, MD, MPH, assistant professor of neurology at Harvard Medical School and neurologist and sleep physician at Boston Children’s Hospital. “We worry that that might be a risk factor for depression or social isolation.” Cognitive-behavioral therapy can help patients with narcolepsy gradually increase their comfort with and exposure to social situations.

Although behavioral treatments are helpful, they are not sufficient to control all the symptoms of narcolepsy. Most patients require pharmacologic treatments, which are the most effective treatments for narcolepsy, said Dr. Thorpy.

Pharmacologic treatments

Previously, neurologists relied on the stimulants methylphenidate and amphetamine, which primarily treated patients’ EDS. But the field is moving away from these drugs because of their tendency to induce side effects and their potential for abuse, said Dr. Thorpy. In this context, modafinil and armodafinil became the mainstay for promoting alertness in patients with narcolepsy.

In recent years, newer medications have emerged that have slightly greater efficacy and better safety profiles than modafinil and armodafinil. Solriamfetol (Sunosi, Jazz Pharmaceuticals), for example, is effective for EDS but does not affect cataplexy. Pitolisant (Wakix, Harmony Biosciences), on the other hand, effectively treats EDS and cataplexy.

Sodium oxybate (Xyrem, Jazz Pharmaceuticals) is the only medication that treats all the symptoms of narcolepsy, said Dr. Thorpy. “That treats the sleepiness, the cataplexy, and the disturbed nocturnal sleep,” he added. Sodium oxybate also appears to reduce sleep paralysis, hallucinations, and disturbed dreams.

A potential concern about sodium oxybate, which has been used since approximately 2000, is its high sodium load. A new formulation called low-sodium oxybate (Xywav, Jazz Pharmaceuticals) “has a slightly better safety profile, particularly in people who have cardiovascular or renal disease,” said Dr. Thorpy. “This is tending to take over the role of regular sodium oxybate.”

Many clinicians who treat patients with narcolepsy develop their own approaches, but the choice of treatment generally depends on the patient’s symptoms, said Dr. Scammell. Modafinil is a good first choice for patients with mild to moderate sleepiness, he added. Pitolisant is another good choice for these patients but is more expensive. Both drugs are well tolerated.

Clinicians can consider solriamfetol and amphetamine for patients with moderate to severe sleepiness. “I generally consider the oxybates to be a second line,” said Dr. Scammell. Although these drugs may be the most effective, and they do help patients a great deal, they have a higher prevalence of side effects and are more expensive, he added. “If we can get good results with something gentle and simple like modafinil, that would be great.”

“There are differences of opinion as to what the first-line treatments are,” said Dr. Thorpy. Some patients prefer to use the traditional stimulants as first-line treatments, but others prefer to avoid them because of their adverse effects. They favor the newer, and unfortunately more expensive, medications instead. But there is no consensus among clinicians about which of the newer medications to use. “There’s no standard treatment, and it’s very hard to develop an algorithm that is acceptable to most physicians treating patients with narcolepsy,” said Dr. Thorpy. Treatment response varies, as well. Some patients respond extremely well to treatment, but clinical trials indicate that even optimal therapy helps patients achieve about 70% of the normal level of alertness. “If they’re sedentary, sitting in a boring meeting or at the computer, they can still fall asleep, even with our current medications,” said Dr. Scammell.

“The hardest symptom of all to treat is the EDS,” agreed Dr. Thorpy. Most patients cannot be treated with one medication alone, and polypharmacy tends to be necessary, he added. Typically, this means the addition of another medication to the regimen to maximize alertness. For other patients, cataplexy is difficult to control, and adding an anticataplectic medication is appropriate. Still, most patients can control their cataplexy with one drug, either oxybate or pitolisant, said Dr. Thorpy.

Investigational treatments

Researchers are trying to develop new medicines with greater potency, and several medications are under investigation. Early studies have shown that reboxetine, an antidepressant medication that affects dopamine and norepinephrine activity, is an effective treatment for EDS and cataplexy. Ongoing phase 3 studies are examining reboxetine for EDS. Another drug known as FT-218 is a once-nightly formulation of sodium oxybate, unlike the twice-nightly formulations of the drug that currently are available. In a phase 3 trial, the drug was associated with significant improvements in wakefulness and reductions in attacks of cataplexy. Avadel, which is developing the drug, submitted it to the U.S. Food and Drug Administration for approval in 2021, but the agency has not yet made a decision about it.

Researchers and patients alike have high hopes for medications that activate the orexin receptors. Orexin stimulates the wake-promoting neurons in the brain. Narcolepsy, and particularly narcolepsy type 1, is characterized by a loss of hypocretin cells in the central nervous system. The loss of these cells promotes sleepiness and disturbed REM sleep. To counteract this loss of cells, several companies are investigating new orexin agonists.

One such medication is TAK-994, which was developed by Takeda. The drug showed great promise for treating EDS and cataplexy, said Dr. Thorpy. But when phase 3 studies suggested that TAK-994 was associated with hepatotoxicity, the company terminated the studies. Nevertheless, other orexin agonists, including Takeda’s TAK-861, are under investigation.

“If we can restore orexin signaling, it could be like giving insulin to type 1 diabetics,” said Dr. Scammell. This class of medications could provide substantial improvements in sleepiness and other symptoms, he added. “I think when orexin agonists become available, it’s going to be quite transformative.” But these drugs are still in early development and will not be available in clinical practice for several years.

Common psychological comorbidities

Certain comorbidities are prevalent among patients with narcolepsy, and psychiatric disorders tend to be the most common. These comorbidities may complicate the management of narcolepsy. Nevertheless, they often are significant enough to require management in their own right, said Dr. Thorpy.

Depression is likely twice as common among patients with narcolepsy than among the general population, said Dr. Scammell. “Whether this is an actual neurobiologic feature of the disease, or whether it is just a reaction to having a challenging disorder isn’t entirely clear,” he added. “But it doesn’t get the attention or treatment that it deserves.”

Partnering with a psychologist or psychiatrist is important because many treatments can exacerbate mood disorders, said Dr. Maski. In general, stimulants, for example, can worsen depression and anxiety and are associated with increased suicide risk. “We oftentimes are using high-dose stimulants in patients, so mood has to be really carefully monitored and managed,” Dr. Maski added.

Cases of depression and suicidal ideation were reported in clinical trials of sodium oxybate. Although these serious adverse events were rare, patients must be monitored very closely even on treatments specifically approved for narcolepsy, said Dr. Maski. Mood disturbances are reported less frequently with modafinil and pitolisant than with stimulants, she noted.

Many times, patients need to take an antidepressant medication, but these drugs could affect the medicines administered for narcolepsy, said Dr. Thorpy. Pitolisant, in particular, may be adversely affected by current antidepressant medications. The only remedies are to change from pitolisant to another narcolepsy medication or to use an antidepressant that does not have histamine 1 receptor antagonism or affect the QTc interval.

Anxiety also is prevalent among patients with narcolepsy, and it can be worsened by traditional stimulants. These drugs also can increase the likelihood of irritability or obsessive-compulsive tendencies. “Traditional stimulants would be best avoided in these patients who have significant anxiety,” said Dr. Thorpy.

The social burden of narcolepsy

The burden of narcolepsy extends beyond psychiatric comorbidities into the social sphere. “Patients with narcolepsy do have greater difficulties in terms of social and interpersonal relationships,” said Dr. Thorpy. The disorder reduces patients’ quality of life, and educational difficulties and job loss are common in this population. “It’s a lifelong, incurable disorder, and these patients suffer an immense burden throughout their life because of the sleepiness that … affects their cognitive abilities,” said Dr. Thorpy.

“There’s an increased reporting of what probably amounts to social isolation,” said Dr. Maski. Patients often report that they must prioritize activities or events because they do not have the energy or alertness to participate in all of them. For instance, adolescents with narcolepsy frequently say that they must forgo after-school extracurricular activities because they need to prioritize studying and getting enough sleep. “Those priorities take away from their normal social life and events that they would like to participate in,” said Dr. Maski.

Another problem is that patients have the impression that others do not understand their condition. They are afraid that they will be perceived as lazy, uninterested, or unmotivated if they fall asleep. “Sometimes they withdraw from social events because they don’t want to be perceived in such a way,” said Dr. Maski. She and her colleagues encourage patients to participate in selected after-school events and to engage in social activities they find meaningful to maintain social networks.

An unpublished study of more than 300 patients with narcolepsy examined the effect of the disorder on patients’ social lives. At the end of the day, many patients “crash and burn,” said Dr. Scammell. Consequently, they do not have as much energy for social activities.

This lack of energy affects patients’ social relationships. The study suggests that patients with narcolepsy do not have as many friends as the general population does. Nevertheless, the frequency of close relationships and marriage was similar between patients with narcolepsy and the general population. “What people are doing is putting their energy into these close relationships, rather than having lots of friends and socializing a lot,” said Dr. Scammell. “I found that heartening, that people were doing their best and developed those close relationships,” which are vitally important for many reasons, he added.

The study, which has been submitted for publication, also asked patients about their sex lives. Many patients reported having had cataplexy during sex, and others reported that their medications caused problems with their sex lives. “Their doctors never ask about these things, and many patients actually would like their doctor to ask about them more,” said Dr. Scammell.

In addition, narcolepsy significantly affects a patient’s ability to drive. Patients with narcolepsy have a three- to fourfold increased risk of car accidents, said Dr. Scammell. This increased risk likely results from patients’ EDS.

But as important as this issue is for patients’ lives, there is no consensus on how to counsel patients about driving, said Dr. Maski. “For instance, it is not really clear if there is value in doing a maintenance of wakefulness test before allowing patients with narcolepsy to drive,” she said. The test is not validated in children or adolescents, which raises questions about how to advise beginning drivers with narcolepsy. “It’s not really clear that passing your maintenance of wakefulness test increases your safety behind the wheel,” said Dr. Maski.

“It’s the rare person with narcolepsy who can easily and safely do a 2-hour drive by themselves,” said Dr. Scammell. Patients must determine what their own limits are, and it is important for clinicians to discuss reasonable limits honestly with their patients. “I almost never would push to have somebody’s license taken away,” said Dr. Scammell. “But there are patients who only can drive around town for short errands, and if it’s anything more than half an hour, they start getting drowsy.”

There is a need for a public awareness campaign about narcolepsy, Dr. Scammell added. Such a campaign was carried out in Italy several years ago, and it included cartoons and TV segments. “It got a lot of people’s attention, and there was a real spike in new and correct diagnoses of narcolepsy,” said Dr. Scammell. But such a broad campaign is expensive, while narcolepsy is rare, and it might not be feasible to reach out to the general population. “But I certainly think it’s worth targeting doctors who are likely to see patients with sleepiness: neurologists, psychiatrists and psychologists, and primary care doctors,” said Dr. Scammell.

The Onyx Liquid Embolic System (Medtronic) effectively occludes cerebral arteriovenous malformations (cAVMs), new observational data suggest. In a prospective, real-world study of more than 100 patients, use of the Onyx system was associated with a cure rate of 86% for cAVMs smaller than 3 cm.

“Endovascular treatment using Onyx is able to achieve, on its own, a very efficient cure rate with a low morbidity and mortality rate,” said investigator Laurent Spelle, MD, PhD, professor of neuroradiology at Paris-Saclay University and chair of NEURI, the Brain Vascular Center, Bicêtre Hospital, also in Paris.

Dr. Spelle presented the findings at the International Stroke Conference sponsored by the American Heart Association.
 

Prospective, multicenter study

Currently, the main treatment options for cAVM are embolization, neurosurgery, and radiosurgery. The Onyx liquid system, one method of providing embolization, uses a biocompatible ethylene vinyl alcohol copolymer.

It has been used in Europe for 22 years as a curative treatment and as a treatment before radiosurgery or neurosurgery. In the United States, Onyx is indicated for presurgical and preradiotherapy treatment only.

For this analysis, the researchers conducted a prospective, multicenter study to evaluate the long-term safety and efficacy of Onyx for the embolization of cAVM as curative treatment or preoperative preparation.

They enrolled 165 patients in the nonrandomized, observational study, which was conducted at 15 hospitals in France. Eligible participants had an untreated cAVM.

Patients were assigned to one of three groups, according to the hospital’s standard of care. One group underwent embolization with Onyx as curative treatment, one received Onyx as preparation for neurosurgery, and one underwent embolization with Onyx as preparation for radiosurgery.

The study’s safety endpoints were device- and procedure-related serious adverse events at 1 month after each embolization. The efficacy endpoints were recovery at 12 months after the last embolization or neurosurgery, or at a minimum of 36 months after radiosurgery.

The researchers defined morbidity as a worsening of modified Rankin Scale score of 2 or more points for patients presenting with baseline mRS of 0 or 1, or a worsening of 1 or more points for patients with an mRS of 2 or greater at baseline. An independent clinical events committee and core laboratory adjudicated the results.
 

‘A fantastic result’

In all, 140 patients were prospectively included, and 212 embolization procedures were performed. The population’s mean age was 41.4 years, and 60% of participants were men. About 61% of patients presented with symptoms, the most common of which were progressive neurologic deficit (41.2%) and headache (36.5%).

Approximately 64% of the cAVMs were ruptured. Most (75.7%) were smaller than 3 cm, and the remainder were between 3 and 6 cm. Most patients (59.3%) did not have an aneurysm.

Eight (3.8%) adverse events were associated with the use of Onyx. The rate of procedure-related neurologic serious adverse events was 7.1% within 1 month post embolization. Three deaths occurred (2.1%), one of which was considered device or procedure related.

A total of 87 patients underwent embolization alone, 14 of whom did not complete the study (2 died, 5 were lost to follow-up, and 7 withdrew). Of the 73 who completed the study, 58 (79.5%) had complete occlusion and full recovery at last follow-up. An additional 6.8% had 99% occlusion.

In addition, 3.4% of the population had significant morbidity, and 18.4% presented at baseline with mRS scores of 3-5. Of the latter group, 81.3% had mRS scores of 0-2 at last visit.

Of 21 patients who underwent subsequent neurosurgery, 18 completed follow-up. Of this group, 94.4% had complete occlusion. Of 32 patients receiving subsequent radiosurgery, 54.8% had complete occlusion, which was “a little bit disappointing,” said Dr. Spelle.

Overall, most patients (92.9%) had improved or stable mRS score. The overall mortality rate was 2.9%, and the rate of significant morbidity was 4.3%.

The rate of improved or stable mRS score was 94.3% for patients who underwent embolization alone, 85.7% for patients who also underwent neurosurgery, and 93.75% for patients who also underwent radiosurgery.

The mortality rate was 3.4% for patients who underwent embolization alone, 4.8% for patients who also underwent neurosurgery, and 0% for patients who also underwent radiosurgery.

The rate of significant morbidity was 2.3% for patients who underwent embolization alone, 9.5% for those who also underwent neurosurgery, and 6.25% for those who also underwent radiosurgery.

“We knew that this treatment was very effective, but this effectiveness was only known in a limited number of centers with a very high level of expertise,” said Dr. Spelle. “We were very pleasantly surprised that a larger-scale, multicenter study conducted in 15 different hospitals in France could achieve such a fantastic result.”

The study sites, however, were all departments in university hospitals with great experience in endovascular treatment of cAVM, he added.
 

Effective in unruptured AVMs?

Commenting on the findings, Mitchell Elkind, MD, professor of neurology and epidemiology, Columbia University, New York, said: “Arteriovenous malformations remain a relatively uncommon but serious cerebrovascular disorder. Any additional tool in the armamentarium to treat these lesions is welcome.”

The study results are encouraging, said Dr. Elkind, who was not involved in the study. They suggest that Onyx embolization can play an important role in the care of these patients. The treatment is associated with “low morbidity and excellent efficacy, particularly in combination with other surgical and radiographic approaches.”

The lack of a direct comparison with alternative embolization materials is a limitation of the study, however. “It is hard to compare Onyx to other agents based on these results,” said Dr. Elkind.

“It is also notable that one-third of the patients in the study had unruptured AVMs, which at least in one randomized trial, ARUBA, were not clearly shown to benefit from an intervention at all,” he continued.

It would have been valuable for the researchers to stratify the study results by ruptured versus unruptured AVMs, Dr. Elkind said.

The study was funded by Medtronic. Dr. Spelle reported receiving honoraria from the company. Dr. Elkind disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The Onyx Liquid Embolic System (Medtronic) effectively occludes cerebral arteriovenous malformations (cAVMs), new observational data suggest. In a prospective, real-world study of more than 100 patients, use of the Onyx system was associated with a cure rate of 86% for cAVMs smaller than 3 cm.

“Endovascular treatment using Onyx is able to achieve, on its own, a very efficient cure rate with a low morbidity and mortality rate,” said investigator Laurent Spelle, MD, PhD, professor of neuroradiology at Paris-Saclay University and chair of NEURI, the Brain Vascular Center, Bicêtre Hospital, also in Paris.

Dr. Spelle presented the findings at the International Stroke Conference sponsored by the American Heart Association.
 

Prospective, multicenter study

Currently, the main treatment options for cAVM are embolization, neurosurgery, and radiosurgery. The Onyx liquid system, one method of providing embolization, uses a biocompatible ethylene vinyl alcohol copolymer.

It has been used in Europe for 22 years as a curative treatment and as a treatment before radiosurgery or neurosurgery. In the United States, Onyx is indicated for presurgical and preradiotherapy treatment only.

For this analysis, the researchers conducted a prospective, multicenter study to evaluate the long-term safety and efficacy of Onyx for the embolization of cAVM as curative treatment or preoperative preparation.

They enrolled 165 patients in the nonrandomized, observational study, which was conducted at 15 hospitals in France. Eligible participants had an untreated cAVM.

Patients were assigned to one of three groups, according to the hospital’s standard of care. One group underwent embolization with Onyx as curative treatment, one received Onyx as preparation for neurosurgery, and one underwent embolization with Onyx as preparation for radiosurgery.

The study’s safety endpoints were device- and procedure-related serious adverse events at 1 month after each embolization. The efficacy endpoints were recovery at 12 months after the last embolization or neurosurgery, or at a minimum of 36 months after radiosurgery.

The researchers defined morbidity as a worsening of modified Rankin Scale score of 2 or more points for patients presenting with baseline mRS of 0 or 1, or a worsening of 1 or more points for patients with an mRS of 2 or greater at baseline. An independent clinical events committee and core laboratory adjudicated the results.
 

‘A fantastic result’

In all, 140 patients were prospectively included, and 212 embolization procedures were performed. The population’s mean age was 41.4 years, and 60% of participants were men. About 61% of patients presented with symptoms, the most common of which were progressive neurologic deficit (41.2%) and headache (36.5%).

Approximately 64% of the cAVMs were ruptured. Most (75.7%) were smaller than 3 cm, and the remainder were between 3 and 6 cm. Most patients (59.3%) did not have an aneurysm.

Eight (3.8%) adverse events were associated with the use of Onyx. The rate of procedure-related neurologic serious adverse events was 7.1% within 1 month post embolization. Three deaths occurred (2.1%), one of which was considered device or procedure related.

A total of 87 patients underwent embolization alone, 14 of whom did not complete the study (2 died, 5 were lost to follow-up, and 7 withdrew). Of the 73 who completed the study, 58 (79.5%) had complete occlusion and full recovery at last follow-up. An additional 6.8% had 99% occlusion.

In addition, 3.4% of the population had significant morbidity, and 18.4% presented at baseline with mRS scores of 3-5. Of the latter group, 81.3% had mRS scores of 0-2 at last visit.

Of 21 patients who underwent subsequent neurosurgery, 18 completed follow-up. Of this group, 94.4% had complete occlusion. Of 32 patients receiving subsequent radiosurgery, 54.8% had complete occlusion, which was “a little bit disappointing,” said Dr. Spelle.

Overall, most patients (92.9%) had improved or stable mRS score. The overall mortality rate was 2.9%, and the rate of significant morbidity was 4.3%.

The rate of improved or stable mRS score was 94.3% for patients who underwent embolization alone, 85.7% for patients who also underwent neurosurgery, and 93.75% for patients who also underwent radiosurgery.

The mortality rate was 3.4% for patients who underwent embolization alone, 4.8% for patients who also underwent neurosurgery, and 0% for patients who also underwent radiosurgery.

The rate of significant morbidity was 2.3% for patients who underwent embolization alone, 9.5% for those who also underwent neurosurgery, and 6.25% for those who also underwent radiosurgery.

“We knew that this treatment was very effective, but this effectiveness was only known in a limited number of centers with a very high level of expertise,” said Dr. Spelle. “We were very pleasantly surprised that a larger-scale, multicenter study conducted in 15 different hospitals in France could achieve such a fantastic result.”

The study sites, however, were all departments in university hospitals with great experience in endovascular treatment of cAVM, he added.
 

Effective in unruptured AVMs?

Commenting on the findings, Mitchell Elkind, MD, professor of neurology and epidemiology, Columbia University, New York, said: “Arteriovenous malformations remain a relatively uncommon but serious cerebrovascular disorder. Any additional tool in the armamentarium to treat these lesions is welcome.”

The study results are encouraging, said Dr. Elkind, who was not involved in the study. They suggest that Onyx embolization can play an important role in the care of these patients. The treatment is associated with “low morbidity and excellent efficacy, particularly in combination with other surgical and radiographic approaches.”

The lack of a direct comparison with alternative embolization materials is a limitation of the study, however. “It is hard to compare Onyx to other agents based on these results,” said Dr. Elkind.

“It is also notable that one-third of the patients in the study had unruptured AVMs, which at least in one randomized trial, ARUBA, were not clearly shown to benefit from an intervention at all,” he continued.

It would have been valuable for the researchers to stratify the study results by ruptured versus unruptured AVMs, Dr. Elkind said.

The study was funded by Medtronic. Dr. Spelle reported receiving honoraria from the company. Dr. Elkind disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The Onyx Liquid Embolic System (Medtronic) effectively occludes cerebral arteriovenous malformations (cAVMs), new observational data suggest. In a prospective, real-world study of more than 100 patients, use of the Onyx system was associated with a cure rate of 86% for cAVMs smaller than 3 cm.

“Endovascular treatment using Onyx is able to achieve, on its own, a very efficient cure rate with a low morbidity and mortality rate,” said investigator Laurent Spelle, MD, PhD, professor of neuroradiology at Paris-Saclay University and chair of NEURI, the Brain Vascular Center, Bicêtre Hospital, also in Paris.

Dr. Spelle presented the findings at the International Stroke Conference sponsored by the American Heart Association.
 

Prospective, multicenter study

Currently, the main treatment options for cAVM are embolization, neurosurgery, and radiosurgery. The Onyx liquid system, one method of providing embolization, uses a biocompatible ethylene vinyl alcohol copolymer.

It has been used in Europe for 22 years as a curative treatment and as a treatment before radiosurgery or neurosurgery. In the United States, Onyx is indicated for presurgical and preradiotherapy treatment only.

For this analysis, the researchers conducted a prospective, multicenter study to evaluate the long-term safety and efficacy of Onyx for the embolization of cAVM as curative treatment or preoperative preparation.

They enrolled 165 patients in the nonrandomized, observational study, which was conducted at 15 hospitals in France. Eligible participants had an untreated cAVM.

Patients were assigned to one of three groups, according to the hospital’s standard of care. One group underwent embolization with Onyx as curative treatment, one received Onyx as preparation for neurosurgery, and one underwent embolization with Onyx as preparation for radiosurgery.

The study’s safety endpoints were device- and procedure-related serious adverse events at 1 month after each embolization. The efficacy endpoints were recovery at 12 months after the last embolization or neurosurgery, or at a minimum of 36 months after radiosurgery.

The researchers defined morbidity as a worsening of modified Rankin Scale score of 2 or more points for patients presenting with baseline mRS of 0 or 1, or a worsening of 1 or more points for patients with an mRS of 2 or greater at baseline. An independent clinical events committee and core laboratory adjudicated the results.
 

‘A fantastic result’

In all, 140 patients were prospectively included, and 212 embolization procedures were performed. The population’s mean age was 41.4 years, and 60% of participants were men. About 61% of patients presented with symptoms, the most common of which were progressive neurologic deficit (41.2%) and headache (36.5%).

Approximately 64% of the cAVMs were ruptured. Most (75.7%) were smaller than 3 cm, and the remainder were between 3 and 6 cm. Most patients (59.3%) did not have an aneurysm.

Eight (3.8%) adverse events were associated with the use of Onyx. The rate of procedure-related neurologic serious adverse events was 7.1% within 1 month post embolization. Three deaths occurred (2.1%), one of which was considered device or procedure related.

A total of 87 patients underwent embolization alone, 14 of whom did not complete the study (2 died, 5 were lost to follow-up, and 7 withdrew). Of the 73 who completed the study, 58 (79.5%) had complete occlusion and full recovery at last follow-up. An additional 6.8% had 99% occlusion.

In addition, 3.4% of the population had significant morbidity, and 18.4% presented at baseline with mRS scores of 3-5. Of the latter group, 81.3% had mRS scores of 0-2 at last visit.

Of 21 patients who underwent subsequent neurosurgery, 18 completed follow-up. Of this group, 94.4% had complete occlusion. Of 32 patients receiving subsequent radiosurgery, 54.8% had complete occlusion, which was “a little bit disappointing,” said Dr. Spelle.

Overall, most patients (92.9%) had improved or stable mRS score. The overall mortality rate was 2.9%, and the rate of significant morbidity was 4.3%.

The rate of improved or stable mRS score was 94.3% for patients who underwent embolization alone, 85.7% for patients who also underwent neurosurgery, and 93.75% for patients who also underwent radiosurgery.

The mortality rate was 3.4% for patients who underwent embolization alone, 4.8% for patients who also underwent neurosurgery, and 0% for patients who also underwent radiosurgery.

The rate of significant morbidity was 2.3% for patients who underwent embolization alone, 9.5% for those who also underwent neurosurgery, and 6.25% for those who also underwent radiosurgery.

“We knew that this treatment was very effective, but this effectiveness was only known in a limited number of centers with a very high level of expertise,” said Dr. Spelle. “We were very pleasantly surprised that a larger-scale, multicenter study conducted in 15 different hospitals in France could achieve such a fantastic result.”

The study sites, however, were all departments in university hospitals with great experience in endovascular treatment of cAVM, he added.
 

Effective in unruptured AVMs?

Commenting on the findings, Mitchell Elkind, MD, professor of neurology and epidemiology, Columbia University, New York, said: “Arteriovenous malformations remain a relatively uncommon but serious cerebrovascular disorder. Any additional tool in the armamentarium to treat these lesions is welcome.”

The study results are encouraging, said Dr. Elkind, who was not involved in the study. They suggest that Onyx embolization can play an important role in the care of these patients. The treatment is associated with “low morbidity and excellent efficacy, particularly in combination with other surgical and radiographic approaches.”

The lack of a direct comparison with alternative embolization materials is a limitation of the study, however. “It is hard to compare Onyx to other agents based on these results,” said Dr. Elkind.

“It is also notable that one-third of the patients in the study had unruptured AVMs, which at least in one randomized trial, ARUBA, were not clearly shown to benefit from an intervention at all,” he continued.

It would have been valuable for the researchers to stratify the study results by ruptured versus unruptured AVMs, Dr. Elkind said.

The study was funded by Medtronic. Dr. Spelle reported receiving honoraria from the company. Dr. Elkind disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Adjunctive treatment with intravenous tirofiban does not improve clinical outcomes in patients with large-vessel occlusion stroke who undergo endovascular treatment within 24 hours of symptom onset, new data suggest.

In a randomized, phase 3 trial of more than 900 patients with acute ischemic stroke who underwent endovascular treatment, the median Modified Rankin Scale (mRS) score at 90 days was 3 both in patients who received tirofiban and those who received placebo.

“There was treatment-effect modification by stroke etiology, where patients with large-artery atherosclerosis [LAA] seemed to benefit from the treatment,” said investigator Raul Nogueira, MD, director of the University of Pittsburgh Medical Center Stroke Institute, during his presentation. “Tirofiban may improve endovascular treatment outcomes in LAA strokes. This obviously requires further investigation in future trials to confirm these findings.”

Results of the RESCUE BT trial were presented at the hybrid International Stroke Conference (ISC) 2022, which was held in New Orleans, Louisiana, and online.
 

Multicenter trial

Endovascular treatment greatly increases the rate of reperfusion and improves functional outcomes in patients with large-vessel occlusion stroke, the researchers note. But mechanical thrombectomy devices may injure the vessel wall, which can lead to clot formation and vessel reocclusion.

Platelet inhibition is a potential tactic for improving outcomes in this setting. Tirofiban, a glycoprotein IIb/IIIa receptor inhibitor, is a reversible antiplatelet drug with a rapid onset of action and a short half-life. The drug’s safety and efficacy in acute coronary syndrome are well established. There has been little evidence to date, however, on whether tirofiban improves outcomes among patients with large-vessel occlusion stroke.

The investigators conducted the Endovascular Treatment With Versus Without Tirofiban for Stroke Patients With Large Vessel Occlusion (RESCUE BT) trial to evaluate the safety and efficacy of IV tirofiban therapy before endovascular treatment in patients with large-vessel occlusion stroke. They recruited consecutive patients at 55 thrombectomy-capable hospitals in China.

Eligible patients were aged 18 years or older and presented within 24 hours of the time they were last seen when well. Baseline National Institutes of Health Stroke Scale (NIHSS) score was required to be 30 or lower, and all patients were required to have plans to undergo endovascular treatment. Eligible patients also had a baseline Alberta Stroke Program Early CT Score of 6 or greater.

Patients were randomized in groups of equal size to placebo or tirofiban and stratified by NIHSS score and occlusion site. Tirofiban was administered in a 10-mcg/kg bolus followed by continuous infusion (0.15 mcg/kg per min) for 24 hours. All patients underwent rapid endovascular treatment.

At the 20th hour after treatment initiation, antiplatelets were administered orally. IV study drug was stopped at the 24th hour.

The study’s primary endpoint was disability level, as measured by overall distribution of the 90-day mRS score. The primary safety endpoints were symptomatic intracranial hemorrhage (ICH) at 48 hours and mortality at 90 days.
 

Increased ICH risk

The investigators screened 1,970 patients and enrolled 950 into their study. The population’s median age was 67 years, and 58.8% of participants were men. In all, 463 participants were randomly assigned to tirofiban, and 485 to placebo. Two patients withdrew consent, and none were lost to follow-up.

Baseline characteristics were well balanced in both groups. One difference, however, was that large-vessel occlusion was less prevalent in the tirofiban group (42.6%) than in the control group (49.1%).

The primary endpoint did not differ between treatment groups. The adjusted common odds ratio was 1.09 (P = .46). “There is perhaps a sign that there is maybe a favorable effect of tirofiban,” said Dr. Nogueira. “However, this did not reach statistical significance.”

The rates of symptomatic ICH and mortality at 90 days did not differ significantly between groups. There was a trend toward a higher rate of symptomatic ICH in the tirofiban group, however. Moreover, the rate of any ICH was 34.9% in the tirofiban group and 28.0% in the control group (P = .02).

In prespecified subgroup analysis, the researchers found that, among patients with large-vessel occlusion, the adjusted common odds ratio was 1.43 favoring tirofiban treatment. No other subgroups showed significant differences.

“In the intention-to-treat analysis, tirofiban did not improve clinical outcomes in the overall study population,” said Dr. Nogueira. “It did increase the rate of any ICH and potentially increased the rate of symptomatic ICH as well.”

The ongoing RESCUE BT2 trial is examining the safety and efficacy of tirofiban in patients with acute ischemic stroke with non–large-vessel occlusion. As of Jan. 20, 781 patients had been assigned randomly to treatment, said Dr. Nogueira.
 

Patient selection crucial

Louise McCullough, MD, PhD, professor and chair of neurology at the University of Texas Health Science Center at Houston, said that the study was well designed.

“The concern with any kind of platelet therapy or adjunctive therapy is hemorrhage,” said Dr. McCullough, who was not involved in the research. The results in the overall population support this concern.

The location of the trial sites may have influenced the results. “It was a multicenter trial, but it was predominantly done in Asia, and we know that there are higher levels of intracranial atherosclerosis in that population,” said Dr. McCullough.

The results indicate a potential benefit of tirofiban in patients with large-vessel occlusion, yet this finding raises practical questions. “It’s often difficult to know if these patients have atherosclerosis until you’re actually in the vessel,” said Dr. McCullough.

The findings may not have immediate practical implications. “I don’t think that in routine clinical practice it’s something that we would offer until we can decide how safe it is,” said Dr. McCullough. The question will be how to select the populations in whom the drug will have the most efficacy.

The study was funded by the National Natural Science Foundation of China, Army Medical University, and Lunan Pharmaceutical Group, the manufacturer of tirofiban. Dr. Nogueira reported holding stock in Brainomix, Viz-AI, Corindus Vascular Robotics, Vesalio, Viz-AI, and Ceretrieve. He has received research support from Corindus Vascular Robotics. Dr. Nogueira reported other financial relationships related to Stryker Neurovascular, Medtronic, Cerenovus, and Phenox. Dr. McCullough has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Adjunctive treatment with intravenous tirofiban does not improve clinical outcomes in patients with large-vessel occlusion stroke who undergo endovascular treatment within 24 hours of symptom onset, new data suggest.

In a randomized, phase 3 trial of more than 900 patients with acute ischemic stroke who underwent endovascular treatment, the median Modified Rankin Scale (mRS) score at 90 days was 3 both in patients who received tirofiban and those who received placebo.

“There was treatment-effect modification by stroke etiology, where patients with large-artery atherosclerosis [LAA] seemed to benefit from the treatment,” said investigator Raul Nogueira, MD, director of the University of Pittsburgh Medical Center Stroke Institute, during his presentation. “Tirofiban may improve endovascular treatment outcomes in LAA strokes. This obviously requires further investigation in future trials to confirm these findings.”

Results of the RESCUE BT trial were presented at the hybrid International Stroke Conference (ISC) 2022, which was held in New Orleans, Louisiana, and online.
 

Multicenter trial

Endovascular treatment greatly increases the rate of reperfusion and improves functional outcomes in patients with large-vessel occlusion stroke, the researchers note. But mechanical thrombectomy devices may injure the vessel wall, which can lead to clot formation and vessel reocclusion.

Platelet inhibition is a potential tactic for improving outcomes in this setting. Tirofiban, a glycoprotein IIb/IIIa receptor inhibitor, is a reversible antiplatelet drug with a rapid onset of action and a short half-life. The drug’s safety and efficacy in acute coronary syndrome are well established. There has been little evidence to date, however, on whether tirofiban improves outcomes among patients with large-vessel occlusion stroke.

The investigators conducted the Endovascular Treatment With Versus Without Tirofiban for Stroke Patients With Large Vessel Occlusion (RESCUE BT) trial to evaluate the safety and efficacy of IV tirofiban therapy before endovascular treatment in patients with large-vessel occlusion stroke. They recruited consecutive patients at 55 thrombectomy-capable hospitals in China.

Eligible patients were aged 18 years or older and presented within 24 hours of the time they were last seen when well. Baseline National Institutes of Health Stroke Scale (NIHSS) score was required to be 30 or lower, and all patients were required to have plans to undergo endovascular treatment. Eligible patients also had a baseline Alberta Stroke Program Early CT Score of 6 or greater.

Patients were randomized in groups of equal size to placebo or tirofiban and stratified by NIHSS score and occlusion site. Tirofiban was administered in a 10-mcg/kg bolus followed by continuous infusion (0.15 mcg/kg per min) for 24 hours. All patients underwent rapid endovascular treatment.

At the 20th hour after treatment initiation, antiplatelets were administered orally. IV study drug was stopped at the 24th hour.

The study’s primary endpoint was disability level, as measured by overall distribution of the 90-day mRS score. The primary safety endpoints were symptomatic intracranial hemorrhage (ICH) at 48 hours and mortality at 90 days.
 

Increased ICH risk

The investigators screened 1,970 patients and enrolled 950 into their study. The population’s median age was 67 years, and 58.8% of participants were men. In all, 463 participants were randomly assigned to tirofiban, and 485 to placebo. Two patients withdrew consent, and none were lost to follow-up.

Baseline characteristics were well balanced in both groups. One difference, however, was that large-vessel occlusion was less prevalent in the tirofiban group (42.6%) than in the control group (49.1%).

The primary endpoint did not differ between treatment groups. The adjusted common odds ratio was 1.09 (P = .46). “There is perhaps a sign that there is maybe a favorable effect of tirofiban,” said Dr. Nogueira. “However, this did not reach statistical significance.”

The rates of symptomatic ICH and mortality at 90 days did not differ significantly between groups. There was a trend toward a higher rate of symptomatic ICH in the tirofiban group, however. Moreover, the rate of any ICH was 34.9% in the tirofiban group and 28.0% in the control group (P = .02).

In prespecified subgroup analysis, the researchers found that, among patients with large-vessel occlusion, the adjusted common odds ratio was 1.43 favoring tirofiban treatment. No other subgroups showed significant differences.

“In the intention-to-treat analysis, tirofiban did not improve clinical outcomes in the overall study population,” said Dr. Nogueira. “It did increase the rate of any ICH and potentially increased the rate of symptomatic ICH as well.”

The ongoing RESCUE BT2 trial is examining the safety and efficacy of tirofiban in patients with acute ischemic stroke with non–large-vessel occlusion. As of Jan. 20, 781 patients had been assigned randomly to treatment, said Dr. Nogueira.
 

Patient selection crucial

Louise McCullough, MD, PhD, professor and chair of neurology at the University of Texas Health Science Center at Houston, said that the study was well designed.

“The concern with any kind of platelet therapy or adjunctive therapy is hemorrhage,” said Dr. McCullough, who was not involved in the research. The results in the overall population support this concern.

The location of the trial sites may have influenced the results. “It was a multicenter trial, but it was predominantly done in Asia, and we know that there are higher levels of intracranial atherosclerosis in that population,” said Dr. McCullough.

The results indicate a potential benefit of tirofiban in patients with large-vessel occlusion, yet this finding raises practical questions. “It’s often difficult to know if these patients have atherosclerosis until you’re actually in the vessel,” said Dr. McCullough.

The findings may not have immediate practical implications. “I don’t think that in routine clinical practice it’s something that we would offer until we can decide how safe it is,” said Dr. McCullough. The question will be how to select the populations in whom the drug will have the most efficacy.

The study was funded by the National Natural Science Foundation of China, Army Medical University, and Lunan Pharmaceutical Group, the manufacturer of tirofiban. Dr. Nogueira reported holding stock in Brainomix, Viz-AI, Corindus Vascular Robotics, Vesalio, Viz-AI, and Ceretrieve. He has received research support from Corindus Vascular Robotics. Dr. Nogueira reported other financial relationships related to Stryker Neurovascular, Medtronic, Cerenovus, and Phenox. Dr. McCullough has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Adjunctive treatment with intravenous tirofiban does not improve clinical outcomes in patients with large-vessel occlusion stroke who undergo endovascular treatment within 24 hours of symptom onset, new data suggest.

In a randomized, phase 3 trial of more than 900 patients with acute ischemic stroke who underwent endovascular treatment, the median Modified Rankin Scale (mRS) score at 90 days was 3 both in patients who received tirofiban and those who received placebo.

“There was treatment-effect modification by stroke etiology, where patients with large-artery atherosclerosis [LAA] seemed to benefit from the treatment,” said investigator Raul Nogueira, MD, director of the University of Pittsburgh Medical Center Stroke Institute, during his presentation. “Tirofiban may improve endovascular treatment outcomes in LAA strokes. This obviously requires further investigation in future trials to confirm these findings.”

Results of the RESCUE BT trial were presented at the hybrid International Stroke Conference (ISC) 2022, which was held in New Orleans, Louisiana, and online.
 

Multicenter trial

Endovascular treatment greatly increases the rate of reperfusion and improves functional outcomes in patients with large-vessel occlusion stroke, the researchers note. But mechanical thrombectomy devices may injure the vessel wall, which can lead to clot formation and vessel reocclusion.

Platelet inhibition is a potential tactic for improving outcomes in this setting. Tirofiban, a glycoprotein IIb/IIIa receptor inhibitor, is a reversible antiplatelet drug with a rapid onset of action and a short half-life. The drug’s safety and efficacy in acute coronary syndrome are well established. There has been little evidence to date, however, on whether tirofiban improves outcomes among patients with large-vessel occlusion stroke.

The investigators conducted the Endovascular Treatment With Versus Without Tirofiban for Stroke Patients With Large Vessel Occlusion (RESCUE BT) trial to evaluate the safety and efficacy of IV tirofiban therapy before endovascular treatment in patients with large-vessel occlusion stroke. They recruited consecutive patients at 55 thrombectomy-capable hospitals in China.

Eligible patients were aged 18 years or older and presented within 24 hours of the time they were last seen when well. Baseline National Institutes of Health Stroke Scale (NIHSS) score was required to be 30 or lower, and all patients were required to have plans to undergo endovascular treatment. Eligible patients also had a baseline Alberta Stroke Program Early CT Score of 6 or greater.

Patients were randomized in groups of equal size to placebo or tirofiban and stratified by NIHSS score and occlusion site. Tirofiban was administered in a 10-mcg/kg bolus followed by continuous infusion (0.15 mcg/kg per min) for 24 hours. All patients underwent rapid endovascular treatment.

At the 20th hour after treatment initiation, antiplatelets were administered orally. IV study drug was stopped at the 24th hour.

The study’s primary endpoint was disability level, as measured by overall distribution of the 90-day mRS score. The primary safety endpoints were symptomatic intracranial hemorrhage (ICH) at 48 hours and mortality at 90 days.
 

Increased ICH risk

The investigators screened 1,970 patients and enrolled 950 into their study. The population’s median age was 67 years, and 58.8% of participants were men. In all, 463 participants were randomly assigned to tirofiban, and 485 to placebo. Two patients withdrew consent, and none were lost to follow-up.

Baseline characteristics were well balanced in both groups. One difference, however, was that large-vessel occlusion was less prevalent in the tirofiban group (42.6%) than in the control group (49.1%).

The primary endpoint did not differ between treatment groups. The adjusted common odds ratio was 1.09 (P = .46). “There is perhaps a sign that there is maybe a favorable effect of tirofiban,” said Dr. Nogueira. “However, this did not reach statistical significance.”

The rates of symptomatic ICH and mortality at 90 days did not differ significantly between groups. There was a trend toward a higher rate of symptomatic ICH in the tirofiban group, however. Moreover, the rate of any ICH was 34.9% in the tirofiban group and 28.0% in the control group (P = .02).

In prespecified subgroup analysis, the researchers found that, among patients with large-vessel occlusion, the adjusted common odds ratio was 1.43 favoring tirofiban treatment. No other subgroups showed significant differences.

“In the intention-to-treat analysis, tirofiban did not improve clinical outcomes in the overall study population,” said Dr. Nogueira. “It did increase the rate of any ICH and potentially increased the rate of symptomatic ICH as well.”

The ongoing RESCUE BT2 trial is examining the safety and efficacy of tirofiban in patients with acute ischemic stroke with non–large-vessel occlusion. As of Jan. 20, 781 patients had been assigned randomly to treatment, said Dr. Nogueira.
 

Patient selection crucial

Louise McCullough, MD, PhD, professor and chair of neurology at the University of Texas Health Science Center at Houston, said that the study was well designed.

“The concern with any kind of platelet therapy or adjunctive therapy is hemorrhage,” said Dr. McCullough, who was not involved in the research. The results in the overall population support this concern.

The location of the trial sites may have influenced the results. “It was a multicenter trial, but it was predominantly done in Asia, and we know that there are higher levels of intracranial atherosclerosis in that population,” said Dr. McCullough.

The results indicate a potential benefit of tirofiban in patients with large-vessel occlusion, yet this finding raises practical questions. “It’s often difficult to know if these patients have atherosclerosis until you’re actually in the vessel,” said Dr. McCullough.

The findings may not have immediate practical implications. “I don’t think that in routine clinical practice it’s something that we would offer until we can decide how safe it is,” said Dr. McCullough. The question will be how to select the populations in whom the drug will have the most efficacy.

The study was funded by the National Natural Science Foundation of China, Army Medical University, and Lunan Pharmaceutical Group, the manufacturer of tirofiban. Dr. Nogueira reported holding stock in Brainomix, Viz-AI, Corindus Vascular Robotics, Vesalio, Viz-AI, and Ceretrieve. He has received research support from Corindus Vascular Robotics. Dr. Nogueira reported other financial relationships related to Stryker Neurovascular, Medtronic, Cerenovus, and Phenox. Dr. McCullough has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The newly approved insomnia drug daridorexant (Quviviq) improves sleep onset in adults, new phase 3 data suggest.  In the first of two studies, a 50-mg dose of daridorexant was associated with a reduction in latency to persistent sleep (LPS) of 11.7 minutes at month 3 versus placebo. The drug also was associated with improved daytime function.

Based on these results, the Food and Drug Administration approved daridorexant for the treatment of insomnia in adults earlier in January.

“The study shows that it is a really good drug that works differently from most other drugs,” said Emmanuel Mignot, MD, PhD, professor of sleep medicine at Stanford (Calif.) University. “It’s more specific to sleep,” Dr. Mignot added.

The findings were published in the February issue of The Lancet Neurology.
 

Two trials, three doses

Daridorexant is a dual orexin receptor antagonist intended to reduce excessive wakefulness. The investigators hypothesized that, because of its therapeutic target, the drug would not cause sleepiness on the morning after administration.

To examine daridorexant’s safety and efficacy, the researchers conducted two double-blind, parallel-group, phase 3 trials. Eligible participants were aged 18 years or older, had moderate to severe insomnia disorder, and had a self-reported history of disturbed sleep at least 3 nights per week for at least 3 months before screening.

In study 1, investigators randomly assigned participants in groups of equal size to daridorexant 25 mg, 50 mg, or placebo. In study 2, participants were randomly assigned to daridorexant 10 mg, 25 mg, or placebo.

During a placebo run-in period, participants underwent polysomnography on two consecutive nights to define baseline values. At the end of months 1 and 3 of the treatment period, participants again underwent 2 nights of polysomnography. A final night of polysomnography occurred during the placebo run-out period.

Self-assessments included the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). This questionnaire, to which participants responded daily, is designed to measure the daytime impairments related to insomnia. The IDSIQ questions focus on sleepiness, mood, alertness, and cognition.

The study’s primary endpoints were change from baseline in wake after sleep onset (WASO) and LPS at months 1 and 3. Secondary endpoints were change from baseline in self-reported total sleep time and change in the IDSIQ sleepiness domain score at months 1 and 3.

The investigators enrolled 930 participants in study 1 and 924 in study 2. In each study, more than two-thirds of participants were women, 39% were aged 65 or older, and demographic and baseline characteristics were similar between treatment groups.
 

Dose-dependent effects

At month 1 in study 1, WASO was reduced by 22.8 minutes (P < .0001) in patients who received the 50-mg dose and by 12.2 minutes (P < .0001) in the 25-mg dose. At month 3, WASO was reduced by 18.3 minutes (P < .0001) in those assigned to 50 mg and by 11.9 minutes (P < .0001) in those assigned to 25 mg.

LPS was reduced by 11.4 minutes (P < .0001) at month 1 and by 11.7 minutes (P < .0001) at month 3 with the 50-mg dose versus placebo. LPS was reduced by 8.3 minutes (P = .0005) at month 1 and by 7.6 minutes (P = .0015) at month 3 with the 25-mg dose versus placebo.

At both time points, self-reported total sleep time was significantly increased and the IDSIQ sleepiness score significantly improved with the 50-mg dose. The 25-mg dose was associated with significant improvements in self-reported total sleep time at both time points, but not with significant improvements in IDSIQ sleepiness score.

In study 2, the 25-mg dose was associated with significant reductions in WASO at month 1 (11.6 minutes, P = .0001) and month 3 (10.3 minutes, P = .0028) compared with placebo. The 25-mg dose was not associated with significant differences in LPS at either time point, however.

Similarly, the 25-mg dose was associated with improvements in self-reported total sleep time, but not with the IDSIQ sleepiness score. The 10-mg dose was not associated with improvements on any endpoint compared with placebo.
 

Longer studies needed

In an accompanying editorial, Kai Spiegelhalder, PhD, University of Freiburg, Germany, and colleagues pointed out that although insomnia disorder is defined by self-reported difficulty initiating or maintaining sleep, none of the primary or secondary endpoints in these trials addressed these symptoms.

However, Dr. Mignot noted the use of the IDSIQ scale is the most interesting aspect of the study. Although difficulty with concentration and mood impairment are major symptoms of insomnia, they are often neglected. “This drug was reversing the daytime impairment that insomniacs have,” said Dr. Mignot. “We now need to systematically study people not only for the effect on sleep, but also that it makes them feel better the day after.”

He added that most of the current hypnotics were not developed to treat insomnia. Daridorexant, in contrast, targets the wake-promoting orexin system. “It works more selectively on sleep and not on other things. Most of the other sleeping pills have more complex effects on the brain,” Dr. Mignot said.

Commenting on the study, John Winkelman, MD, PhD, professor of psychiatry at Harvard Medical School, Boston, said the low prevalence of side effects associated with daridorexant was remarkable. “This is not what most of the benzodiazepine receptor agonists looked like,” said Dr. Winkelman, who was not involved with the research.

Many insomnia drugs affect transmitter systems that are widespread in the brain, thus provoking side effects. But orexin-receptor antagonists “don’t seem to produce a lot of side effects,” he noted.

Although the study duration was reasonable, longer studies will be necessary, he added. “And it would be nice to see comparative data. Prescribers want to see some context.” said Dr. Winkelman.

The study was funded by Idorsia Pharmaceuticals. Dr. Mignot reported receiving research or clinical trial funding from Axsome, Jazz Pharmaceuticals, Avadel, Apple, Huami, Sunovion, and Takeda. He has also received consulting fees or speakers’ conference reimbursement from Idorsia, Centessa Pharmaceuticals, Jazz Pharmaceuticals, Avadel, Dreem, and Takeda. Dr. Winkelman has consulted for Idorsia and has participated in investigator-initiated studies supported by Merck.

A version of this article first appeared on Medscape.com.

The newly approved insomnia drug daridorexant (Quviviq) improves sleep onset in adults, new phase 3 data suggest.  In the first of two studies, a 50-mg dose of daridorexant was associated with a reduction in latency to persistent sleep (LPS) of 11.7 minutes at month 3 versus placebo. The drug also was associated with improved daytime function.

Based on these results, the Food and Drug Administration approved daridorexant for the treatment of insomnia in adults earlier in January.

“The study shows that it is a really good drug that works differently from most other drugs,” said Emmanuel Mignot, MD, PhD, professor of sleep medicine at Stanford (Calif.) University. “It’s more specific to sleep,” Dr. Mignot added.

The findings were published in the February issue of The Lancet Neurology.
 

Two trials, three doses

Daridorexant is a dual orexin receptor antagonist intended to reduce excessive wakefulness. The investigators hypothesized that, because of its therapeutic target, the drug would not cause sleepiness on the morning after administration.

To examine daridorexant’s safety and efficacy, the researchers conducted two double-blind, parallel-group, phase 3 trials. Eligible participants were aged 18 years or older, had moderate to severe insomnia disorder, and had a self-reported history of disturbed sleep at least 3 nights per week for at least 3 months before screening.

In study 1, investigators randomly assigned participants in groups of equal size to daridorexant 25 mg, 50 mg, or placebo. In study 2, participants were randomly assigned to daridorexant 10 mg, 25 mg, or placebo.

During a placebo run-in period, participants underwent polysomnography on two consecutive nights to define baseline values. At the end of months 1 and 3 of the treatment period, participants again underwent 2 nights of polysomnography. A final night of polysomnography occurred during the placebo run-out period.

Self-assessments included the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). This questionnaire, to which participants responded daily, is designed to measure the daytime impairments related to insomnia. The IDSIQ questions focus on sleepiness, mood, alertness, and cognition.

The study’s primary endpoints were change from baseline in wake after sleep onset (WASO) and LPS at months 1 and 3. Secondary endpoints were change from baseline in self-reported total sleep time and change in the IDSIQ sleepiness domain score at months 1 and 3.

The investigators enrolled 930 participants in study 1 and 924 in study 2. In each study, more than two-thirds of participants were women, 39% were aged 65 or older, and demographic and baseline characteristics were similar between treatment groups.
 

Dose-dependent effects

At month 1 in study 1, WASO was reduced by 22.8 minutes (P < .0001) in patients who received the 50-mg dose and by 12.2 minutes (P < .0001) in the 25-mg dose. At month 3, WASO was reduced by 18.3 minutes (P < .0001) in those assigned to 50 mg and by 11.9 minutes (P < .0001) in those assigned to 25 mg.

LPS was reduced by 11.4 minutes (P < .0001) at month 1 and by 11.7 minutes (P < .0001) at month 3 with the 50-mg dose versus placebo. LPS was reduced by 8.3 minutes (P = .0005) at month 1 and by 7.6 minutes (P = .0015) at month 3 with the 25-mg dose versus placebo.

At both time points, self-reported total sleep time was significantly increased and the IDSIQ sleepiness score significantly improved with the 50-mg dose. The 25-mg dose was associated with significant improvements in self-reported total sleep time at both time points, but not with significant improvements in IDSIQ sleepiness score.

In study 2, the 25-mg dose was associated with significant reductions in WASO at month 1 (11.6 minutes, P = .0001) and month 3 (10.3 minutes, P = .0028) compared with placebo. The 25-mg dose was not associated with significant differences in LPS at either time point, however.

Similarly, the 25-mg dose was associated with improvements in self-reported total sleep time, but not with the IDSIQ sleepiness score. The 10-mg dose was not associated with improvements on any endpoint compared with placebo.
 

Longer studies needed

In an accompanying editorial, Kai Spiegelhalder, PhD, University of Freiburg, Germany, and colleagues pointed out that although insomnia disorder is defined by self-reported difficulty initiating or maintaining sleep, none of the primary or secondary endpoints in these trials addressed these symptoms.

However, Dr. Mignot noted the use of the IDSIQ scale is the most interesting aspect of the study. Although difficulty with concentration and mood impairment are major symptoms of insomnia, they are often neglected. “This drug was reversing the daytime impairment that insomniacs have,” said Dr. Mignot. “We now need to systematically study people not only for the effect on sleep, but also that it makes them feel better the day after.”

He added that most of the current hypnotics were not developed to treat insomnia. Daridorexant, in contrast, targets the wake-promoting orexin system. “It works more selectively on sleep and not on other things. Most of the other sleeping pills have more complex effects on the brain,” Dr. Mignot said.

Commenting on the study, John Winkelman, MD, PhD, professor of psychiatry at Harvard Medical School, Boston, said the low prevalence of side effects associated with daridorexant was remarkable. “This is not what most of the benzodiazepine receptor agonists looked like,” said Dr. Winkelman, who was not involved with the research.

Many insomnia drugs affect transmitter systems that are widespread in the brain, thus provoking side effects. But orexin-receptor antagonists “don’t seem to produce a lot of side effects,” he noted.

Although the study duration was reasonable, longer studies will be necessary, he added. “And it would be nice to see comparative data. Prescribers want to see some context.” said Dr. Winkelman.

The study was funded by Idorsia Pharmaceuticals. Dr. Mignot reported receiving research or clinical trial funding from Axsome, Jazz Pharmaceuticals, Avadel, Apple, Huami, Sunovion, and Takeda. He has also received consulting fees or speakers’ conference reimbursement from Idorsia, Centessa Pharmaceuticals, Jazz Pharmaceuticals, Avadel, Dreem, and Takeda. Dr. Winkelman has consulted for Idorsia and has participated in investigator-initiated studies supported by Merck.

A version of this article first appeared on Medscape.com.

The newly approved insomnia drug daridorexant (Quviviq) improves sleep onset in adults, new phase 3 data suggest.  In the first of two studies, a 50-mg dose of daridorexant was associated with a reduction in latency to persistent sleep (LPS) of 11.7 minutes at month 3 versus placebo. The drug also was associated with improved daytime function.

Based on these results, the Food and Drug Administration approved daridorexant for the treatment of insomnia in adults earlier in January.

“The study shows that it is a really good drug that works differently from most other drugs,” said Emmanuel Mignot, MD, PhD, professor of sleep medicine at Stanford (Calif.) University. “It’s more specific to sleep,” Dr. Mignot added.

The findings were published in the February issue of The Lancet Neurology.
 

Two trials, three doses

Daridorexant is a dual orexin receptor antagonist intended to reduce excessive wakefulness. The investigators hypothesized that, because of its therapeutic target, the drug would not cause sleepiness on the morning after administration.

To examine daridorexant’s safety and efficacy, the researchers conducted two double-blind, parallel-group, phase 3 trials. Eligible participants were aged 18 years or older, had moderate to severe insomnia disorder, and had a self-reported history of disturbed sleep at least 3 nights per week for at least 3 months before screening.

In study 1, investigators randomly assigned participants in groups of equal size to daridorexant 25 mg, 50 mg, or placebo. In study 2, participants were randomly assigned to daridorexant 10 mg, 25 mg, or placebo.

During a placebo run-in period, participants underwent polysomnography on two consecutive nights to define baseline values. At the end of months 1 and 3 of the treatment period, participants again underwent 2 nights of polysomnography. A final night of polysomnography occurred during the placebo run-out period.

Self-assessments included the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). This questionnaire, to which participants responded daily, is designed to measure the daytime impairments related to insomnia. The IDSIQ questions focus on sleepiness, mood, alertness, and cognition.

The study’s primary endpoints were change from baseline in wake after sleep onset (WASO) and LPS at months 1 and 3. Secondary endpoints were change from baseline in self-reported total sleep time and change in the IDSIQ sleepiness domain score at months 1 and 3.

The investigators enrolled 930 participants in study 1 and 924 in study 2. In each study, more than two-thirds of participants were women, 39% were aged 65 or older, and demographic and baseline characteristics were similar between treatment groups.
 

Dose-dependent effects

At month 1 in study 1, WASO was reduced by 22.8 minutes (P < .0001) in patients who received the 50-mg dose and by 12.2 minutes (P < .0001) in the 25-mg dose. At month 3, WASO was reduced by 18.3 minutes (P < .0001) in those assigned to 50 mg and by 11.9 minutes (P < .0001) in those assigned to 25 mg.

LPS was reduced by 11.4 minutes (P < .0001) at month 1 and by 11.7 minutes (P < .0001) at month 3 with the 50-mg dose versus placebo. LPS was reduced by 8.3 minutes (P = .0005) at month 1 and by 7.6 minutes (P = .0015) at month 3 with the 25-mg dose versus placebo.

At both time points, self-reported total sleep time was significantly increased and the IDSIQ sleepiness score significantly improved with the 50-mg dose. The 25-mg dose was associated with significant improvements in self-reported total sleep time at both time points, but not with significant improvements in IDSIQ sleepiness score.

In study 2, the 25-mg dose was associated with significant reductions in WASO at month 1 (11.6 minutes, P = .0001) and month 3 (10.3 minutes, P = .0028) compared with placebo. The 25-mg dose was not associated with significant differences in LPS at either time point, however.

Similarly, the 25-mg dose was associated with improvements in self-reported total sleep time, but not with the IDSIQ sleepiness score. The 10-mg dose was not associated with improvements on any endpoint compared with placebo.
 

Longer studies needed

In an accompanying editorial, Kai Spiegelhalder, PhD, University of Freiburg, Germany, and colleagues pointed out that although insomnia disorder is defined by self-reported difficulty initiating or maintaining sleep, none of the primary or secondary endpoints in these trials addressed these symptoms.

However, Dr. Mignot noted the use of the IDSIQ scale is the most interesting aspect of the study. Although difficulty with concentration and mood impairment are major symptoms of insomnia, they are often neglected. “This drug was reversing the daytime impairment that insomniacs have,” said Dr. Mignot. “We now need to systematically study people not only for the effect on sleep, but also that it makes them feel better the day after.”

He added that most of the current hypnotics were not developed to treat insomnia. Daridorexant, in contrast, targets the wake-promoting orexin system. “It works more selectively on sleep and not on other things. Most of the other sleeping pills have more complex effects on the brain,” Dr. Mignot said.

Commenting on the study, John Winkelman, MD, PhD, professor of psychiatry at Harvard Medical School, Boston, said the low prevalence of side effects associated with daridorexant was remarkable. “This is not what most of the benzodiazepine receptor agonists looked like,” said Dr. Winkelman, who was not involved with the research.

Many insomnia drugs affect transmitter systems that are widespread in the brain, thus provoking side effects. But orexin-receptor antagonists “don’t seem to produce a lot of side effects,” he noted.

Although the study duration was reasonable, longer studies will be necessary, he added. “And it would be nice to see comparative data. Prescribers want to see some context.” said Dr. Winkelman.

The study was funded by Idorsia Pharmaceuticals. Dr. Mignot reported receiving research or clinical trial funding from Axsome, Jazz Pharmaceuticals, Avadel, Apple, Huami, Sunovion, and Takeda. He has also received consulting fees or speakers’ conference reimbursement from Idorsia, Centessa Pharmaceuticals, Jazz Pharmaceuticals, Avadel, Dreem, and Takeda. Dr. Winkelman has consulted for Idorsia and has participated in investigator-initiated studies supported by Merck.

A version of this article first appeared on Medscape.com.

Inpatient and outpatient treatments of transient ischemic attack (TIA) or minor ischemic stroke (mIS) yield comparable safety outcomes, new research suggests. In a meta-analysis of more than 200,000 patients with TIA or mIS, risk for subsequent stroke within 90 days was 2.1% for those treated in a TIA clinic versus 2.8% for patients treated in inpatient settings, which was not significantly different. The risk for patients treated in an emergency department was higher, at 3.5%.

“The message is that if you do the correct risk stratification and then triage patients based on their risk profile, you can safely discharge and have a timely follow-up for the patients who have low risk for a subsequent event,” said coinvestigator Ramin Zand, MD, vascular neurologist and stroke attending physician at Geisinger Health System, Danville, Pennsylvania.

The findings were published online Jan. 5 in JAMA Network Open.
 

Higher risk in EDs

There is currently no consensus on the care protocol for patients with TIA or mIS, and the rate at which these patients are hospitalized varies by region, hospital, and practitioner, the investigators noted.

Previous studies have indicated that outpatient management of certain individuals with TIA can be safe and cost-effective.

The current researchers searched for retrospective and prospective studies of adult patients that provided information about ischemic stroke after TIA or mIS. Studies that used time- and tissue-based definitions of TIA were included, as well as studies that used various definitions of mIS.

The investigators examined care provided at TIA clinics, inpatient settings (such as medical-surgical units, stroke units, or observation units), EDs, and unspecified settings. Their main aim was to compare outcomes between TIA clinics and inpatient settings.

In all, 226,683 patients (recruited between 1981 and 2018) from 71 studies were included in the meta-analysis. The studies examined 101 cohorts, 24 of which were studied prospectively. Among the 5,636 patients who received care in TIA clinics, the mean age was 65.7 years, and 50.8% of this group were men. Among the 130,139 inpatients, the mean age was 78.3 years, and 61.6% of the group were women.

Results showed no significant difference in risk for subsequent stroke between patients treated in the inpatient and outpatient settings.

Among patients treated in a TIA clinic, risk for subsequent stroke following a TIA or mIS was 0.3% within 2 days, 1.0% within 7 days, 1.3% within 30 days, and 2.1% within 90 days. Among those treated as inpatients, risk for subsequent stroke was 0.5% within 2 days, 1.2% within 7 days, 1.6% within 30 days, and 2.8% within 90 days.

Risk for subsequent stroke was higher among patients treated in the ED and in unspecified settings. At the EDs, the risk was 1.9% within 2 days, 3.4% within 7 days, 3.5% within 30 days, and 3.5% within 90 days. Among those treated in unspecified settings, the risk was 2.2% within 2 days, 3.4% within 7 days, 4.2% within 30 days, and 6.0% within 90 days.

Patients treated in the ED also had a significantly higher risk for subsequent stroke at 2 and 7 days, compared with those treated in inpatient settings and a significantly higher risk for subsequent stroke at 2, 7, and 90 days, compared with those treated in TIA clinics.
 

‘Most comprehensive look’

“This is the most comprehensive look at all the studies to try and answer this research question,” said Dr. Zand. The results were similar to what was expected, he added.

The infrastructure and resources differed among the sites at which the various studies were conducted, and the investigators adjusted for these differences as much as possible, Dr. Zand noted. A certain amount of selection bias may remain, but it does not affect the overall conclusion, he added.

“Timely outpatient care among low-risk TIA patients is both feasible and safe,” he said.

Dr. Zand noted that the findings have implications not only for patient management but also for the management of the health system. “It’s not feasible nor desirable to admit all the TIA patients, especially with the lessons that we learned from COVID, the burden on the health systems, and the fact that many hospitals are operating at full capacity right now,” he said.

The recommendation is to hospitalize high-risk patients and provide outpatient evaluation and workup to low-risk patients, he added. “This is exactly what we saw in this study,” Dr. Zand said.
 

Selection bias?

Commenting on the research, Louis R. Caplan, MD, professor of neurology at Harvard Medical School, Boston, noted that evaluation of patients with TIA or mIS “can be done very well as an outpatient” if clinicians have experienced personnel, the outpatient facilities to do the studies necessary, and criteria in place for deciding who to admit or not admit.

However, the decision on whether to choose an inpatient or outpatient approach for a particular patient is complicated, said Dr. Caplan, who was not involved with the research.

Clinicians must consider factors such as whether the patient is mobile, has a car, or has a significant other. The patient’s symptoms and past illnesses also influence the decision, he added.

Dr. Caplan noted that in the meta-analysis, far fewer patients were seen in the TIA clinics than were seen in the inpatient setting. In addition, none of the studies used uniform criteria to determine which patients should undergo workup as outpatients and which as inpatients. “There was a lot of selection bias that may have had nothing to do with how sick the person was,” Dr. Caplan said.

In addition, few hospitals in the United States have an outpatient TIA clinic, he noted. Most of the studies of TIA clinics that the researchers examined were conducted in Europe. “It’s easier to do [that] in Europe because of their socialized medicine,” said Dr. Caplan.

But TIA clinics should be more widespread in the U.S., he added. “Insurance companies should be willing to pay for comparable facilities, inpatient and outpatient,” he said.

The study was conducted without external funding. Dr. Zand reported no relevant financial relationships. Dr. Caplan was an investigator for TIAregistry.org, which analyzed the outcomes of treatment in TIA clinics in Europe.

A version of this article first appeared on Medscape.com.

Inpatient and outpatient treatments of transient ischemic attack (TIA) or minor ischemic stroke (mIS) yield comparable safety outcomes, new research suggests. In a meta-analysis of more than 200,000 patients with TIA or mIS, risk for subsequent stroke within 90 days was 2.1% for those treated in a TIA clinic versus 2.8% for patients treated in inpatient settings, which was not significantly different. The risk for patients treated in an emergency department was higher, at 3.5%.

“The message is that if you do the correct risk stratification and then triage patients based on their risk profile, you can safely discharge and have a timely follow-up for the patients who have low risk for a subsequent event,” said coinvestigator Ramin Zand, MD, vascular neurologist and stroke attending physician at Geisinger Health System, Danville, Pennsylvania.

The findings were published online Jan. 5 in JAMA Network Open.
 

Higher risk in EDs

There is currently no consensus on the care protocol for patients with TIA or mIS, and the rate at which these patients are hospitalized varies by region, hospital, and practitioner, the investigators noted.

Previous studies have indicated that outpatient management of certain individuals with TIA can be safe and cost-effective.

The current researchers searched for retrospective and prospective studies of adult patients that provided information about ischemic stroke after TIA or mIS. Studies that used time- and tissue-based definitions of TIA were included, as well as studies that used various definitions of mIS.

The investigators examined care provided at TIA clinics, inpatient settings (such as medical-surgical units, stroke units, or observation units), EDs, and unspecified settings. Their main aim was to compare outcomes between TIA clinics and inpatient settings.

In all, 226,683 patients (recruited between 1981 and 2018) from 71 studies were included in the meta-analysis. The studies examined 101 cohorts, 24 of which were studied prospectively. Among the 5,636 patients who received care in TIA clinics, the mean age was 65.7 years, and 50.8% of this group were men. Among the 130,139 inpatients, the mean age was 78.3 years, and 61.6% of the group were women.

Results showed no significant difference in risk for subsequent stroke between patients treated in the inpatient and outpatient settings.

Among patients treated in a TIA clinic, risk for subsequent stroke following a TIA or mIS was 0.3% within 2 days, 1.0% within 7 days, 1.3% within 30 days, and 2.1% within 90 days. Among those treated as inpatients, risk for subsequent stroke was 0.5% within 2 days, 1.2% within 7 days, 1.6% within 30 days, and 2.8% within 90 days.

Risk for subsequent stroke was higher among patients treated in the ED and in unspecified settings. At the EDs, the risk was 1.9% within 2 days, 3.4% within 7 days, 3.5% within 30 days, and 3.5% within 90 days. Among those treated in unspecified settings, the risk was 2.2% within 2 days, 3.4% within 7 days, 4.2% within 30 days, and 6.0% within 90 days.

Patients treated in the ED also had a significantly higher risk for subsequent stroke at 2 and 7 days, compared with those treated in inpatient settings and a significantly higher risk for subsequent stroke at 2, 7, and 90 days, compared with those treated in TIA clinics.
 

‘Most comprehensive look’

“This is the most comprehensive look at all the studies to try and answer this research question,” said Dr. Zand. The results were similar to what was expected, he added.

The infrastructure and resources differed among the sites at which the various studies were conducted, and the investigators adjusted for these differences as much as possible, Dr. Zand noted. A certain amount of selection bias may remain, but it does not affect the overall conclusion, he added.

“Timely outpatient care among low-risk TIA patients is both feasible and safe,” he said.

Dr. Zand noted that the findings have implications not only for patient management but also for the management of the health system. “It’s not feasible nor desirable to admit all the TIA patients, especially with the lessons that we learned from COVID, the burden on the health systems, and the fact that many hospitals are operating at full capacity right now,” he said.

The recommendation is to hospitalize high-risk patients and provide outpatient evaluation and workup to low-risk patients, he added. “This is exactly what we saw in this study,” Dr. Zand said.
 

Selection bias?

Commenting on the research, Louis R. Caplan, MD, professor of neurology at Harvard Medical School, Boston, noted that evaluation of patients with TIA or mIS “can be done very well as an outpatient” if clinicians have experienced personnel, the outpatient facilities to do the studies necessary, and criteria in place for deciding who to admit or not admit.

However, the decision on whether to choose an inpatient or outpatient approach for a particular patient is complicated, said Dr. Caplan, who was not involved with the research.

Clinicians must consider factors such as whether the patient is mobile, has a car, or has a significant other. The patient’s symptoms and past illnesses also influence the decision, he added.

Dr. Caplan noted that in the meta-analysis, far fewer patients were seen in the TIA clinics than were seen in the inpatient setting. In addition, none of the studies used uniform criteria to determine which patients should undergo workup as outpatients and which as inpatients. “There was a lot of selection bias that may have had nothing to do with how sick the person was,” Dr. Caplan said.

In addition, few hospitals in the United States have an outpatient TIA clinic, he noted. Most of the studies of TIA clinics that the researchers examined were conducted in Europe. “It’s easier to do [that] in Europe because of their socialized medicine,” said Dr. Caplan.

But TIA clinics should be more widespread in the U.S., he added. “Insurance companies should be willing to pay for comparable facilities, inpatient and outpatient,” he said.

The study was conducted without external funding. Dr. Zand reported no relevant financial relationships. Dr. Caplan was an investigator for TIAregistry.org, which analyzed the outcomes of treatment in TIA clinics in Europe.

A version of this article first appeared on Medscape.com.

Inpatient and outpatient treatments of transient ischemic attack (TIA) or minor ischemic stroke (mIS) yield comparable safety outcomes, new research suggests. In a meta-analysis of more than 200,000 patients with TIA or mIS, risk for subsequent stroke within 90 days was 2.1% for those treated in a TIA clinic versus 2.8% for patients treated in inpatient settings, which was not significantly different. The risk for patients treated in an emergency department was higher, at 3.5%.

“The message is that if you do the correct risk stratification and then triage patients based on their risk profile, you can safely discharge and have a timely follow-up for the patients who have low risk for a subsequent event,” said coinvestigator Ramin Zand, MD, vascular neurologist and stroke attending physician at Geisinger Health System, Danville, Pennsylvania.

The findings were published online Jan. 5 in JAMA Network Open.
 

Higher risk in EDs

There is currently no consensus on the care protocol for patients with TIA or mIS, and the rate at which these patients are hospitalized varies by region, hospital, and practitioner, the investigators noted.

Previous studies have indicated that outpatient management of certain individuals with TIA can be safe and cost-effective.

The current researchers searched for retrospective and prospective studies of adult patients that provided information about ischemic stroke after TIA or mIS. Studies that used time- and tissue-based definitions of TIA were included, as well as studies that used various definitions of mIS.

The investigators examined care provided at TIA clinics, inpatient settings (such as medical-surgical units, stroke units, or observation units), EDs, and unspecified settings. Their main aim was to compare outcomes between TIA clinics and inpatient settings.

In all, 226,683 patients (recruited between 1981 and 2018) from 71 studies were included in the meta-analysis. The studies examined 101 cohorts, 24 of which were studied prospectively. Among the 5,636 patients who received care in TIA clinics, the mean age was 65.7 years, and 50.8% of this group were men. Among the 130,139 inpatients, the mean age was 78.3 years, and 61.6% of the group were women.

Results showed no significant difference in risk for subsequent stroke between patients treated in the inpatient and outpatient settings.

Among patients treated in a TIA clinic, risk for subsequent stroke following a TIA or mIS was 0.3% within 2 days, 1.0% within 7 days, 1.3% within 30 days, and 2.1% within 90 days. Among those treated as inpatients, risk for subsequent stroke was 0.5% within 2 days, 1.2% within 7 days, 1.6% within 30 days, and 2.8% within 90 days.

Risk for subsequent stroke was higher among patients treated in the ED and in unspecified settings. At the EDs, the risk was 1.9% within 2 days, 3.4% within 7 days, 3.5% within 30 days, and 3.5% within 90 days. Among those treated in unspecified settings, the risk was 2.2% within 2 days, 3.4% within 7 days, 4.2% within 30 days, and 6.0% within 90 days.

Patients treated in the ED also had a significantly higher risk for subsequent stroke at 2 and 7 days, compared with those treated in inpatient settings and a significantly higher risk for subsequent stroke at 2, 7, and 90 days, compared with those treated in TIA clinics.
 

‘Most comprehensive look’

“This is the most comprehensive look at all the studies to try and answer this research question,” said Dr. Zand. The results were similar to what was expected, he added.

The infrastructure and resources differed among the sites at which the various studies were conducted, and the investigators adjusted for these differences as much as possible, Dr. Zand noted. A certain amount of selection bias may remain, but it does not affect the overall conclusion, he added.

“Timely outpatient care among low-risk TIA patients is both feasible and safe,” he said.

Dr. Zand noted that the findings have implications not only for patient management but also for the management of the health system. “It’s not feasible nor desirable to admit all the TIA patients, especially with the lessons that we learned from COVID, the burden on the health systems, and the fact that many hospitals are operating at full capacity right now,” he said.

The recommendation is to hospitalize high-risk patients and provide outpatient evaluation and workup to low-risk patients, he added. “This is exactly what we saw in this study,” Dr. Zand said.
 

Selection bias?

Commenting on the research, Louis R. Caplan, MD, professor of neurology at Harvard Medical School, Boston, noted that evaluation of patients with TIA or mIS “can be done very well as an outpatient” if clinicians have experienced personnel, the outpatient facilities to do the studies necessary, and criteria in place for deciding who to admit or not admit.

However, the decision on whether to choose an inpatient or outpatient approach for a particular patient is complicated, said Dr. Caplan, who was not involved with the research.

Clinicians must consider factors such as whether the patient is mobile, has a car, or has a significant other. The patient’s symptoms and past illnesses also influence the decision, he added.

Dr. Caplan noted that in the meta-analysis, far fewer patients were seen in the TIA clinics than were seen in the inpatient setting. In addition, none of the studies used uniform criteria to determine which patients should undergo workup as outpatients and which as inpatients. “There was a lot of selection bias that may have had nothing to do with how sick the person was,” Dr. Caplan said.

In addition, few hospitals in the United States have an outpatient TIA clinic, he noted. Most of the studies of TIA clinics that the researchers examined were conducted in Europe. “It’s easier to do [that] in Europe because of their socialized medicine,” said Dr. Caplan.

But TIA clinics should be more widespread in the U.S., he added. “Insurance companies should be willing to pay for comparable facilities, inpatient and outpatient,” he said.

The study was conducted without external funding. Dr. Zand reported no relevant financial relationships. Dr. Caplan was an investigator for TIAregistry.org, which analyzed the outcomes of treatment in TIA clinics in Europe.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved the dual orexin receptor antagonist daridorexant (Quviviq) for the treatment of insomnia in adults, the drug’s manufacturer, Idorsia, has announced.

The FDA’s decision was based partly on a phase 3 trial of adults with moderate to severe insomnia who were randomly assigned to receive 25 or 50 mg of daridorexant or matching placebo. Daridorexant was associated with dose-dependent improvements in wake after sleep onset, total sleep time, and latency to persistent sleep.

FDA_icon3_web.jpg

Whereas the overall results are very positive, the improvements in daytime functioning are especially “exciting,” Thomas Roth, PhD, director of the Sleep Disorders and Research Center at Henry Ford Hospital in Detroit, said in an interview.

“That’s sort of a big deal. For me, that’s the biggest deal there is,” said Dr. Roth, who was a consultant on the design of the phase 3 trial and on the interpretation of the data.

The drug will be available in doses of 25 mg and 50 mg, and the FDA has recommended that it be classified as a controlled substance. After it is scheduled by the Drug Enforcement Administration, daridorexant is expected to be made available in May.
 

Favorable safety profile

Insomnia is a common disorder characterized by difficulty falling asleep or staying asleep and by early-morning awakenings. Patients with insomnia often report fatigue, irritability, and difficulty with concentration. The condition can also result in significant problems with work and social activities, thus contributing to anxiety or depression.

As with other dual orexin receptor antagonists, daridorexant competitively binds with both orexin receptors in the lateral hypothalamus to block the activity of orexin in a reversible way. This approach decreases the downstream action of the wake-promoting neurotransmitters that are overactive in patients with insomnia.

The phase 3 trial measured daytime functioning using the new Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ), a patient-reported outcome instrument. Daridorexant was associated with significant improvements in daytime function, particularly in sleepiness and mood.

Previous trials of other dual orexin receptor antagonists did not use the IDSIQ as an outcome, so it is not possible to compare daridorexant with those drugs in this respect, Dr. Roth noted. Researchers also have not conducted head-to-head trials of the drug with other dual orexin receptor antagonists.

Daridorexant also had a favorable safety profile and was not associated with rebound insomnia or withdrawal effects. The most common adverse events were headache and somnolence or fatigue.

“They had no effect on sleep stage distribution [and] they had no significant effects on sleep and breathing in people with mild to moderate sleep apnea,” said Dr. Roth, who presented the phase 3 findings at SLEEP 2020. 

In addition to serving as a consultant for Idorsia on the trial design and interpretation of results, Dr. Roth has also served as a consultant for other companies that develop sleep agents.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved the dual orexin receptor antagonist daridorexant (Quviviq) for the treatment of insomnia in adults, the drug’s manufacturer, Idorsia, has announced.

The FDA’s decision was based partly on a phase 3 trial of adults with moderate to severe insomnia who were randomly assigned to receive 25 or 50 mg of daridorexant or matching placebo. Daridorexant was associated with dose-dependent improvements in wake after sleep onset, total sleep time, and latency to persistent sleep.

FDA_icon3_web.jpg

Whereas the overall results are very positive, the improvements in daytime functioning are especially “exciting,” Thomas Roth, PhD, director of the Sleep Disorders and Research Center at Henry Ford Hospital in Detroit, said in an interview.

“That’s sort of a big deal. For me, that’s the biggest deal there is,” said Dr. Roth, who was a consultant on the design of the phase 3 trial and on the interpretation of the data.

The drug will be available in doses of 25 mg and 50 mg, and the FDA has recommended that it be classified as a controlled substance. After it is scheduled by the Drug Enforcement Administration, daridorexant is expected to be made available in May.
 

Favorable safety profile

Insomnia is a common disorder characterized by difficulty falling asleep or staying asleep and by early-morning awakenings. Patients with insomnia often report fatigue, irritability, and difficulty with concentration. The condition can also result in significant problems with work and social activities, thus contributing to anxiety or depression.

As with other dual orexin receptor antagonists, daridorexant competitively binds with both orexin receptors in the lateral hypothalamus to block the activity of orexin in a reversible way. This approach decreases the downstream action of the wake-promoting neurotransmitters that are overactive in patients with insomnia.

The phase 3 trial measured daytime functioning using the new Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ), a patient-reported outcome instrument. Daridorexant was associated with significant improvements in daytime function, particularly in sleepiness and mood.

Previous trials of other dual orexin receptor antagonists did not use the IDSIQ as an outcome, so it is not possible to compare daridorexant with those drugs in this respect, Dr. Roth noted. Researchers also have not conducted head-to-head trials of the drug with other dual orexin receptor antagonists.

Daridorexant also had a favorable safety profile and was not associated with rebound insomnia or withdrawal effects. The most common adverse events were headache and somnolence or fatigue.

“They had no effect on sleep stage distribution [and] they had no significant effects on sleep and breathing in people with mild to moderate sleep apnea,” said Dr. Roth, who presented the phase 3 findings at SLEEP 2020. 

In addition to serving as a consultant for Idorsia on the trial design and interpretation of results, Dr. Roth has also served as a consultant for other companies that develop sleep agents.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved the dual orexin receptor antagonist daridorexant (Quviviq) for the treatment of insomnia in adults, the drug’s manufacturer, Idorsia, has announced.

The FDA’s decision was based partly on a phase 3 trial of adults with moderate to severe insomnia who were randomly assigned to receive 25 or 50 mg of daridorexant or matching placebo. Daridorexant was associated with dose-dependent improvements in wake after sleep onset, total sleep time, and latency to persistent sleep.

FDA_icon3_web.jpg

Whereas the overall results are very positive, the improvements in daytime functioning are especially “exciting,” Thomas Roth, PhD, director of the Sleep Disorders and Research Center at Henry Ford Hospital in Detroit, said in an interview.

“That’s sort of a big deal. For me, that’s the biggest deal there is,” said Dr. Roth, who was a consultant on the design of the phase 3 trial and on the interpretation of the data.

The drug will be available in doses of 25 mg and 50 mg, and the FDA has recommended that it be classified as a controlled substance. After it is scheduled by the Drug Enforcement Administration, daridorexant is expected to be made available in May.
 

Favorable safety profile

Insomnia is a common disorder characterized by difficulty falling asleep or staying asleep and by early-morning awakenings. Patients with insomnia often report fatigue, irritability, and difficulty with concentration. The condition can also result in significant problems with work and social activities, thus contributing to anxiety or depression.

As with other dual orexin receptor antagonists, daridorexant competitively binds with both orexin receptors in the lateral hypothalamus to block the activity of orexin in a reversible way. This approach decreases the downstream action of the wake-promoting neurotransmitters that are overactive in patients with insomnia.

The phase 3 trial measured daytime functioning using the new Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ), a patient-reported outcome instrument. Daridorexant was associated with significant improvements in daytime function, particularly in sleepiness and mood.

Previous trials of other dual orexin receptor antagonists did not use the IDSIQ as an outcome, so it is not possible to compare daridorexant with those drugs in this respect, Dr. Roth noted. Researchers also have not conducted head-to-head trials of the drug with other dual orexin receptor antagonists.

Daridorexant also had a favorable safety profile and was not associated with rebound insomnia or withdrawal effects. The most common adverse events were headache and somnolence or fatigue.

“They had no effect on sleep stage distribution [and] they had no significant effects on sleep and breathing in people with mild to moderate sleep apnea,” said Dr. Roth, who presented the phase 3 findings at SLEEP 2020. 

In addition to serving as a consultant for Idorsia on the trial design and interpretation of results, Dr. Roth has also served as a consultant for other companies that develop sleep agents.

A version of this article first appeared on Medscape.com.

Diabetes mellitus (DM) is associated with Parkinson’s disease (PD) development, as well as more severe symptoms and more rapid disease progression, new research suggests.

In a systematic review, patients with type 2 diabetes were 34% more likely to develop PD than those without comorbid DM. In addition, patients with both conditions had significantly worse scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) and worse cognitive performance.

Together, the results suggest that “DM may be a facilitating factor of neurodegeneration,” wrote the investigators, led by Gennaro Pagano, MD, PhD, expert medical director at Roche Pharma Research and Early Development, in Basel, Switzerland.

The findings were published in a recent issue of the Journal of Parkinson’s Disease.
 

Unanswered questions

Researchers have long proposed a potential relationship between diabetes and PD. However, case-control studies have yielded conflicting results about this relationship – and previous systematic reviews have failed to clarify the question.

In the current systematic review and meta-analysis, investigators identified relevant studies in databases such as MEDLINE/PubMed, Cochrane CENTRAL, and Scopus.

Eligible studies reported prevalence of DM in patients with PD, reported incidence of PD in those with and those without DM, and analyzed Parkinson’s phenotype and progression in those with and those without DM.

The researchers identified 3,829 articles in their initial search, evaluated 90 articles in detail, and included 43 studies in their analysis. Study quality was judged to be moderate or good, and the investigators did not find significant publication bias.

Twenty-one studies that encompassed 11,396 patients were examined to determine prevalence of DM in PD. This prevalence was calculated to be 10.02%, which is similar to the global prevalence of 9.3% reported in 2019.

The researchers also analyzed 12 cohort studies that included 17,797,221 patients to calculate risk for PD in patients with comorbid diabetes. The pooled summary odds ratio for incident PD among patients with type 2 diabetes was 1.34.

The evaluation of the effect of diabetes on PD severity was based on 10 studies that included 603 patients with both diseases. Because data on motor symptoms were not available for all studies, the researchers considered Hoehn and Yahr stage, UPDRS score, and cognitive impairment.

Patients with both conditions had a worse Hoehn and Yahr stage (standardized mean difference, 0.36; P < .001), and higher UPDRS score (SMD, 0.60; P < .001). In 7 of the 10 studies, diabetes was associated with worse cognitive performance in patients with PD.
 

Mechanisms uncertain

The mechanisms of the effect of diabetes on risk for and severity of PD are uncertain, but the researchers have developed hypotheses.

“Overlapping mechanisms between insulin resistance, mitochondrial dysfunction, oxidative stress, and alpha-synuclein expression could influence the development of the neurodegeneration process,” they wrote.

Because the current analysis demonstrated a trend toward more pronounced cognitive decline in patients with the comorbidities, clinicians should pay particular attention to the progression of motor and cognitive symptoms in patients with these diseases, the investigators noted.

“Additional studies are needed in order to better define the clinical phenotype of PD-DM patients and explore the role of antidiabetic drugs on PD progression,” they wrote.

They add that future studies also are needed to evaluate whether antidiabetic drugs might reduce risk for PD in these patients.

The investigators noted several limitations of their research. In many of the studies they examined, for example, diagnostic criteria of type 2 diabetes and PD were based only on medical records or self-reported health questionnaires. The diagnoses were rarely confirmed.

In addition, not all studies clearly stated that their populations presented with type 2 diabetes. Finally, patients with diabetes may be at increased risk for cardiovascular death, which could affect follow-up related to the development of PD, the investigators noted.

A version of this article first appeared on Medscape.com.

Diabetes mellitus (DM) is associated with Parkinson’s disease (PD) development, as well as more severe symptoms and more rapid disease progression, new research suggests.

In a systematic review, patients with type 2 diabetes were 34% more likely to develop PD than those without comorbid DM. In addition, patients with both conditions had significantly worse scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) and worse cognitive performance.

Together, the results suggest that “DM may be a facilitating factor of neurodegeneration,” wrote the investigators, led by Gennaro Pagano, MD, PhD, expert medical director at Roche Pharma Research and Early Development, in Basel, Switzerland.

The findings were published in a recent issue of the Journal of Parkinson’s Disease.
 

Unanswered questions

Researchers have long proposed a potential relationship between diabetes and PD. However, case-control studies have yielded conflicting results about this relationship – and previous systematic reviews have failed to clarify the question.

In the current systematic review and meta-analysis, investigators identified relevant studies in databases such as MEDLINE/PubMed, Cochrane CENTRAL, and Scopus.

Eligible studies reported prevalence of DM in patients with PD, reported incidence of PD in those with and those without DM, and analyzed Parkinson’s phenotype and progression in those with and those without DM.

The researchers identified 3,829 articles in their initial search, evaluated 90 articles in detail, and included 43 studies in their analysis. Study quality was judged to be moderate or good, and the investigators did not find significant publication bias.

Twenty-one studies that encompassed 11,396 patients were examined to determine prevalence of DM in PD. This prevalence was calculated to be 10.02%, which is similar to the global prevalence of 9.3% reported in 2019.

The researchers also analyzed 12 cohort studies that included 17,797,221 patients to calculate risk for PD in patients with comorbid diabetes. The pooled summary odds ratio for incident PD among patients with type 2 diabetes was 1.34.

The evaluation of the effect of diabetes on PD severity was based on 10 studies that included 603 patients with both diseases. Because data on motor symptoms were not available for all studies, the researchers considered Hoehn and Yahr stage, UPDRS score, and cognitive impairment.

Patients with both conditions had a worse Hoehn and Yahr stage (standardized mean difference, 0.36; P < .001), and higher UPDRS score (SMD, 0.60; P < .001). In 7 of the 10 studies, diabetes was associated with worse cognitive performance in patients with PD.
 

Mechanisms uncertain

The mechanisms of the effect of diabetes on risk for and severity of PD are uncertain, but the researchers have developed hypotheses.

“Overlapping mechanisms between insulin resistance, mitochondrial dysfunction, oxidative stress, and alpha-synuclein expression could influence the development of the neurodegeneration process,” they wrote.

Because the current analysis demonstrated a trend toward more pronounced cognitive decline in patients with the comorbidities, clinicians should pay particular attention to the progression of motor and cognitive symptoms in patients with these diseases, the investigators noted.

“Additional studies are needed in order to better define the clinical phenotype of PD-DM patients and explore the role of antidiabetic drugs on PD progression,” they wrote.

They add that future studies also are needed to evaluate whether antidiabetic drugs might reduce risk for PD in these patients.

The investigators noted several limitations of their research. In many of the studies they examined, for example, diagnostic criteria of type 2 diabetes and PD were based only on medical records or self-reported health questionnaires. The diagnoses were rarely confirmed.

In addition, not all studies clearly stated that their populations presented with type 2 diabetes. Finally, patients with diabetes may be at increased risk for cardiovascular death, which could affect follow-up related to the development of PD, the investigators noted.

A version of this article first appeared on Medscape.com.

Diabetes mellitus (DM) is associated with Parkinson’s disease (PD) development, as well as more severe symptoms and more rapid disease progression, new research suggests.

In a systematic review, patients with type 2 diabetes were 34% more likely to develop PD than those without comorbid DM. In addition, patients with both conditions had significantly worse scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) and worse cognitive performance.

Together, the results suggest that “DM may be a facilitating factor of neurodegeneration,” wrote the investigators, led by Gennaro Pagano, MD, PhD, expert medical director at Roche Pharma Research and Early Development, in Basel, Switzerland.

The findings were published in a recent issue of the Journal of Parkinson’s Disease.
 

Unanswered questions

Researchers have long proposed a potential relationship between diabetes and PD. However, case-control studies have yielded conflicting results about this relationship – and previous systematic reviews have failed to clarify the question.

In the current systematic review and meta-analysis, investigators identified relevant studies in databases such as MEDLINE/PubMed, Cochrane CENTRAL, and Scopus.

Eligible studies reported prevalence of DM in patients with PD, reported incidence of PD in those with and those without DM, and analyzed Parkinson’s phenotype and progression in those with and those without DM.

The researchers identified 3,829 articles in their initial search, evaluated 90 articles in detail, and included 43 studies in their analysis. Study quality was judged to be moderate or good, and the investigators did not find significant publication bias.

Twenty-one studies that encompassed 11,396 patients were examined to determine prevalence of DM in PD. This prevalence was calculated to be 10.02%, which is similar to the global prevalence of 9.3% reported in 2019.

The researchers also analyzed 12 cohort studies that included 17,797,221 patients to calculate risk for PD in patients with comorbid diabetes. The pooled summary odds ratio for incident PD among patients with type 2 diabetes was 1.34.

The evaluation of the effect of diabetes on PD severity was based on 10 studies that included 603 patients with both diseases. Because data on motor symptoms were not available for all studies, the researchers considered Hoehn and Yahr stage, UPDRS score, and cognitive impairment.

Patients with both conditions had a worse Hoehn and Yahr stage (standardized mean difference, 0.36; P < .001), and higher UPDRS score (SMD, 0.60; P < .001). In 7 of the 10 studies, diabetes was associated with worse cognitive performance in patients with PD.
 

Mechanisms uncertain

The mechanisms of the effect of diabetes on risk for and severity of PD are uncertain, but the researchers have developed hypotheses.

“Overlapping mechanisms between insulin resistance, mitochondrial dysfunction, oxidative stress, and alpha-synuclein expression could influence the development of the neurodegeneration process,” they wrote.

Because the current analysis demonstrated a trend toward more pronounced cognitive decline in patients with the comorbidities, clinicians should pay particular attention to the progression of motor and cognitive symptoms in patients with these diseases, the investigators noted.

“Additional studies are needed in order to better define the clinical phenotype of PD-DM patients and explore the role of antidiabetic drugs on PD progression,” they wrote.

They add that future studies also are needed to evaluate whether antidiabetic drugs might reduce risk for PD in these patients.

The investigators noted several limitations of their research. In many of the studies they examined, for example, diagnostic criteria of type 2 diabetes and PD were based only on medical records or self-reported health questionnaires. The diagnoses were rarely confirmed.

In addition, not all studies clearly stated that their populations presented with type 2 diabetes. Finally, patients with diabetes may be at increased risk for cardiovascular death, which could affect follow-up related to the development of PD, the investigators noted.

A version of this article first appeared on Medscape.com.

In large-vessel occlusion stroke, results of a randomized trial failed to show noninferiority of direct mechanical thrombectomy using the Solitaire device to the combination of intravenous (IV) thrombolysis plus mechanical thrombectomy.

In the prospective, multicenter trial, the rate of good functional outcome was 57% for patients who underwent direct thrombectomy and 65% among patients who received IV thrombolysis before undergoing thrombectomy. This result failed to demonstrate noninferiority of direct mechanical thrombectomy compared to combination therapy, the researchers conclude.

“Good outcome was high in both treatment arms, with the point estimate in favor of the bridging cohort,” said lead investigator Urs Fischer, MD, co-chair of the stroke center at Inselspital, Bern University Hospital, Switzerland, during his presentation. “Postinterventional reperfusion was very high in both treatment arms and higher in patients with bridging thrombolysis, compared to direct mechanical thrombectomy.”

The findings were presented at the 13th World Stroke Congress (WSC) 2021.
 

Two views of thrombolysis

The value of bridging thrombolysis for patients who undergo mechanical thrombectomy is a matter of debate. One argument is that, for patients with large-vessel occlusion, IV thrombolysis may improve reperfusion before and after thrombectomy and yield better clinical outcomes. The opposing argument is that bridging thrombolysis may increase the risk for distal emboli, delay mechanical thrombectomy, and increase the rate of hemorrhage.

The researchers conducted the SWIFT DIRECT trial to investigate this question. They enrolled patients with acute ischemic stroke due to occlusion of the internal carotid artery or the M1 segment of the middle cerebral artery.

The trial was conducted at 48 sites in seven European countries and Canada. The investigators randomly assigned patients to receive IV alteplase (0.9 mg/kg) plus mechanical thrombectomy with the Solitaire device or to receive direct mechanical thrombectomy with the same device. Treatment was open label, but the assessment of endpoints was blinded.

Investigators assigned 423 patients to treatment, and 408 were included in the full analysis set. Of this group, 201 participants received direct mechanical thrombectomy, and 207 received IV thrombolysis plus thrombectomy. There were three crossovers in each treatment arm.

The primary outcome was functional independence, defined as a Modified Rankin Scale (mRS) score of 0-2, at 90 days. Secondary outcomes included mortality at 90 days, mRS shift, change in National Institutes of Health Stroke Scale (NIHSS) score at 24 hours, successful reperfusion, and symptomatic and asymptomatic intracranial hemorrhage (ICH).
 

Noninferiority not demonstrated

At baseline, patient characteristics were well balanced between the treatment groups. The median age of the patients was 72 years, and about 50% of participants were women. The median NIHSS score was 17 in both arms.

Approximately 57% of patients who underwent direct thrombectomy and 65% of those who received IV thrombolysis plus thrombectomy were functionally independent at 90 days, the primary outcome.

In addition, the researchers found no difference in mRS shift, mortality at 90 days, or change in NIHSS score at 24 hours. Postinterventional reperfusion was very high in both arms and was higher in patients who received IV tissue plasminogen activator, compared with those who received direct mechanical thrombectomy, said Dr. Fischer.

The rate of successful postinterventional reperfusion, however, was higher among patients who received thrombolysis than among those who underwent direct thrombectomy. The rate of symptomatic ICH was 1.5% in the direct thrombectomy group and 4.9% in the thrombolysis-plus-thrombectomy group.
 

New endpoints needed?

The investigators used noninferiority margins of 12%. “This question about the noninferiority margins, that’s a very tricky and difficult one in randomized clinical trials,” said Dr. Fischer. The investigators defined their margin using the 2015 HERMES data because no trials had yet compared direct mechanical thrombectomy and bridging thrombolysis at the time.

The researchers are performing a pooled analysis of all the trials that compared bridging thrombolysis with direct mechanical thrombectomy. “We are therefore looking at several margins, and I think this is the way we should look at these noninferiority margins,” said Dr. Fischer. “There’s not a clear-cut level which you can define.”

Enrollment in the trial was well balanced with respect to gender, which is not always the case in stroke studies, said Kevin Sheth, MD, professor of neurology and neurosurgery at Yale School of Medicine, New Haven, Conn., who commented on the study for this news organization.

The findings indicate that the likelihood of there being a difference between groups on this question is low, said Dr. Sheth. Both groups had large-vessel occlusion, both received thrombectomy, and both achieved reperfusion. But the higher rate of successful reperfusion in the bridging cohort was not reflected in any of the clinical endpoints that the investigators examined.

Observing a difference in this context will require very large trials or different endpoints that are more responsive to the intervention, said Dr. Sheth. “This is going to be a challenge for not just this but for any neuroprotection trial in the future,” he said.

The study was supported by Medtronic. Dr. Fischer has served as a consultant for Medtronic, Stryker, and CSL Behring. Dr. Sheth has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

In large-vessel occlusion stroke, results of a randomized trial failed to show noninferiority of direct mechanical thrombectomy using the Solitaire device to the combination of intravenous (IV) thrombolysis plus mechanical thrombectomy.

In the prospective, multicenter trial, the rate of good functional outcome was 57% for patients who underwent direct thrombectomy and 65% among patients who received IV thrombolysis before undergoing thrombectomy. This result failed to demonstrate noninferiority of direct mechanical thrombectomy compared to combination therapy, the researchers conclude.

“Good outcome was high in both treatment arms, with the point estimate in favor of the bridging cohort,” said lead investigator Urs Fischer, MD, co-chair of the stroke center at Inselspital, Bern University Hospital, Switzerland, during his presentation. “Postinterventional reperfusion was very high in both treatment arms and higher in patients with bridging thrombolysis, compared to direct mechanical thrombectomy.”

The findings were presented at the 13th World Stroke Congress (WSC) 2021.
 

Two views of thrombolysis

The value of bridging thrombolysis for patients who undergo mechanical thrombectomy is a matter of debate. One argument is that, for patients with large-vessel occlusion, IV thrombolysis may improve reperfusion before and after thrombectomy and yield better clinical outcomes. The opposing argument is that bridging thrombolysis may increase the risk for distal emboli, delay mechanical thrombectomy, and increase the rate of hemorrhage.

The researchers conducted the SWIFT DIRECT trial to investigate this question. They enrolled patients with acute ischemic stroke due to occlusion of the internal carotid artery or the M1 segment of the middle cerebral artery.

The trial was conducted at 48 sites in seven European countries and Canada. The investigators randomly assigned patients to receive IV alteplase (0.9 mg/kg) plus mechanical thrombectomy with the Solitaire device or to receive direct mechanical thrombectomy with the same device. Treatment was open label, but the assessment of endpoints was blinded.

Investigators assigned 423 patients to treatment, and 408 were included in the full analysis set. Of this group, 201 participants received direct mechanical thrombectomy, and 207 received IV thrombolysis plus thrombectomy. There were three crossovers in each treatment arm.

The primary outcome was functional independence, defined as a Modified Rankin Scale (mRS) score of 0-2, at 90 days. Secondary outcomes included mortality at 90 days, mRS shift, change in National Institutes of Health Stroke Scale (NIHSS) score at 24 hours, successful reperfusion, and symptomatic and asymptomatic intracranial hemorrhage (ICH).
 

Noninferiority not demonstrated

At baseline, patient characteristics were well balanced between the treatment groups. The median age of the patients was 72 years, and about 50% of participants were women. The median NIHSS score was 17 in both arms.

Approximately 57% of patients who underwent direct thrombectomy and 65% of those who received IV thrombolysis plus thrombectomy were functionally independent at 90 days, the primary outcome.

In addition, the researchers found no difference in mRS shift, mortality at 90 days, or change in NIHSS score at 24 hours. Postinterventional reperfusion was very high in both arms and was higher in patients who received IV tissue plasminogen activator, compared with those who received direct mechanical thrombectomy, said Dr. Fischer.

The rate of successful postinterventional reperfusion, however, was higher among patients who received thrombolysis than among those who underwent direct thrombectomy. The rate of symptomatic ICH was 1.5% in the direct thrombectomy group and 4.9% in the thrombolysis-plus-thrombectomy group.
 

New endpoints needed?

The investigators used noninferiority margins of 12%. “This question about the noninferiority margins, that’s a very tricky and difficult one in randomized clinical trials,” said Dr. Fischer. The investigators defined their margin using the 2015 HERMES data because no trials had yet compared direct mechanical thrombectomy and bridging thrombolysis at the time.

The researchers are performing a pooled analysis of all the trials that compared bridging thrombolysis with direct mechanical thrombectomy. “We are therefore looking at several margins, and I think this is the way we should look at these noninferiority margins,” said Dr. Fischer. “There’s not a clear-cut level which you can define.”

Enrollment in the trial was well balanced with respect to gender, which is not always the case in stroke studies, said Kevin Sheth, MD, professor of neurology and neurosurgery at Yale School of Medicine, New Haven, Conn., who commented on the study for this news organization.

The findings indicate that the likelihood of there being a difference between groups on this question is low, said Dr. Sheth. Both groups had large-vessel occlusion, both received thrombectomy, and both achieved reperfusion. But the higher rate of successful reperfusion in the bridging cohort was not reflected in any of the clinical endpoints that the investigators examined.

Observing a difference in this context will require very large trials or different endpoints that are more responsive to the intervention, said Dr. Sheth. “This is going to be a challenge for not just this but for any neuroprotection trial in the future,” he said.

The study was supported by Medtronic. Dr. Fischer has served as a consultant for Medtronic, Stryker, and CSL Behring. Dr. Sheth has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

In large-vessel occlusion stroke, results of a randomized trial failed to show noninferiority of direct mechanical thrombectomy using the Solitaire device to the combination of intravenous (IV) thrombolysis plus mechanical thrombectomy.

In the prospective, multicenter trial, the rate of good functional outcome was 57% for patients who underwent direct thrombectomy and 65% among patients who received IV thrombolysis before undergoing thrombectomy. This result failed to demonstrate noninferiority of direct mechanical thrombectomy compared to combination therapy, the researchers conclude.

“Good outcome was high in both treatment arms, with the point estimate in favor of the bridging cohort,” said lead investigator Urs Fischer, MD, co-chair of the stroke center at Inselspital, Bern University Hospital, Switzerland, during his presentation. “Postinterventional reperfusion was very high in both treatment arms and higher in patients with bridging thrombolysis, compared to direct mechanical thrombectomy.”

The findings were presented at the 13th World Stroke Congress (WSC) 2021.
 

Two views of thrombolysis

The value of bridging thrombolysis for patients who undergo mechanical thrombectomy is a matter of debate. One argument is that, for patients with large-vessel occlusion, IV thrombolysis may improve reperfusion before and after thrombectomy and yield better clinical outcomes. The opposing argument is that bridging thrombolysis may increase the risk for distal emboli, delay mechanical thrombectomy, and increase the rate of hemorrhage.

The researchers conducted the SWIFT DIRECT trial to investigate this question. They enrolled patients with acute ischemic stroke due to occlusion of the internal carotid artery or the M1 segment of the middle cerebral artery.

The trial was conducted at 48 sites in seven European countries and Canada. The investigators randomly assigned patients to receive IV alteplase (0.9 mg/kg) plus mechanical thrombectomy with the Solitaire device or to receive direct mechanical thrombectomy with the same device. Treatment was open label, but the assessment of endpoints was blinded.

Investigators assigned 423 patients to treatment, and 408 were included in the full analysis set. Of this group, 201 participants received direct mechanical thrombectomy, and 207 received IV thrombolysis plus thrombectomy. There were three crossovers in each treatment arm.

The primary outcome was functional independence, defined as a Modified Rankin Scale (mRS) score of 0-2, at 90 days. Secondary outcomes included mortality at 90 days, mRS shift, change in National Institutes of Health Stroke Scale (NIHSS) score at 24 hours, successful reperfusion, and symptomatic and asymptomatic intracranial hemorrhage (ICH).
 

Noninferiority not demonstrated

At baseline, patient characteristics were well balanced between the treatment groups. The median age of the patients was 72 years, and about 50% of participants were women. The median NIHSS score was 17 in both arms.

Approximately 57% of patients who underwent direct thrombectomy and 65% of those who received IV thrombolysis plus thrombectomy were functionally independent at 90 days, the primary outcome.

In addition, the researchers found no difference in mRS shift, mortality at 90 days, or change in NIHSS score at 24 hours. Postinterventional reperfusion was very high in both arms and was higher in patients who received IV tissue plasminogen activator, compared with those who received direct mechanical thrombectomy, said Dr. Fischer.

The rate of successful postinterventional reperfusion, however, was higher among patients who received thrombolysis than among those who underwent direct thrombectomy. The rate of symptomatic ICH was 1.5% in the direct thrombectomy group and 4.9% in the thrombolysis-plus-thrombectomy group.
 

New endpoints needed?

The investigators used noninferiority margins of 12%. “This question about the noninferiority margins, that’s a very tricky and difficult one in randomized clinical trials,” said Dr. Fischer. The investigators defined their margin using the 2015 HERMES data because no trials had yet compared direct mechanical thrombectomy and bridging thrombolysis at the time.

The researchers are performing a pooled analysis of all the trials that compared bridging thrombolysis with direct mechanical thrombectomy. “We are therefore looking at several margins, and I think this is the way we should look at these noninferiority margins,” said Dr. Fischer. “There’s not a clear-cut level which you can define.”

Enrollment in the trial was well balanced with respect to gender, which is not always the case in stroke studies, said Kevin Sheth, MD, professor of neurology and neurosurgery at Yale School of Medicine, New Haven, Conn., who commented on the study for this news organization.

The findings indicate that the likelihood of there being a difference between groups on this question is low, said Dr. Sheth. Both groups had large-vessel occlusion, both received thrombectomy, and both achieved reperfusion. But the higher rate of successful reperfusion in the bridging cohort was not reflected in any of the clinical endpoints that the investigators examined.

Observing a difference in this context will require very large trials or different endpoints that are more responsive to the intervention, said Dr. Sheth. “This is going to be a challenge for not just this but for any neuroprotection trial in the future,” he said.

The study was supported by Medtronic. Dr. Fischer has served as a consultant for Medtronic, Stryker, and CSL Behring. Dr. Sheth has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Respected psychiatrist and psychoanalyst Irwin Marcus, MD, died on October 3. He was 102. Dedicated to his profession, Dr. Marcus was seeing patients until earlier this year. His long and illustrious career included creating and founding programs and organizations wherever he saw a need.

Among his many professional accomplishments, Dr. Marcus helped found the child and adolescent psychiatry program at Tulane University School of Medicine, New Orleans, and was one of the founders and a past president of the New Orleans Psychoanalytic Institute.

Dr. Marcus was also former chairman of the psychiatric department at Touro Infirmary and clinical professor emeritus at Louisiana State University Medical School, both in New Orleans.

“He initiated a number of traditions that are still important to us – community outreach, treating underserved youth, and strong interdisciplinary relationships,” Charles H. Zeanah, Jr., MD, current Mary Peters Sellars-Polchow chair of psychiatry at Tulane, told this news organization.

Dr. Marcus also continued to treat adult patients by phone and at his home until mid-June of this year. He had also started writing a children’s book.

It was his “tremendous work ethic” and creativity that kept him working past the age of 100, his wife, Angela Hill, a former news anchor, said in an interview.

Even vision loss resulting from macular degeneration and long-standing hearing problems did not stop him, she noted.

“He was always thinking creatively; he was always thinking intellectually,” said Ms. Hill. “That was, to me, the marvel of him.”
 

Wartime service, brain-trauma clinic

Born in Chicago in 1919, Dr. Marcus studied first at the Illinois Institute of Technology before transferring to the University of Illinois School of Medicine.

Neurosurgery was an early interest, and Dr. Marcus undertook his medical residency at Cook County Hospital in Chicago. The day after the bombing of Pearl Harbor, he enlisted in the U.S. Army.

During World War II, Dr. Marcus served in the Army Medical Corps and treated brain injuries and other wounds before he was badly injured himself and had to return to the United States for treatment.

After his recovery, he worked at an army medical facility in El Paso, Texas. On the basis of his earlier experiences, he founded a clinic there to diagnose and treat brain trauma.

After the war, Dr. Marcus continued his studies at Columbia University’s College of Physicians and Surgeons, in New York. Soon, his focus became psychiatry, child psychiatry, and psychoanalysis.

In 1951, Dr. Marcus accepted a position at Tulane. He created the Family Study Unit there the following year. Dr. Zeanah noted that the original name was chosen out of concern over the stigma associated with the term “child psychiatry.”

However, the environment changed relatively quickly, and the unit soon became known as Tulane Child Psychiatry.
 

Research, books, helmet patent

Dr. Marcus received Tulane’s first research grant in child psychiatry from the National Institute of Mental Health to investigate the potential mechanisms behind accident-prone children. That interest was inspired by his own clinical experience.

The findings, which were published in Monographs of the Society for Research in Child Development, showed that being accident prone was a nonspecific response to stressors from multiple sources, including a temperamental disposition, parent-child conflict, and family conflict.

To provide care to young patients, Dr. Marcus collaborated with the Children’s Bureau, the Jewish Children’s Home, the German Protestant’s Orphan Asylum, and Associated Catholic Charities.
 

‘He saved my life’

In 2002, Dr. Marcus participated in the 50th anniversary celebration of Tulane’s child psychiatry program. He returned in 2009 for what would be his final grand rounds presentation, which included an inspiring interview with Dr. Zeanah.

“He talked about the early history of child psychiatry, the things that he’d been trying to do, and some of the challenges that he faced,” Dr. Zeanah said.

Dr. Marcus’s former patients often told Ms. Hill how much he had helped them, she said.

“People would walk up and say, ‘Angela, Irwin won’t tell you this, but he saved my life,’” said Ms. Hill. “A couple walked up at a restaurant, and both of them said, ‘He saved our family.’”

Throughout his professional life, Dr. Marcus continued to strive toward growth and providing aid, she added.

“That is the bottom line of Irwin Marcus: All of his work was to help,” said Ms. Hill.

A version of this article first appeared on Medscape.

Respected psychiatrist and psychoanalyst Irwin Marcus, MD, died on October 3. He was 102. Dedicated to his profession, Dr. Marcus was seeing patients until earlier this year. His long and illustrious career included creating and founding programs and organizations wherever he saw a need.

Among his many professional accomplishments, Dr. Marcus helped found the child and adolescent psychiatry program at Tulane University School of Medicine, New Orleans, and was one of the founders and a past president of the New Orleans Psychoanalytic Institute.

Dr. Marcus was also former chairman of the psychiatric department at Touro Infirmary and clinical professor emeritus at Louisiana State University Medical School, both in New Orleans.

“He initiated a number of traditions that are still important to us – community outreach, treating underserved youth, and strong interdisciplinary relationships,” Charles H. Zeanah, Jr., MD, current Mary Peters Sellars-Polchow chair of psychiatry at Tulane, told this news organization.

Dr. Marcus also continued to treat adult patients by phone and at his home until mid-June of this year. He had also started writing a children’s book.

It was his “tremendous work ethic” and creativity that kept him working past the age of 100, his wife, Angela Hill, a former news anchor, said in an interview.

Even vision loss resulting from macular degeneration and long-standing hearing problems did not stop him, she noted.

“He was always thinking creatively; he was always thinking intellectually,” said Ms. Hill. “That was, to me, the marvel of him.”
 

Wartime service, brain-trauma clinic

Born in Chicago in 1919, Dr. Marcus studied first at the Illinois Institute of Technology before transferring to the University of Illinois School of Medicine.

Neurosurgery was an early interest, and Dr. Marcus undertook his medical residency at Cook County Hospital in Chicago. The day after the bombing of Pearl Harbor, he enlisted in the U.S. Army.

During World War II, Dr. Marcus served in the Army Medical Corps and treated brain injuries and other wounds before he was badly injured himself and had to return to the United States for treatment.

After his recovery, he worked at an army medical facility in El Paso, Texas. On the basis of his earlier experiences, he founded a clinic there to diagnose and treat brain trauma.

After the war, Dr. Marcus continued his studies at Columbia University’s College of Physicians and Surgeons, in New York. Soon, his focus became psychiatry, child psychiatry, and psychoanalysis.

In 1951, Dr. Marcus accepted a position at Tulane. He created the Family Study Unit there the following year. Dr. Zeanah noted that the original name was chosen out of concern over the stigma associated with the term “child psychiatry.”

However, the environment changed relatively quickly, and the unit soon became known as Tulane Child Psychiatry.
 

Research, books, helmet patent

Dr. Marcus received Tulane’s first research grant in child psychiatry from the National Institute of Mental Health to investigate the potential mechanisms behind accident-prone children. That interest was inspired by his own clinical experience.

The findings, which were published in Monographs of the Society for Research in Child Development, showed that being accident prone was a nonspecific response to stressors from multiple sources, including a temperamental disposition, parent-child conflict, and family conflict.

To provide care to young patients, Dr. Marcus collaborated with the Children’s Bureau, the Jewish Children’s Home, the German Protestant’s Orphan Asylum, and Associated Catholic Charities.
 

‘He saved my life’

In 2002, Dr. Marcus participated in the 50th anniversary celebration of Tulane’s child psychiatry program. He returned in 2009 for what would be his final grand rounds presentation, which included an inspiring interview with Dr. Zeanah.

“He talked about the early history of child psychiatry, the things that he’d been trying to do, and some of the challenges that he faced,” Dr. Zeanah said.

Dr. Marcus’s former patients often told Ms. Hill how much he had helped them, she said.

“People would walk up and say, ‘Angela, Irwin won’t tell you this, but he saved my life,’” said Ms. Hill. “A couple walked up at a restaurant, and both of them said, ‘He saved our family.’”

Throughout his professional life, Dr. Marcus continued to strive toward growth and providing aid, she added.

“That is the bottom line of Irwin Marcus: All of his work was to help,” said Ms. Hill.

A version of this article first appeared on Medscape.

Respected psychiatrist and psychoanalyst Irwin Marcus, MD, died on October 3. He was 102. Dedicated to his profession, Dr. Marcus was seeing patients until earlier this year. His long and illustrious career included creating and founding programs and organizations wherever he saw a need.

Among his many professional accomplishments, Dr. Marcus helped found the child and adolescent psychiatry program at Tulane University School of Medicine, New Orleans, and was one of the founders and a past president of the New Orleans Psychoanalytic Institute.

Dr. Marcus was also former chairman of the psychiatric department at Touro Infirmary and clinical professor emeritus at Louisiana State University Medical School, both in New Orleans.

“He initiated a number of traditions that are still important to us – community outreach, treating underserved youth, and strong interdisciplinary relationships,” Charles H. Zeanah, Jr., MD, current Mary Peters Sellars-Polchow chair of psychiatry at Tulane, told this news organization.

Dr. Marcus also continued to treat adult patients by phone and at his home until mid-June of this year. He had also started writing a children’s book.

It was his “tremendous work ethic” and creativity that kept him working past the age of 100, his wife, Angela Hill, a former news anchor, said in an interview.

Even vision loss resulting from macular degeneration and long-standing hearing problems did not stop him, she noted.

“He was always thinking creatively; he was always thinking intellectually,” said Ms. Hill. “That was, to me, the marvel of him.”
 

Wartime service, brain-trauma clinic

Born in Chicago in 1919, Dr. Marcus studied first at the Illinois Institute of Technology before transferring to the University of Illinois School of Medicine.

Neurosurgery was an early interest, and Dr. Marcus undertook his medical residency at Cook County Hospital in Chicago. The day after the bombing of Pearl Harbor, he enlisted in the U.S. Army.

During World War II, Dr. Marcus served in the Army Medical Corps and treated brain injuries and other wounds before he was badly injured himself and had to return to the United States for treatment.

After his recovery, he worked at an army medical facility in El Paso, Texas. On the basis of his earlier experiences, he founded a clinic there to diagnose and treat brain trauma.

After the war, Dr. Marcus continued his studies at Columbia University’s College of Physicians and Surgeons, in New York. Soon, his focus became psychiatry, child psychiatry, and psychoanalysis.

In 1951, Dr. Marcus accepted a position at Tulane. He created the Family Study Unit there the following year. Dr. Zeanah noted that the original name was chosen out of concern over the stigma associated with the term “child psychiatry.”

However, the environment changed relatively quickly, and the unit soon became known as Tulane Child Psychiatry.
 

Research, books, helmet patent

Dr. Marcus received Tulane’s first research grant in child psychiatry from the National Institute of Mental Health to investigate the potential mechanisms behind accident-prone children. That interest was inspired by his own clinical experience.

The findings, which were published in Monographs of the Society for Research in Child Development, showed that being accident prone was a nonspecific response to stressors from multiple sources, including a temperamental disposition, parent-child conflict, and family conflict.

To provide care to young patients, Dr. Marcus collaborated with the Children’s Bureau, the Jewish Children’s Home, the German Protestant’s Orphan Asylum, and Associated Catholic Charities.
 

‘He saved my life’

In 2002, Dr. Marcus participated in the 50th anniversary celebration of Tulane’s child psychiatry program. He returned in 2009 for what would be his final grand rounds presentation, which included an inspiring interview with Dr. Zeanah.

“He talked about the early history of child psychiatry, the things that he’d been trying to do, and some of the challenges that he faced,” Dr. Zeanah said.

Dr. Marcus’s former patients often told Ms. Hill how much he had helped them, she said.

“People would walk up and say, ‘Angela, Irwin won’t tell you this, but he saved my life,’” said Ms. Hill. “A couple walked up at a restaurant, and both of them said, ‘He saved our family.’”

Throughout his professional life, Dr. Marcus continued to strive toward growth and providing aid, she added.

“That is the bottom line of Irwin Marcus: All of his work was to help,” said Ms. Hill.

A version of this article first appeared on Medscape.

Rituximab reduces relapses and MRI activity in patients with relapsing-remitting multiple sclerosis (MS) more effectively than dimethyl fumarate, natalizumab, and injectable drugs, according to new research.

The risk for a first relapse was 6 times higher in patients receiving interferon beta or glatiramer acetate, compared with those receiving rituximab. But the level of disability at 3 years was only marginally different between the drugs studied.

The small differences in Expanded Disability Status Scale (EDSS) score are surprising, said investigator Peter Alping, a clinical assistant and doctoral student in the Department of Clinical Neuroscience at the Karolinska Institutet, Stockholm, as he presented the data. “It could be that we have too-short follow-up, so that EDSS doesn’t have time to diverge between therapies.”

He presented the findings at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

COMBAT-MS study

Direct comparisons of disease-modifying therapies (DMTs) for MS can help neurologists choose the most appropriate treatment for a given patient. To compare the effectiveness of the most common initial DMTs administered in Sweden, the researchers examined data from the COMBAT-MS study.

They identified all patients who initiated an injectable therapy (interferon beta or glatiramer acetate), dimethyl fumarate, natalizumab, or rituximab as a first treatment between Jan. 1, 2011, and Dec. 14, 2020. Eligible participants had prospectively recorded outcome data in the Swedish MS Register. Follow-up for a participant continued even if the participant stopped receiving therapy.

The investigators replaced missing data using multiple imputation. They adjusted for potential confounders using stabilized inverse probability of treatment weighting with baseline variables. These variables included age, sex, disease duration, geographical region, EDSS score, and relapses.
 

Rituximab reduced relapses

The researchers included 1,938 first-ever treatment episodes in their analysis. Of this group, 858 were associated with injectables, 339 with dimethyl fumarate, 269 with natalizumab, and 472 with rituximab.

Participants’ baseline characteristics differed by the DMT that they used. Patients who initiated natalizumab were the youngest, had the shortest disease duration, and had the most previous relapses.

For each outcome, the investigators compared all other therapies with rituximab. After they adjusted the data, they found that the hazard ratio for first relapse was 6.0 for injectables, 2.9 for dimethyl fumarate, and 1.8 for natalizumab.

In the adjusted model, the MRI lesion rate ratio for injectables, compared with rituximab, was 4.5. The rate ratio was 4.8 for dimethyl fumarate and 1.9 for natalizumab.

But differences in EDSS score at 3 years from treatment initiation were small. EDSS score in patients who received injectables was 0.24 points higher, compared with those receiving rituximab. EDSS score was 0.05 points higher in patients receiving dimethyl fumarate and 0.01 points lower in patients receiving natalizumab.

The risk for treatment discontinuation, however, differed significantly between therapies. The HR for treatment discontinuation was 32.7 for injectables, 20.3 for dimethyl fumarate, and 16.3 for natalizumab, compared with rituximab.

Among patients receiving dimethyl fumarate and injectables, the main reasons for discontinuing therapy were inadequate effect and adverse events. The main reason for discontinuation among patients receiving natalizumab was categorized as “other reason,” which mostly reflected John Cunningham virus positivity and concern for developing progressive multifocal leukoencephalopathy.
 

‘The uncertainty continues’

“These differences that we see in the effectiveness can be somewhat surprising, especially when it comes to natalizumab,” which is considered very effective, said Mr. Alping. The vulnerable period that occurs after switching from natalizumab may partly explain the difference. “This is something to keep in mind when starting patients on natalizumab treatment in the clinic,” Mr. Alping added.

Although rituximab is not indicated for MS, many clinics are using it in this population, said Robert Fox, MD, staff neurologist at the Mellen Center for MS and vice chair for research at the Neurological Institute of Cleveland Clinic, both in Cleveland, Ohio. Dr. Fox was not involved in the study.

“Assessing the generalizability of the study outside Sweden will be important,” he added, “but I would be surprised if their findings did not hold up to external validation.”

The way that the researchers addressed missing data could affect the interpretation of the findings. “Depending upon how much data was missing, their imputation methods may have a high level of uncertainty,” said Dr. Fox.

The researchers’ adjustments for baseline differences also raise questions. “Even though MRI was an outcome, it doesn’t appear they adjusted for baseline differences in MRI between the groups,” Dr. Fox observed.

Moreover, the study was conducted over a long period of time. “We know there are time effects in MS, with a very different disease activity expected from patients over time,” said Dr. Fox. For example, relapse rates in placebo groups of MS trials tend to decline over time. “This time effect likely impacted their results.”

But the disability findings may be the most important part of the study, according to Dr. Fox. The lack of significant difference in disability progression between therapies “highlights that a couple relapses or lesions on MRI may be too small to translate into long-term differences in disability progression,” he said.

“The long-term implications of small differences in relapse and MRI outcomes may be very small,” Dr. Fox went on. “Thus, the uncertainty continues around escalation treatment versus initial highly effective treatment paradigms.”

The Patient-Centered Outcomes Research Institute, the Swedish Research Council, and NEURO Sweden funded this study. Mr. Alping disclosed no relevant financial relationships. Dr. Fox receives consulting fees from the companies that manufacture all the therapies analyzed in the study.

A version of this article first appeared on Medscape.com.

Rituximab reduces relapses and MRI activity in patients with relapsing-remitting multiple sclerosis (MS) more effectively than dimethyl fumarate, natalizumab, and injectable drugs, according to new research.

The risk for a first relapse was 6 times higher in patients receiving interferon beta or glatiramer acetate, compared with those receiving rituximab. But the level of disability at 3 years was only marginally different between the drugs studied.

The small differences in Expanded Disability Status Scale (EDSS) score are surprising, said investigator Peter Alping, a clinical assistant and doctoral student in the Department of Clinical Neuroscience at the Karolinska Institutet, Stockholm, as he presented the data. “It could be that we have too-short follow-up, so that EDSS doesn’t have time to diverge between therapies.”

He presented the findings at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

COMBAT-MS study

Direct comparisons of disease-modifying therapies (DMTs) for MS can help neurologists choose the most appropriate treatment for a given patient. To compare the effectiveness of the most common initial DMTs administered in Sweden, the researchers examined data from the COMBAT-MS study.

They identified all patients who initiated an injectable therapy (interferon beta or glatiramer acetate), dimethyl fumarate, natalizumab, or rituximab as a first treatment between Jan. 1, 2011, and Dec. 14, 2020. Eligible participants had prospectively recorded outcome data in the Swedish MS Register. Follow-up for a participant continued even if the participant stopped receiving therapy.

The investigators replaced missing data using multiple imputation. They adjusted for potential confounders using stabilized inverse probability of treatment weighting with baseline variables. These variables included age, sex, disease duration, geographical region, EDSS score, and relapses.
 

Rituximab reduced relapses

The researchers included 1,938 first-ever treatment episodes in their analysis. Of this group, 858 were associated with injectables, 339 with dimethyl fumarate, 269 with natalizumab, and 472 with rituximab.

Participants’ baseline characteristics differed by the DMT that they used. Patients who initiated natalizumab were the youngest, had the shortest disease duration, and had the most previous relapses.

For each outcome, the investigators compared all other therapies with rituximab. After they adjusted the data, they found that the hazard ratio for first relapse was 6.0 for injectables, 2.9 for dimethyl fumarate, and 1.8 for natalizumab.

In the adjusted model, the MRI lesion rate ratio for injectables, compared with rituximab, was 4.5. The rate ratio was 4.8 for dimethyl fumarate and 1.9 for natalizumab.

But differences in EDSS score at 3 years from treatment initiation were small. EDSS score in patients who received injectables was 0.24 points higher, compared with those receiving rituximab. EDSS score was 0.05 points higher in patients receiving dimethyl fumarate and 0.01 points lower in patients receiving natalizumab.

The risk for treatment discontinuation, however, differed significantly between therapies. The HR for treatment discontinuation was 32.7 for injectables, 20.3 for dimethyl fumarate, and 16.3 for natalizumab, compared with rituximab.

Among patients receiving dimethyl fumarate and injectables, the main reasons for discontinuing therapy were inadequate effect and adverse events. The main reason for discontinuation among patients receiving natalizumab was categorized as “other reason,” which mostly reflected John Cunningham virus positivity and concern for developing progressive multifocal leukoencephalopathy.
 

‘The uncertainty continues’

“These differences that we see in the effectiveness can be somewhat surprising, especially when it comes to natalizumab,” which is considered very effective, said Mr. Alping. The vulnerable period that occurs after switching from natalizumab may partly explain the difference. “This is something to keep in mind when starting patients on natalizumab treatment in the clinic,” Mr. Alping added.

Although rituximab is not indicated for MS, many clinics are using it in this population, said Robert Fox, MD, staff neurologist at the Mellen Center for MS and vice chair for research at the Neurological Institute of Cleveland Clinic, both in Cleveland, Ohio. Dr. Fox was not involved in the study.

“Assessing the generalizability of the study outside Sweden will be important,” he added, “but I would be surprised if their findings did not hold up to external validation.”

The way that the researchers addressed missing data could affect the interpretation of the findings. “Depending upon how much data was missing, their imputation methods may have a high level of uncertainty,” said Dr. Fox.

The researchers’ adjustments for baseline differences also raise questions. “Even though MRI was an outcome, it doesn’t appear they adjusted for baseline differences in MRI between the groups,” Dr. Fox observed.

Moreover, the study was conducted over a long period of time. “We know there are time effects in MS, with a very different disease activity expected from patients over time,” said Dr. Fox. For example, relapse rates in placebo groups of MS trials tend to decline over time. “This time effect likely impacted their results.”

But the disability findings may be the most important part of the study, according to Dr. Fox. The lack of significant difference in disability progression between therapies “highlights that a couple relapses or lesions on MRI may be too small to translate into long-term differences in disability progression,” he said.

“The long-term implications of small differences in relapse and MRI outcomes may be very small,” Dr. Fox went on. “Thus, the uncertainty continues around escalation treatment versus initial highly effective treatment paradigms.”

The Patient-Centered Outcomes Research Institute, the Swedish Research Council, and NEURO Sweden funded this study. Mr. Alping disclosed no relevant financial relationships. Dr. Fox receives consulting fees from the companies that manufacture all the therapies analyzed in the study.

A version of this article first appeared on Medscape.com.

Rituximab reduces relapses and MRI activity in patients with relapsing-remitting multiple sclerosis (MS) more effectively than dimethyl fumarate, natalizumab, and injectable drugs, according to new research.

The risk for a first relapse was 6 times higher in patients receiving interferon beta or glatiramer acetate, compared with those receiving rituximab. But the level of disability at 3 years was only marginally different between the drugs studied.

The small differences in Expanded Disability Status Scale (EDSS) score are surprising, said investigator Peter Alping, a clinical assistant and doctoral student in the Department of Clinical Neuroscience at the Karolinska Institutet, Stockholm, as he presented the data. “It could be that we have too-short follow-up, so that EDSS doesn’t have time to diverge between therapies.”

He presented the findings at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

COMBAT-MS study

Direct comparisons of disease-modifying therapies (DMTs) for MS can help neurologists choose the most appropriate treatment for a given patient. To compare the effectiveness of the most common initial DMTs administered in Sweden, the researchers examined data from the COMBAT-MS study.

They identified all patients who initiated an injectable therapy (interferon beta or glatiramer acetate), dimethyl fumarate, natalizumab, or rituximab as a first treatment between Jan. 1, 2011, and Dec. 14, 2020. Eligible participants had prospectively recorded outcome data in the Swedish MS Register. Follow-up for a participant continued even if the participant stopped receiving therapy.

The investigators replaced missing data using multiple imputation. They adjusted for potential confounders using stabilized inverse probability of treatment weighting with baseline variables. These variables included age, sex, disease duration, geographical region, EDSS score, and relapses.
 

Rituximab reduced relapses

The researchers included 1,938 first-ever treatment episodes in their analysis. Of this group, 858 were associated with injectables, 339 with dimethyl fumarate, 269 with natalizumab, and 472 with rituximab.

Participants’ baseline characteristics differed by the DMT that they used. Patients who initiated natalizumab were the youngest, had the shortest disease duration, and had the most previous relapses.

For each outcome, the investigators compared all other therapies with rituximab. After they adjusted the data, they found that the hazard ratio for first relapse was 6.0 for injectables, 2.9 for dimethyl fumarate, and 1.8 for natalizumab.

In the adjusted model, the MRI lesion rate ratio for injectables, compared with rituximab, was 4.5. The rate ratio was 4.8 for dimethyl fumarate and 1.9 for natalizumab.

But differences in EDSS score at 3 years from treatment initiation were small. EDSS score in patients who received injectables was 0.24 points higher, compared with those receiving rituximab. EDSS score was 0.05 points higher in patients receiving dimethyl fumarate and 0.01 points lower in patients receiving natalizumab.

The risk for treatment discontinuation, however, differed significantly between therapies. The HR for treatment discontinuation was 32.7 for injectables, 20.3 for dimethyl fumarate, and 16.3 for natalizumab, compared with rituximab.

Among patients receiving dimethyl fumarate and injectables, the main reasons for discontinuing therapy were inadequate effect and adverse events. The main reason for discontinuation among patients receiving natalizumab was categorized as “other reason,” which mostly reflected John Cunningham virus positivity and concern for developing progressive multifocal leukoencephalopathy.
 

‘The uncertainty continues’

“These differences that we see in the effectiveness can be somewhat surprising, especially when it comes to natalizumab,” which is considered very effective, said Mr. Alping. The vulnerable period that occurs after switching from natalizumab may partly explain the difference. “This is something to keep in mind when starting patients on natalizumab treatment in the clinic,” Mr. Alping added.

Although rituximab is not indicated for MS, many clinics are using it in this population, said Robert Fox, MD, staff neurologist at the Mellen Center for MS and vice chair for research at the Neurological Institute of Cleveland Clinic, both in Cleveland, Ohio. Dr. Fox was not involved in the study.

“Assessing the generalizability of the study outside Sweden will be important,” he added, “but I would be surprised if their findings did not hold up to external validation.”

The way that the researchers addressed missing data could affect the interpretation of the findings. “Depending upon how much data was missing, their imputation methods may have a high level of uncertainty,” said Dr. Fox.

The researchers’ adjustments for baseline differences also raise questions. “Even though MRI was an outcome, it doesn’t appear they adjusted for baseline differences in MRI between the groups,” Dr. Fox observed.

Moreover, the study was conducted over a long period of time. “We know there are time effects in MS, with a very different disease activity expected from patients over time,” said Dr. Fox. For example, relapse rates in placebo groups of MS trials tend to decline over time. “This time effect likely impacted their results.”

But the disability findings may be the most important part of the study, according to Dr. Fox. The lack of significant difference in disability progression between therapies “highlights that a couple relapses or lesions on MRI may be too small to translate into long-term differences in disability progression,” he said.

“The long-term implications of small differences in relapse and MRI outcomes may be very small,” Dr. Fox went on. “Thus, the uncertainty continues around escalation treatment versus initial highly effective treatment paradigms.”

The Patient-Centered Outcomes Research Institute, the Swedish Research Council, and NEURO Sweden funded this study. Mr. Alping disclosed no relevant financial relationships. Dr. Fox receives consulting fees from the companies that manufacture all the therapies analyzed in the study.

A version of this article first appeared on Medscape.com.