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Statement Offers Guidance for Management of Brain AVMs

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A joint statement from the American Heart Association and the American Stroke Association offers clinicans guidance on the management of brain arteriovenous malformations.

Recent studies have helped clarify the natural history risks of intracranial hemorrhage (ICH) and seizure in patients with unruptured brain arteriovenous malformations (AVMs). In addition, researchers have completed the first randomized trial of interventional therapy versus conservative management for unruptured brain AVMs. Nevertheless, data to guide treatment decisions remain limited, and “considerable uncertainties … face physicians managing patients with ruptured and unruptured brain AVMs,” according to a scientific statement for healthcare professionals from the American Heart Association (AHA) and American Stroke Association (ASA). Optimal management of unruptured brain AVMs is a subject of debate, and discussion of treatment options should include careful consideration of natural history risks, the relative risks of intervention strategies, and patients’ life expectancy, the authors said.

The scientific statement on the management of brain AVMs was published in the August issue of Stroke. It updates the American Heart Association’s 2001 statement on this topic. The report reviews epidemiology, diagnosis, natural history, treatment, and management of ruptured and unruptured brain AVMs, as well as areas requiring more evidence. The American Academy of Neurology affirmed the value of the statement as an educational tool for neurologists. The Society of NeuroInterventional Surgery endorsed it, and the American Association of Neurological Surgeons/Congress of Neurological Surgeons Joint Cerebrovascular Section affirmed its educational benefit.

An Uncommon Lesion

Brain AVMs are uncommon, may present with spontaneous ICH, seizures, or headache, and typically present in young adults. Neurologists may identify incidental asymptomatic AVMs when patients undergo brain imaging for other reasons. The primary goal of treatment is prevention of hemorrhagic stroke.

Colin P. Derdeyn, MD, Professor of Neurology and Radiology at the University of Iowa in Iowa City and chair of the group that wrote the scientific statement, and colleagues searched all English-language articles on brain AVMs in humans that had been published following the 2001 statement. “Advances … include the accumulation of new data related to epidemiology, biology, imaging, outcomes with treatment, and introduction of new embolic agents,” the authors said. “Most notable of these data are the results of the first randomized trial of intervention for unruptured brain AVMs, the ARUBA trial (A Randomized Trial of Unruptured Brain Arteriovenous Malformations).”

ARUBA enrolled 226 adult patients with unruptured brain AVMs between 2007 and 2013. Patients were randomized to receive medical management alone or medical management with interventional therapy (eg, resection, embolization, or stereotactic radiosurgery alone or in combination).

A preplanned interim analysis found that after a mean follow-up of 33 months, the risk of stroke or death was more than three times higher in the intervention group (30.7%) than in the medical management group (10.1%). The analysis included data from 224 participants at 39 sites worldwide. On the recommendation of the ARUBA Data and Safety Monitoring Board, the National Institute of Neurological Disorders and Stroke stopped enrollment and stated that “under the experimental conditions in this trial, the interim analysis … shows that medical management is superior to intervention in patients with unruptured brain AVMs.”

Although ARUBA and an observational study by Al-Shahi Salman et al support a conservative approach to management, the studies had relatively short follow-up, considering the long duration of hemorrhage risk for patients with untreated brain AVMs. Furthermore, complication rates in the treatment arms in ARUBA were much higher than expected, the authors said. “The primary end points of ARUBA [ie, stroke or death] in the intervention group for Spetzler-Martin (SM) grade I (14.3%), II (43.3%), and III (57.1%) AVMs are higher than would have been expected in contemporary series, particularly for surgery or radiosurgery performed alone,” the authors said.

Additional studies are needed to better define long-term risks of stroke and seizure and to identify specific predictors of hemorrhagic stroke. “Long-term follow-up of participants in the ARUBA trial will be valuable for determining whether the superiority of conservative management over intervention observed in that study persists in the long term,” they said. “Further randomized controlled trials are justified to investigate the reproducibility of the findings of ARUBA and to investigate whether the balance of risk between conservative management and intervention is different in specific groups (eg, patients with SM grade I brain AVM).”

Recommendations for Management

Neurologists can inform patients about natural history risks, which are reliably quantified over approximately 10 years for ICH and approximately five years for epileptic seizure, the authors said. The annual risk of a first-ever ICH from an unruptured brain AVM is approximately 1%. The five-year risk of developing a first seizure is approximately 8%, and the five-year risk of developing epilepsy after a first seizure is approximately 58%.

Discussion of treatment options should consider natural history risks “weighed carefully against the relative risks of different intervention strategies and life expectancy,” the authors said. The SM grading scale is useful for predicting the risk of surgical resection.

For the management of patients with ruptured brain AVMs, the authors recommend that the evaluation of underlying brain AVMs and management of an initial hemorrhage follow the AHA and ASA’s 2015 spontaneous ICH management guidelines. The annual risk of recurrent ICH from a ruptured brain AVM is approximately 5%, and increasing age, deep venous drainage, arterial aneurysms, and female sex may increase the risk.

—Jake Remaly

Opioids Are Overprescribed for Migraine

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An investigation into racial disparities in migraine treatment found no evidence of such but did find that opioids are overused, migraine-specific drugs are underused, and migrainerurs may be undertreated with preventive medications.

Opiates are overused, and acute analgesics with high-quality evidence may be underused, for the treatment of migraine, according to research published online ahead of print June 26 in Cephalalgia. In addition, migraine may be undertreated with preventive medications. These prescribing patterns do not significantly differ by patients’ race, however.

“People were prescribed opioids as much as they were prescribed medications that are much better for migraines,” said lead author Larry Charleston IV, MD, Assistant Professor of Neurology at the University of Michigan Medical School in Ann Arbor. Opiate-related mortality is rapidly increasing in the United States. Evidence suggests that opiates are less effective than nonopiate alternatives and should be used rarely, if at all, the authors noted.

Analyzing Nationally Representative Data

In the US, racial disparities in migraine burden have been reported. Migraine in African Americans is more frequent, more severe, more likely to become chronic, and associated with more depression and lower quality of life, compared with migraine in non-Hispanic whites. Lower-quality medication treatment for migraine may explain this difference, but little is known about the quality of migraine prescribing patterns in the US or whether racial differences exist.

Dr. Charleston and James F. Burke, MD, Associate Professor of Neurology at the University of Michigan Medical School, hypothesized that racial differences in the use of high-quality abortive, prophylactic medications would exist in ambulatory care settings, and that the quality of medical treatment for migraine disorders would be suboptimal in minority populations. To test these hypotheses, they analyzed all headache visits for patients over age 18 in the National Ambulatory Medical Care Survey (NAMCS) from 2006 to 2013.

The investigators defined quality of migraine care by using the American Academy of Neurology Headache Quality Measure Set. Researchers then assigned patients to one of three race or ethnicity categories—non-Hispanic white, African American, and Hispanic. Patients who reported other races or ethnicities were excluded.

The researchers assigned patients to one of four abortive agent categories—no abortive agent prescribed, all high-quality abortive agents (ie, triptans or dihydroergotamine), some low-quality abortive agents, or any opiate agent. In addition, the investigators assigned patients to one of four prophylactic agent categories—no prophylactic agent, all high-quality prophylaxis, some low-quality prophylaxis, or all low-quality prophylaxis. Finally, researchers made racial comparisons using descriptive statistics after applying NAMCS survey weights.

Prophylactic Agents Are Likely Underused

A total of 2,860 visits were included in the study, representing approximately 50 million migraine visits in the US from 2006 to 2013; 76% of patients were non-Hispanic white, 10% were African American, and 10% were Hispanic. Hispanic patients were more likely to be seen in a given practice for the first time, compared with non-Hispanic whites or African Americans. Researchers also observed a trend toward less private insurance and more Medicaid among African American and Hispanic patients, compared with non-Hispanic white patients.

Although overall migraine prescribing patterns were suboptimal, researchers did not find any major differences by race. “It is possible, though, that more modest racial differences in abortive prescribing exist, but that we lacked statistical power to identify those differences,” said Drs. Charleston and Burke.

In all, 41.3% of African Americans, 40.8% of non-Hispanic whites, and 41.2% of Hispanic patients received no prophylactic treatment. A total of 18.8% of African Americans, 11.9% of non-Hispanic whites, and 6.9% of Hispanic patients received exclusively Level A prophylaxis.

Forty-seven percent of African Americans, 38.2% of non-Hispanic whites, and 36.3% of Hispanic patients received no abortive treatments. In all, 15.3% of African Americans, 19.4% of non-Hispanic whites, and 17.7% of Hispanic patients received exclusively Level A abortive agents. About 15.2% of patients had a prescription for opiates, but no racial differences were observed.

In addition, African Americans were 4% less likely to receive all high-quality abortive agents, and Hispanic patients were 5% less likely to receive all high-quality prophylactic agents, compared with non-Hispanic whites. Neither of these differences was statistically significant, said the researchers.

“Understanding what drives these prescribing patterns and improving overall migraine prescribing should be a central concern for headache care practitioners and quality-improvement initiatives, and a target of future interventions,” said Drs. Charleston and Burke.

One limitation of this study was that researchers had no details on headache severity or duration. Another limitation was that the researchers did not control for socioeconomic status.

—Erica Tricarico

EEG-Based Risk Score May Predict Likelihood of Seizures in Hospitalized Patients

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The 2HELPS2B score ranges from 0–7 and indicates a seizure risk of 5% to greater than 95%.

A risk score based on EEG variables and seizure history may quickly and accurately aid clinical judgment of seizure risk in patients who are critically ill, according to research published online ahead of print October 9 in JAMA Neurology.

Studies have detected a high incidence of subclinical seizures in patients with sepsis, traumatic brain injury, and other conditions, but no simple, validated method exists to assess a patient’s seizure risk using a combination of factors. Aaron F. Struck, MD, Assistant Professor of Neurology at the University of Wisconsin in Madison, and colleagues sought to create a simple scoring system associated with the probability of seizures in patients with acute illness.

Data From Three Centers

The investigators created the scoring system using data from a multicenter prospective database. The database included clinical and electrographic variables from patients who had more than six hours of uninterrupted EEG recordings for clinical indications other than epilepsy monitoring unit admissions. The continuous EEG sessions were recorded at Emory University Hospital in Atlanta, Brigham and Women’s Hospital in Boston, and Yale New Haven Hospital in Connecticut. In all, 5,427 continuous EEGs were performed on 4,772 patients (49.9% men; median age, 61).

To build their scoring model, the investigators used a machine-learning method, Risk-Calibrated Supersparse Linear Integer Model (RiskSLIM), that considered 24 candidate variables. The researchers used cross-validation to validate the model’s accuracy and risk calibration.

The final model, which the researchers called 2HELPS2B, had an area under the curve of 0.819 and an average calibration error of 2.7%. A patient’s score ranges from 0–7 and is based on the following six variables:

brief (ictal) rhythmic discharges (B[I]RDS) (2 points)
presence of lateralized periodic discharges, lateralized rhythmic delta activity, or bilateral independent periodic discharges (1 point)
prior seizure (1 point)
sporadic epileptiform discharges (1 point)
frequency greater than 2.0 Hz for any periodic or rhythmic pattern (1 point)
presence of “plus” features (ie, superimposed, rhythmic, sharp, or fast activity) (1 point).

The seizure risk associated with each score from 0–5 was 5%, 12%, 27%, 50%, 73%, and 88%, respectively. For a score of 6 or 7, the probable seizure risk was greater than 95%.

The large sample size and use of data from multiple centers are among the study’s strengths. Limitations of the study include that duration of EEG was not included in the database, and that no sessions of less than six hours were included in the study.

“The 2HELPS2B score is an easy-to-use tool to augment clinical judgment of the risk for seizures in individual patients,” Dr. Struck and colleagues said. “The simplicity of the system allows for easy integration into clinical workflow. With increasing familiarity, 2HELPS2B will improve communication between EEG interpreters and clinicians through the use of a quickly comprehensible single number to describe seizure risk for patients on continuous EEG.”

Questions Remain

The investigators designed “a simple scale with good accuracy, which can be easily used by clinicians to estimate seizure risk in their patients,” said Barry M. Czeisler, MD, Assistant Professor of Neurology and Neurosurgery at New York University School of Medicine, and Jan Claassen, MD, PhD, Associate Professor of Neurology at Columbia University College of Physicians and Surgeons in New York, in an accompanying editorial. Still, the score is unvalidated for prediction based on less than six hours of EEG recordings and should be validated in prospective studies, they said.

A seizure risk scale has the potential to inform clinical practice. “Certain patients may not need to stay on continuous EEG for a long time if their seizure risk is low,” but an acceptable level of risk remains unclear, said Drs. Czeisler and Claassen. In addition, the score potentially could guide which patterns of features warrant more aggressive treatment, such as with additional antiepileptic medication. “Appropriate risk stratification using 2HELPS2B may allow us to answer these questions adequately in the near future,” they said. “The development of adequate measurement tools is often necessary to appropriately study a condition, which in turn may allow for future optimization of treatment algorithms.”

—Jake Remaly

Poor Cognitive Function Is Associated With Increased Risk of Parkinsonism

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Results suggest the possibility of early intervention and support the Braak hypothesis of Parkinson’s disease progression.

Poor cognitive function is associated with an increased risk of incident parkinsonism, including probable Parkinson’s disease, according to research published online ahead of print September 25 in JAMA Neurology. The association is strong beyond eight years of follow-up and holds for patients with incident parkinsonism without dementia.

Cognitive loss is not among the Movement Disorder Society’s criteria for prodromal Parkinson’s disease because prospective evidence about this variable was lacking when the criteria were developed. “Our results, as well as those of other published studies, suggest that cognitive dysfunction now warrants inclusion as a prodromal marker,” said Sirwan K. L. Darweesh, MD, of the Department of Epidemiology at Erasmus MC University Medical Center in Rotterdam, the Netherlands.

Prospective Data From the Rotterdam Study

Dr. Darweesh and colleagues conducted research to test their hypothesis that poor cognitive function is associated with an increased risk of parkinsonism. They examined participants in the prospective, population-based Rotterdam Study, which began in 1990. The study instituted a comprehensive battery of cognitive tests between 2002 and 2008, and Dr. Darweesh and colleagues used this period as the baseline of their investigation. During this time, researchers assessed cognitive function in 7,386 participants who were free of parkinsonism and dementia. The assessments included the Stroop color word test, letter-digit substitution, verbal fluency, and word learning.

During follow-up, participants presented for serial in-person examinations, and investigators had full access to participants’ medical records. Follow-up ended on January 1, 2015. The main outcome was the hazard ratio for incident parkinsonism per standard deviation decrease in global cognition. The researchers adjusted the data for age and sex.

Education Did Not Affect the Association

The population’s mean age was 65, and 57.4% of the population was female. During a median follow-up of 8.3 years, 79 participants (1.1%) received a diagnosis of incident parkinsonism. Of these patients, 57 (72.2%) received a diagnosis of probable Parkinson’s disease. Among participants with incident parkinsonism, 24 (30.4%) received a diagnosis of incident dementia. In addition, 446 people (6.1%) who remained free of incident parkinsonism received a diagnosis of incident dementia.

Each standard-deviation decrease in global cognition was associated with a 79% increase in the risk of incident parkinsonism. After the researchers censored people with incident dementia and restricted the analysis to patients with incident parkinsonism who were examined by a neurologist or geriatrician, the association remained strong beyond the first eight years of follow-up. Adjustment for education did not affect the association, but adjustment for subtle motor signs weakened it slightly. Poor cognitive functioning also was associated with probable Parkinson’s disease (hazard ratio [HR], 1.52) and with a joint end point of probable Parkinson’s disease or dementia with Lewy bodies (HR, 1.59).

Incident parkinsonism was associated with lower scores on letter-digit substitution (HR, 1.59), verbal fluency (HR, 1.61), and inverted interference task Stroop color word test (HR, 1.56). The association with word learning delayed-task scores was weaker (HR, 1.18).

A possible explanation for the association is that “low baseline cognitive scores may indicate ongoing cognitive decline in prediagnostic patients who probably will develop parkinsonism, most of whom have prediagnostic Parkinson’s disease.” Another possible explanation is that people who probably will develop parkinsonism in mid- or late life never attain a high level of cognitive functioning in early life, said the researchers.

Results May Prompt Screening and Interventions

The study results are broadly applicable because they come from a large, community-based cohort with low attrition, said Ethan G. Brown, MD, a clinical fellow, and Caroline M. Tanner, MD, PhD, Professor of Neurology, both at the University of California, San Francisco, in an accompanying editorial. The researchers may have overlooked some participants’ cognitive impairment, however, because the neuropsychologic assessment was not as thorough as recommended. Also, the study design made specialist adjudication of all diagnoses of Parkinson’s disease impossible, and the primary outcome was incident parkinsonism, rather than incident Parkinson’s disease.

The findings nevertheless reiterate the presence of cognitive impairment early in Parkinson’s disease, thus emphasizing the need for therapeutic trials to target this symptom, said Drs. Brown and Tanner. The study also provides guidance for identifying people most at risk for Parkinson’s disease.

In addition, Dr. Darweesh’s group has found evidence that supports the Braak hypothesis about Parkinson’s disease progression, said Drs. Brown and Tanner. The data challenge the idea that synuclein pathology always spreads through the vagus and substantia nigra.

“Now we … know that people with early mild cognitive impairment, especially in the setting of subtle motor findings, may have prodromal Parkinson’s disease,” said Drs. Brown and Tanner. “This recognition can allow physicians to screen for falls or other nonmotor aspects of Parkinson’s disease in these cases and provide early treatment for these symptoms. Physicians may recommend interventions, such as physical activity, that are helpful for motor and cognitive changes in Parkinson’s disease.”

—Erik Greb

Trials Clarify Benefit of PFO Closure After Stroke

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Closure of a patent foramen ovale after cryptogenic stroke reduces recurrent stroke risk, according to results from three randomized trials.

Among patients with a patent foramen ovale (PFO) who have had a cryptogenic stroke, closure of the PFO reduces the risk of recurrent stroke, compared with medical therapy alone, according to three studies published in the September 14 issue of the New England Journal of Medicine. PFO closure, however, entailed increased risk of atrial fibrillation and, in two of the studies, venous thromboembolism.

In prior trials, PFO closure did not have a statistically significant effect on stroke risk, although the results suggested potential benefit. In an editorial accompanying the new trial results, Allan H. Ropper, MD, said that various limitations of the prior studies, including inclusion of patients whose prior stroke would not benefit from PFO closure, could help explain the positive results of the current studies—the CLOSE and Gore REDUCE trials and extended follow-up from the RESPECT trial. Dr. Ropper is Professor of Neurology at Harvard Medical School and Raymond D. Adams Master Clinician and Executive Vice Chairman of the Department of Neurology at Brigham and Women’s Hospital in Boston.

Persuasive Effect

Together, the trials indicate the importance of considering the characteristics of a PFO when assessing whether a patient may be an appropriate candidate for the procedure, Dr. Ropper said. In the CLOSE trial, patients had to have a large interatrial shunt at rest or an atrial septal aneurysm. While rates of stroke in the PFO closure groups in all of the studies were low, “in the CLOSE trial, no patient in the PFO closure group had a stroke, whereas stroke occurred in 6% of the patients in the antiplatelet-only group.”

The Gore REDUCE trial represented a “middle ground” in that most patients (81%) had a moderate or large interatrial shunt. In that trial, PFO closure was associated with significantly reduced risk of recurrent stroke, compared with antiplatelet therapy alone (1.4% vs 5.4%).

The primary analysis of the RESPECT trial, published in 2013, suggested a potential benefit, but the primary result was not statistically significant. The trial nevertheless provided a reasonable assurance of safety and effectiveness, and the FDA approved the device studied in the trial, the Amplatzer PFO Occluder (St. Jude Medical, St. Paul), in October 2016. The primary analysis included a median of 2.1 years of follow-up, whereas the current analysis included a median of 5.9 years of follow-up. Through the extended follow-up, 3.6% of patients in the PFO closure group had recurrent ischemic stroke, compared with 5.8% of patients in the medical therapy group.

“Therefore, in patients who have had a stroke, are younger than 60 years of age, and have a PFO with characteristics that are highly likely to allow paradoxical embolism to occur, the effect of closure becomes persuasive,” Dr. Ropper said. “Restricting PFO closure entirely to patients with high-risk characteristics of the PFO may perhaps be too conservative, but the boundaries of the features that support the procedure are becoming clearer.”

CLOSE

In the CLOSE trial, Jean-Louis Mas, MD, Professor of Neurology at Paris Descartes University and Head of the Neurology Department at Sainte-Anne Hospital in Paris, and colleagues enrolled patients who had had a recent cryptogenic stroke attributed to a PFO with an associated atrial septal aneurysm or large interatrial shunt.

The investigators assigned in a 1:1:1 ratio patients age 16 to 60 to transcatheter PFO closure plus long-term antiplatelet therapy, antiplatelet therapy alone, or oral anticoagulation. The primary outcome was occurrence of stroke. In all, 663 patients were randomized and followed for a mean of 5.3 years.

“No stroke occurred among the 238 patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the antiplatelet-only group (hazard ratio, 0.03),” the researchers said. “Procedural complication from PFO closure occurred in 14 patients (5.9%). The rate of atrial fibrillation was higher in the PFO closure group than in the antiplatelet-only group (4.6% vs 0.9%). The number of serious adverse events did not differ significantly between the treatment groups.” The trial was underpowered to determine the effects of oral anticoagulant therapy versus antiplatelet therapy.

Unlike in prior studies, CLOSE “included only patients who had PFO features that have been associated with cryptogenic stroke” and researchers “used a standardized evaluation to define a previous cryptogenic stroke,” the authors noted.

REDUCE

In the Gore REDUCE trial, investigators enrolled patients with a PFO who had had a cryptogenic stroke. Lars Søndergaard, MD, of the Department of Cardiology at Rigshospitalet, University of Copenhagen, and colleagues randomly assigned patients 2:1 to undergo PFO closure (with the Helex Septal Occluder or Cardioform Septal Occluder; W.L. Gore and Associates, Newark, Delaware) plus antiplatelet therapy or to receive antiplatelet therapy alone. Patients underwent brain imaging at baseline and 24 months. Coprimary end points were freedom from clinical evidence of ischemic stroke through at least 24 months after randomization and the 24-month incidence of new brain infarction (ie, clinical ischemic stroke or silent brain infarction on imaging).

The investigators enrolled 664 patients (mean age, 45.2). During a median follow-up of 3.2 years, clinical ischemic stroke occurred in six of 441 patients (1.4%) in the PFO closure group and in 12 of 223 patients (5.4%) in the antiplatelet-only group (hazard ratio, 0.23). The incidence of new brain infarctions was lower in the PFO closure group than in the antiplatelet-only group (5.7% vs 11.3%), but the incidence of silent brain infarction did not differ significantly between the study groups.

Serious adverse events occurred in 23.1% of the patients in the PFO closure group and 27.8% of the patients in the antiplatelet-only group. Serious device-related adverse events occurred in six patients (1.4%) in the PFO closure group. Atrial fibrillation or flutter occurred in significantly more patients in the PFO closure group than in the antiplatelet-only group (6.6% vs 0.4%). Most cases of atrial fibrillation or flutter were detected within 45 days after the procedure and resolved within two weeks after onset.

RESPECT

In RESPECT, among patients age 18 to 60 who had had a cryptogenic ischemic stroke, closure of a PFO was associated with a lower rate of recurrent ischemic strokes than medical therapy alone during extended follow-up.

Jeffrey L. Saver, MD, Director of the University of California, Los Angeles Comprehensive Stroke Center and Professor of Neurology at the David Geffen School of Medicine at UCLA, and colleagues randomly assigned patients who had a PFO and had had a cryptogenic ischemic stroke to undergo closure of the PFO with the Amplatzer PFO Occluder or to receive medical therapy alone (ie, aspirin, warfarin, clopidogrel, or aspirin combined with extended-release dipyridamole). After the device was implanted, patients in the PFO closure group received aspirin plus clopidogrel daily for one month, followed by aspirin monotherapy for five months. Subsequent antithrombotic therapy was at the site investigator’s discretion.

The investigators enrolled 980 patients (mean age, 45.9) at 69 sites and followed patients for a median of 5.9 years. In the intention-to-treat population, recurrent ischemic stroke occurred in 18 patients in the PFO closure group (3.6%) and in 28 patients in the medical-therapy group (5.8%), resulting in rates of 0.58 events per 100 patient-years and 1.07 events per 100 patient-years, respectively (hazard ratio with PFO closure vs medical therapy, 0.55).

“The relative difference in the rate of recurrent ischemic stroke between PFO closure and medical therapy alone was large (45% lower with PFO closure), but the absolute difference was small (0.49 fewer events per 100 patient-years with PFO closure),” the authors said. “Nonetheless, the cumulative absolute benefit had clinical relevance, since patients in this trial were younger … than the general population of patients who have stroke and thus faced a longer period of risk for recurrent stroke.”

Venous thromboembolism (ie, pulmonary embolism and deep-vein thrombosis) was more common in the PFO closure group than in the medical-therapy group. Among patients in the PFO closure group, those with a history of overt deep-vein thrombosis had a higher incidence of venous thromboembolic events. A lower intensity of antithrombotic therapy, including less common use of anticoagulant agents, in the PFO closure group, compared with the medical therapy group, “may have contributed to the higher rate of venous thromboembolism in the PFO closure group,” the researchers said. “These findings provide indirect support for the recent revision in the national management guidelines that endorsed lifelong anticoagulation therapy in patients with overt deep-vein thrombosis.”

In addition, seven periprocedural events of atrial fibrillation occurred in the PFO closure group, all of which resolved before the patients’ discharge from the hospital.

Assessment by Neurologist and Cardiologist Is Key

“The key to appropriate device use is comprehensive clinical assessment by both a neurologist and a cardiologist to confirm the diagnosis of ischemic stroke and exclude other possible causes,” said Andrew Farb, MD, of the FDA’s Center for Devices and Radiological Health in Silver Spring, Maryland, and colleagues, in a perspective accompanying the RESPECT trial results. The Amplatzer PFO Occluder’s labeled directions for use outline the recommended evaluation, which includes brain MRI or CT, transesophageal echocardiography, prolonged cardiac rhythm monitoring, intracranial and extracranial arterial imaging, and assessment for a hypercoagulable state. “Clearly, a deliberate, systematic assessment of the patient’s underlying conditions and the risks associated with ischemic stroke is needed before closure of a PFO can be recommended,” Dr. Farb and his coauthors said. The published results of the REDUCE and CLOSE trials “appear to support the general conclusions reached by the FDA in the evaluation of the Amplatzer PFO Occluder,” they said.

—Jake Remaly

Are Two Antithrombotic Agents Better Than Three?

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Researchers compare dual antithrombotic therapy that includes dabigatran with triple antithrombotic therapy that includes warfarin.

Dual antithrombotic therapy with dabigatran and a P2Y12 inhibitor (eg, clopidogrel or ticagrelor) is associated with a lower risk of bleeding, compared with standard triple antithrombotic therapy, after percutaneous coronary intervention (PCI) for patients with atrial fibrillation, according to research published online ahead of print August 27 in the New England Journal of Medicine. Dual therapy also is noninferior to triple therapy regarding the risk of thromboembolic events.

“Patients who received two anticlotting medications—including one of a newer class of drug—had fewer bleeding events without being more at risk for a stroke or other cardiac events,” said Christopher P. Cannon, MD, Professor of Medicine at Harvard Medical School and a cardiovascular medicine specialist at Brigham and Women’s Hospital in Boston, and colleagues.

Standard triple antithrombotic therapy (ie, warfarin plus two antiplatelet agents) has been associated with a high risk of bleeding, thus prompting researchers to seek a better approach to treatment. One emerging therapy omits aspirin from the standard regimen and uses a single P2Y₁₂inhibitor in combination with an oral anticoagulant. A moderate-sized trial found that this form of dual-therapy lowered the risk of bleeding, compared with standard triple therapy. Another trial supported standard triple therapy for a shorter duration. Finally, a recent trial found that the risk of bleeding was lower with a regimen of reduced-dose rivaroxaban plus a P2Y₁₂ inhibitor than with standard triple therapy.

Dual Therapy Versus Triple Therapy

To compare two regimens of dual antithrombotic therapy that include dabigatran with a regimen of triple antithrombotic therapy that includes warfarin, Dr. Cannon and colleagues conducted the RE-DUAL PCI trial. Eligible participants were 18 or older, had nonvalvular atrial fibrillation, and had successfully undergone PCI with a bare-metal or drug-eluting stent within the previous 120 hours. Patients with bioprosthetic or mechanical heart valves, severe renal insufficiency, or other major coexisting conditions were excluded.

All patients in the United States and nonelderly patients in other countries were randomized 1:1:1 to receive triple therapy with warfarin plus a PSY₁₂ inhibitor and aspirin for one to three months, or to receive dual therapy with dabigatran (110 mg or 150 mg twice daily) plus a P2Y₁₂ inhibitor and no aspirin. Outside the US, elderly patients (ie, 70 or older in Japan and 80 or older elsewhere) were randomized 1:1 to receive 110 mg of dual therapy or triple therapy.

The primary end point was the first major or clinically relevant nonmajor bleeding event. A major secondary end point was the composite of thromboembolic events (ie, myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization. Other secondary end points included a composite of thromboembolic events or death, as well as the individual thromboembolic events and definite stent thrombosis.

No Significant Difference in Serious Adverse Events Between Groups

Between July 21, 2014, and October 31, 2016, 2,725 participants underwent randomization at 414 sites in 41 countries. The mean age of participants was 70.8. The mean duration of treatment with the trial anticoagulant was 12.3 months, and the mean duration of follow-up was 14 months. Six patients were lost to follow-up. Most patients received clopidogrel as their P2Y₁₂inhibitor, and 12% received ticagrelor.

The incidence of the primary end point was 15.4% in the 110-mg dual-therapy group, compared with 26.9% in the triple-therapy group, and 20.2% in the 150-mg dual-therapy group, compared with 25.7% in the corresponding triple-therapy group. The incidence of the composite efficacy end point was 13.7% in both dual-therapy groups combined, compared with 13.4% in the triple-therapy group.

Researchers found no significant difference between groups in the rate of serious adverse events. Fatal serious adverse events occurred during treatment in 38 patients in the 100-mg dual-therapy group, 24 patients in the 150-mg dual-therapy group, and 41 patients in the triple-therapy group.

“We now have new information to help select the right treatment for individual patients,” said Dr. Cannon. “With respect to the results for both the bleeding and thromboembolic-event end points, we may only speculate on the relative contributions of the omission of aspirin and the type of oral anticoagulant in the dual-therapy groups and the triple-therapy group. A trial conducted with a formal two-by-two factorial design would be able to discern these contributions, and one such trial is ongoing.”

One limitation of this trial was that researchers enrolled a smaller number of patients than initially planned. The power of the trial to examine efficacy according to dabigatran dose consequently was limited, said the authors.

This study was supported by Boehringer Ingelheim.

—Erica Tricarico

Loss of Functional Connectivity May Cause Hallucinations in Parkinson’s Disease

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Hallucinations may result from a global loss of network efficiency, rather than from a focal disturbance.

Visual hallucinations in Parkinson’s disease may arise from a global loss of network efficiency in the brain that disturbs visual attention and visual processing, according to research published online ahead of print September 27 in Radiology. A specific pattern of brain disconnection on fMRI may therefore help predict the development of visual hallucinations in patients with Parkinson’s disease.

An imperfect understanding of the pathophysiology behind visual hallucinations in Parkinson’s disease has hindered the development of effective treatments. Previous fMRI studies of these symptoms focused on task-based imaging, but visual hallucinations are associated with the development of cognitive decline, which could have influenced participants’ ability to perform specific tasks in the imager.

Dagmar H. Hepp, MD, of the Department of Neurology at VU University Medical Center in Amsterdam, and colleagues retrospectively examined resting-state fMRI data for 55 patients with Parkinson’s disease and 15 healthy controls who participated in a prospective cohort study. Of the participants with Parkinson’s disease, 15 had visual hallucinations. Dr. Hepp’s team calculated functional connectivity between 47 brain regions of interest. They compared whole-brain and region-specific means of connectivity using a general linear model with false discovery rate control for multiple comparisons.

In eight regions in the occipital lobe and paracentral area, functional connectivity was lower in all patients with Parkinson’s disease, compared with controls. Compared with controls, patients with Parkinson’s disease and visual hallucinations—but not patients with Parkinson’s disease without visual hallucinations—had nine brain regions with reduced functional connectivity. These regions were in the frontal cortex (ie, the superior frontal gyrus), temporal cortex (eg, the superior temporal gyrus), rolandic operculum, occipital cortex, and striatum. Connectivity of the superior temporal gyrus was correlated with orientation, attention, praxis, perception, and intraextra dimensional set shifting. Loss of functional connectivity of the rolandic operculum correlated with lower cognitive test scores in the subdomains of praxis and perception.

The superior frontal gyrus contributes to the allocation and maintenance of visuospatial attention and inhibitory control. This region also may allow an individual to reflect on sensory experience and judge its possible significance in relation to the self. Investigators believe that the superior temporal gyrus influences visual attention and controls the dorsal and ventral visual streams. Disconnection of frontal and temporal areas may impair the discrimination of external perceptions from internally generated information.

“Our findings argue against the notion that a single specific functional brain region or network is the neural substrate of visual hallucinations in Parkinson’s disease, but rather supply further evidence for a more global loss of network efficiency, which could drive disturbed attentional and visual processing and thereby lead to visual hallucinations in Parkinson’s disease,” the authors concluded.

—Erik Greb

Smell Test May Identify Increased Risk of Parkinson’s Disease

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The association between hyposmia and Parkinson’s disease appears stronger among whites than among blacks.

A smell test may identify people at increased risk of incident Parkinson’s disease as many as 10 years before diagnosis, according to research published in the October 3 issue of Neurology. The association between poor olfaction and incident Parkinson’s disease may be stronger among men than among women, and among whites than among blacks, and this possibility requires further investigation, said the authors.

“Earlier studies had shown prediction of Parkinson’s disease about four to five years after the smell test was taken,” said Honglei Chen, MD, PhD, Professor of Epidemiology and Biostatistics at the Michigan State University College of Human Medicine in East Lansing. “Our study shows that this test may be able to inform the risk much earlier than that.”

A Prospective Study of the Elderly

Dr. Chen and colleagues examined data for 1,510 white participants and 952 black participants in the Health, Aging, and Body Composition study. During clinical examinations in 1999 and 2000, the participants underwent the Brief Smell Identification Test (BSIT). The researchers followed the population until the date of Parkinson’s disease diagnosis, death, last contact, or August 31, 2012, whichever came first. Parkinson’s disease was diagnosed retrospectively using several data sources. Dr. Chen and colleagues used multivariable Cox models to estimate hazard ratios for Parkinson’s disease.

Participants’ mean age was 76. About 49% of participants were male, and approximately 39% of the population was black. During a mean follow-up duration of 9.8 years, the researchers identified 42 incident cases of Parkinson’s disease, including 30 white participants and 12 black participants.

Patients in the lowest tertile of BSIT scores (ie, those with the worst olfaction) were older and more likely to be male, black, and current smokers, compared with participants in the highest tertile of BSIT scores. Participants in the lowest BSIT tertile also were less likely to report education beyond high school or optimal health.

Olfaction Predicted Parkinson’s Disease

Overall, poor olfaction was associated with a higher risk of Parkinson’s disease. Compared with the highest BSIT tertile, the hazard ratio for Parkinson’s disease was 1.3 for the middle tertile and 4.8 for the lowest tertile. The association between olfaction and Parkinson’s disease was stronger among whites than among blacks, and stronger among men than among women.

Furthermore, the association between olfaction and Parkinson’s disease was significant for the first five years of follow-up, as well as for the period of follow-up after five years. In lagged analyses that excluded the first years of follow-up, the association remained similarly strong for the first six years of follow-up (hazard ratio, 4.1–5.0), after which point the hazard ratio decreased to 2.9.

“Previous studies have shown that black people are more likely to have a poor sense of smell than whites, and yet may be less likely to develop Parkinson’s disease,” said Dr. Chen. “We found no statistical significance for a link between poor sense of smell and Parkinson’s disease in blacks, but that may have been due to the small sample size. More research is needed to further investigate a possible link.”

Several Factors Could Explain Hyposmia

“The observation that black participants have higher prevalence of hyposmia yet lower incidence of Parkinson’s disease needs further clarification to determine whether this observation is simply methodologic … or if there is a true biologic explanation,” said Gene L. Bowman, ND, MPH, Adjunct Assistant Professor of Neurology at Oregon Health and Science University in Portland, in an accompanying editorial.

One of the study’s limitations is that other factors besides neurodegeneration could explain hyposmia. The cause of the olfactory dysfunction observed in the study could be a subject for further research. “More granularity on the specific aspects of the smell tests that are impaired (eg, detection, identification, intensity) would help time-constrained clinicians focus on the most relevant tests,” Dr. Bowman concluded.

—Erik Greb

How Does Cladribine Compare With Other MS Therapies?

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An observational study confirms cladribine’s benefits and provides information about its comparative efficacy.

New data confirm cladribine’s efficacy as a treatment for relapsing-remitting multiple sclerosis (MS), according to results published online ahead of print August 1 in Multiple Sclerosis Journal. The drug’s effect on relapses is comparable to that of fingolimod, and its effect on disability accumulation is comparable to those of interferon β and fingolimod. Compared with interferon, fingolimod, and natalizumab, cladribine may be associated with superior recovery from disability.

A phase III trial demonstrated that, compared with placebo, cladribine reduced relapse rate and increased the likelihood of remaining free from three-month confirmed disability progression in patients with relapsing-remitting MS. The European Medicines Agency approved the therapy in August 2017. Cladribine’s potential position in the treatment landscape is unclear, however, because no direct comparisons of cladribine with other MS therapies are available.

An Analysis of Matched Cohorts

Tomas Kalincik, MD, PhD, Professor of Medicine at Royal Melbourne Hospital in Australia, and colleagues conducted a propensity score–matched analysis of observational data from MSBase, including patients from the Australian Cladribine Product Familiarization Program, to compare the effectiveness of cladribine to that of interferon β, fingolimod, and natalizumab. Eligible participants had relapsing-remitting MS, received one of the study medications as monotherapy for one or more years, and had no prior exposure to alemtuzumab, mitoxantrone, rituximab, or hematopoietic stem cell transplantation.

Patients received 3.5 mg/kg of oral cladribine, 44 μg of subcutaneous interferon β-1a three times weekly, 0.5 mg/day of oral fingolimod, or 300 μg of IV natalizumab every four weeks. Data were recorded during routine clinical practice. The primary end points were the proportion of patients free from relapses, disability accumulation, and disability improvement while on study therapy.

Cladribine Was Associated With Superior Disability Improvement

The researchers included 37 patients treated with cladribine, 1,940 patients treated with interferon β, 1,892 patients treated with fingolimod, and 1,410 patients treated with natalizumab in their analysis. The investigators noted only small differences in baseline characteristics between the matched cohorts.

Compared with participants receiving interferon β, patients receiving cladribine were less likely to have a relapse during the first year of treatment (hazard ratio [HR], 0.6). The proportion of relapse-free patients was 86% in the cladribine group and 70% in the interferon β group. The probability of disability accumulation was similar for these drugs (HR, 0.41), but the cladribine group was more likely to have disability improvement (HR, 15).

The proportion of relapse-free patients at one year was 79% in the cladribine and fingolimod groups, and cumulative hazards of a relapse did not differ between the two groups (HR, 1.2). The probability of disability accumulation was similar for cladribine and fingolimod (HR, 1.8), but the probability of disability improvement was greater for cladribine (HR, 3.9).

The probability of relapse was higher with cladribine than with natalizumab (HR, 1.8), but the proportions of relapse-free patients at the end of year one were 80% and 81%, respectively. The probability of disability accumulation was greater in the cladribine group than in the natalizumab group (HR, 2.5). The probability of disability improvement was greater among patients receiving cladribine than among those receiving natalizumab (HR, 4). Sensitivity analyses largely confirmed the results of the primary analyses.

“Six-month confirmed improvement of disability was observed in 10%–20% of the cladribine cohort during the first year, which was superior to all three comparator therapies. This [finding] is of interest in the context of the comparison to natalizumab, which is known to be associated with a marked improvement in disability early after its commencement,” said Dr. Kalincik and colleagues. “Improvement in disability in a cohort with this profile is unexpected.”

The study’s main limitation is the small size of the cladribine cohort, said the authors. Another limitation is the brief duration of follow-up for the cladribine group, which precludes conclusions about long-term outcomes. Nevertheless, the comparative effectiveness results “represent timely information about the role of cladribine in the management of MS,” Dr. Kalincik concluded.

—Erik Greb

Genomic Profiling May Improve Pediatric Brain Tumor Treatment

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Next-generation sequencing of pediatric gliomas provides objective data that promote diagnostic accuracy.

Genomic profiling of 282 pediatric gliomas detected genetic alterations in 96% of the cases, according to research published online ahead of print September 14 in the Oncologist. Information about genetic alterations may inform prognosis and help identify effective treatments, the researchers said.

Shakti Ramkissoon, MD, PhD, Associate Medical Director at Foundation Medicine in Morrisville, North Carolina, and colleagues studied 125 low-grade gliomas and 157 high-grade gliomas taken from children at medical centers in the US. Foundation Medicine, a genomic profiling company based in Cambridge, Massachusetts, supported the study, which is the largest to date of pediatric gliomas profiled by next-generation sequencing.

The investigators sequenced 315 cancer-related genes and 28 genes commonly rearranged in cancer. Patients’ median age was 11, and 50% were male.

The most frequently altered genes differed between low- and high-grade gliomas. In low-grade gliomas, BRAF was altered in 48% of cases. In addition, FGFR1 missense (17.6%), NF1 loss of function (8.8%), and TP53 (5.6%) mutations also were detected. Among high-grade gliomas, the genes most frequently mutated were TP53 (49%), H3F3A (37.6%), ATRX (24.2%), NF1 (22.2%), and PDGFRA (21.7%).

Studies indicate that low-grade gliomas with BRAF fusions, compared with BRAF mutations, have better outcomes, Dr. Ramkissoon said. “Therefore, determining the BRAF status for all pediatric low-grade gliomas is important for clinical management,” he said.

In addition, genetic mutations may highlight potential therapeutic targets. “Although surgical resection remains the most effective treatment option for pediatric low-grade gliomas, tumors located in eloquent areas not amenable to surgical resection (eg, motor cortex) require alternative therapeutic strategies,” the researchers said. “We report a multiply recurrent NF1-mutated pilocytic astrocytoma previously treated with surgery alone that now shows a remarkable response to dual inhibitor therapy (everolimus and trametinib) following three months of treatment.”

The study demonstrates that genomic profiling can be integrated into routine clinical practice, Dr. Ramkissoon said. “Comprehensive genomic profiling of pediatric gliomas provides objective data that promote diagnostic accuracy and enhance clinical decision-making,” the researchers concluded.

—Jake Remaly

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