Neurology

A gene therapy for Parkinson’s disease, focusing on the subthalamic nucleus, appears to lead to the formation of unique brain circuitry that correlates with clinical improvement.

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In a paper published online Nov. 28 in Science Translational Medicine, researchers describe the findings of a metabolic imaging study to explore the mechanism underlying benefits seen in a phase 2, blinded, sham-controlled clinical trial of the gene therapy.

The therapy in question used an adeno-associated viral vector to deliver the gene for glutamic acid decarboxylase into the subthalamic nucleus – a region of the brain known to be overactivated in Parkinson’s disease – which was intended to have an inhibitory effect on the neurons in that region.

Martin Niethammer, MD, PhD, of the Center for Neurosciences at The Feinstein Institute for Medical Research in New York, and his coauthors used ¹⁸F-fluorodeoxyglucose positron emission tomography at baseline, 6, and 12 months in 15 gene-therapy patients and 21 sham-treated patients, which revealed the development of new brain circuits in patients treated with the gene therapy.

The circuits, which researchers called the glutamic acid decarboxylase-related pattern, or GADRP, presented with increased metabolism in the premotor region – which also extended into the adjacent motor cortex – and in the supramarginal gyrus. There was also decreased metabolic activity in the caudate, anterior putamen, and adjacent globus pallidus; the ventral anterior and medial dorsal thalamic nuclei; and in the inferior frontal gyrus.

All 15 patients who received the gene therapy showed significant trends in GADRP expression after the treatment, compared with patients who underwent the sham procedure. Furthermore, these correlated significantly with improved clinical outcomes.

The imaging also revealed increased connectivity between regions in the GADRP space among patients who received the gene therapy, with researchers noting five new intrahemispheric node-to-node connections in these patients that were not seen in the sham procedure group.

These included connection linking the left caudate nucleus to the left superior frontal node, the right superior frontal node to the right supramarginal gyrus, and linking the left anterior putamen and globus pallidus with the ipsilateral thalamic node.

The authors also found that overall connectivity in the network rose to “abnormal” levels in the 12 months after gene therapy, while no similar increases were seen in the sham group.

Given that deep brain stimulation for Parkinson’s disease also targets the subthalamic nucleus, researchers looked at changes to the GADRP network in these patients, compared with those who received sham therapy and those who received gene therapy.

They saw that changes in GADRP expression were significantly different between the gene therapy-treated patients and those treated with deep brain stimulation and sham surgery. However, the differences between deep brain stimulation and sham surgery were not significant.

“The current study indicates that customized networks can be characterized using functional imaging data acquired in randomized, controlled phase 2 clinical trials and, if validated, could be used as quantitative outcome measures in more definitive, later-stage clinical trials,” the authors wrote.

The study was supported by Neurologix. Two authors were consultants and stockholders of MeiraGTx.

SOURCE: Niethammer N et al. Sci Transl Med. 2018 Nov 28. doi: 10.1126/scitranslmed.aau0713.

A gene therapy for Parkinson’s disease, focusing on the subthalamic nucleus, appears to lead to the formation of unique brain circuitry that correlates with clinical improvement.

copyright graphicsdunia4you/Thinkstock

In a paper published online Nov. 28 in Science Translational Medicine, researchers describe the findings of a metabolic imaging study to explore the mechanism underlying benefits seen in a phase 2, blinded, sham-controlled clinical trial of the gene therapy.

The therapy in question used an adeno-associated viral vector to deliver the gene for glutamic acid decarboxylase into the subthalamic nucleus – a region of the brain known to be overactivated in Parkinson’s disease – which was intended to have an inhibitory effect on the neurons in that region.

Martin Niethammer, MD, PhD, of the Center for Neurosciences at The Feinstein Institute for Medical Research in New York, and his coauthors used ¹⁸F-fluorodeoxyglucose positron emission tomography at baseline, 6, and 12 months in 15 gene-therapy patients and 21 sham-treated patients, which revealed the development of new brain circuits in patients treated with the gene therapy.

The circuits, which researchers called the glutamic acid decarboxylase-related pattern, or GADRP, presented with increased metabolism in the premotor region – which also extended into the adjacent motor cortex – and in the supramarginal gyrus. There was also decreased metabolic activity in the caudate, anterior putamen, and adjacent globus pallidus; the ventral anterior and medial dorsal thalamic nuclei; and in the inferior frontal gyrus.

All 15 patients who received the gene therapy showed significant trends in GADRP expression after the treatment, compared with patients who underwent the sham procedure. Furthermore, these correlated significantly with improved clinical outcomes.

The imaging also revealed increased connectivity between regions in the GADRP space among patients who received the gene therapy, with researchers noting five new intrahemispheric node-to-node connections in these patients that were not seen in the sham procedure group.

These included connection linking the left caudate nucleus to the left superior frontal node, the right superior frontal node to the right supramarginal gyrus, and linking the left anterior putamen and globus pallidus with the ipsilateral thalamic node.

The authors also found that overall connectivity in the network rose to “abnormal” levels in the 12 months after gene therapy, while no similar increases were seen in the sham group.

Given that deep brain stimulation for Parkinson’s disease also targets the subthalamic nucleus, researchers looked at changes to the GADRP network in these patients, compared with those who received sham therapy and those who received gene therapy.

They saw that changes in GADRP expression were significantly different between the gene therapy-treated patients and those treated with deep brain stimulation and sham surgery. However, the differences between deep brain stimulation and sham surgery were not significant.

“The current study indicates that customized networks can be characterized using functional imaging data acquired in randomized, controlled phase 2 clinical trials and, if validated, could be used as quantitative outcome measures in more definitive, later-stage clinical trials,” the authors wrote.

The study was supported by Neurologix. Two authors were consultants and stockholders of MeiraGTx.

SOURCE: Niethammer N et al. Sci Transl Med. 2018 Nov 28. doi: 10.1126/scitranslmed.aau0713.

A gene therapy for Parkinson’s disease, focusing on the subthalamic nucleus, appears to lead to the formation of unique brain circuitry that correlates with clinical improvement.

copyright graphicsdunia4you/Thinkstock

In a paper published online Nov. 28 in Science Translational Medicine, researchers describe the findings of a metabolic imaging study to explore the mechanism underlying benefits seen in a phase 2, blinded, sham-controlled clinical trial of the gene therapy.

The therapy in question used an adeno-associated viral vector to deliver the gene for glutamic acid decarboxylase into the subthalamic nucleus – a region of the brain known to be overactivated in Parkinson’s disease – which was intended to have an inhibitory effect on the neurons in that region.

Martin Niethammer, MD, PhD, of the Center for Neurosciences at The Feinstein Institute for Medical Research in New York, and his coauthors used ¹⁸F-fluorodeoxyglucose positron emission tomography at baseline, 6, and 12 months in 15 gene-therapy patients and 21 sham-treated patients, which revealed the development of new brain circuits in patients treated with the gene therapy.

The circuits, which researchers called the glutamic acid decarboxylase-related pattern, or GADRP, presented with increased metabolism in the premotor region – which also extended into the adjacent motor cortex – and in the supramarginal gyrus. There was also decreased metabolic activity in the caudate, anterior putamen, and adjacent globus pallidus; the ventral anterior and medial dorsal thalamic nuclei; and in the inferior frontal gyrus.

All 15 patients who received the gene therapy showed significant trends in GADRP expression after the treatment, compared with patients who underwent the sham procedure. Furthermore, these correlated significantly with improved clinical outcomes.

The imaging also revealed increased connectivity between regions in the GADRP space among patients who received the gene therapy, with researchers noting five new intrahemispheric node-to-node connections in these patients that were not seen in the sham procedure group.

These included connection linking the left caudate nucleus to the left superior frontal node, the right superior frontal node to the right supramarginal gyrus, and linking the left anterior putamen and globus pallidus with the ipsilateral thalamic node.

The authors also found that overall connectivity in the network rose to “abnormal” levels in the 12 months after gene therapy, while no similar increases were seen in the sham group.

Given that deep brain stimulation for Parkinson’s disease also targets the subthalamic nucleus, researchers looked at changes to the GADRP network in these patients, compared with those who received sham therapy and those who received gene therapy.

They saw that changes in GADRP expression were significantly different between the gene therapy-treated patients and those treated with deep brain stimulation and sham surgery. However, the differences between deep brain stimulation and sham surgery were not significant.

“The current study indicates that customized networks can be characterized using functional imaging data acquired in randomized, controlled phase 2 clinical trials and, if validated, could be used as quantitative outcome measures in more definitive, later-stage clinical trials,” the authors wrote.

The study was supported by Neurologix. Two authors were consultants and stockholders of MeiraGTx.

SOURCE: Niethammer N et al. Sci Transl Med. 2018 Nov 28. doi: 10.1126/scitranslmed.aau0713.

Opioids are still often overprescribed after surgery and the quantity of the prescription is associated with higher patient-reported consumption, according to a population-based study of surgery patients.

sdominick/iStock/Getty Images

Ryan Howard, MD, FACS, of the department of surgery at the University of Michigan, Ann Arbor, and his coauthors analyzed data from the Michigan Surgical Quality Collaborative and sampled 2,392 patients who underwent 1 of 12 common surgical procedures in Michigan between Jan. 1 and Sept. 30, 2017, and were prescribed opioids for pain. For all patients, the quantity of opioid prescribed – converted to oral morphine equivalents (OMEs) to adjust for varying potency – was considerably greater than the quantity actually consumed by the patient, wrote Dr. Howard and his colleagues in JAMA Surgery.

The study findings have troubling implications, the authors suggested. “Overprescribing was universally observed in this cohort, affecting each of the 12 procedures analyzed. This phenomenon was not limited to single, outlier institutions, but was widespread across many hospitals. This resulted in increased opioid consumption among patients who received larger prescriptions, as well as tens of thousands of leftover pills in 9 months that entered communities across the state of Michigan.”

The median amount prescribed was 150 OMEs, the equivalent of 30 pills of hydrocodone/acetaminophen, 5/325 mg. The median consumed, as reported by patients, was 45 OMEs, or 9 pills, meaning only 27% of the prescribed amount was used. Prescription size was also strongly associated with higher consumption; patients used an additional 0.53 OMEs (95% confidence interval, 0.40-0.65; P less than .001), or 5.3 more pills, for every 10 extra pills prescribed. The larger the initial prescription, the more patients used, an association that persisted when the data were adjusted for procedure and patient-specific factors such as postoperative pain.

The study’s acknowledged limitations included an inability to estimate how many patients were contacted for patient-reported outcome collection, which obscures how representative this sample may be of the patient population in general. There was also no data gathered regarding preoperative opioid use, a near certainty in this cohort given a 3%-4% prevalence of chronic opioid use.

That said, the investigators noted that “intentionally keeping future recommendations liberal in quantity may ultimately aid with widespread adoption, especially for clinicians concerned that prescribing reductions may lead to increased pain and calls for refills after surgery.” They commended local efforts already underway to combat this issue– including their own work at the University of Michigan, where evidence-based prescribing recommendations resulted in a 63% reduction in opioid prescription size without an increase in refills or pain – but reiterated that more needs to be done at a state level.

The authors offered a possible reason for the link between prescription size and patient consumption. “A plausible explanation for the association between prescription size and medication use is the anchoring and adjustment heuristic. This is a psychologic heuristic wherein a piece of information serves as an anchor on which adjustments are made to reach an estimation or decision. For example, obesity literature has shown that food intake increases with portion size. In this case, a larger amount of opioids may serve as a mental anchor by which patients estimate their analgesic needs.”

Michael Englesbe, MD, Jennifer Waljee,MD, and Chad Brummett, MD, reported receiving funding from the Michigan Department of Health and Human Services and the National Institute on Drug Abuse. Joceline Vu, MD, reported receiving funding from the National Institutes of Health Ruth L. Kirschstein National Research Service Award; Jay Lee, MD, reported receiving funding from the National Cancer Institute.

SOURCE: Howard R et al. JAMA Surg. 2018 Nov 7. doi: 10.1001/jamasurg.2018.4234.

Opioids are still often overprescribed after surgery and the quantity of the prescription is associated with higher patient-reported consumption, according to a population-based study of surgery patients.

sdominick/iStock/Getty Images

Ryan Howard, MD, FACS, of the department of surgery at the University of Michigan, Ann Arbor, and his coauthors analyzed data from the Michigan Surgical Quality Collaborative and sampled 2,392 patients who underwent 1 of 12 common surgical procedures in Michigan between Jan. 1 and Sept. 30, 2017, and were prescribed opioids for pain. For all patients, the quantity of opioid prescribed – converted to oral morphine equivalents (OMEs) to adjust for varying potency – was considerably greater than the quantity actually consumed by the patient, wrote Dr. Howard and his colleagues in JAMA Surgery.

The study findings have troubling implications, the authors suggested. “Overprescribing was universally observed in this cohort, affecting each of the 12 procedures analyzed. This phenomenon was not limited to single, outlier institutions, but was widespread across many hospitals. This resulted in increased opioid consumption among patients who received larger prescriptions, as well as tens of thousands of leftover pills in 9 months that entered communities across the state of Michigan.”

The median amount prescribed was 150 OMEs, the equivalent of 30 pills of hydrocodone/acetaminophen, 5/325 mg. The median consumed, as reported by patients, was 45 OMEs, or 9 pills, meaning only 27% of the prescribed amount was used. Prescription size was also strongly associated with higher consumption; patients used an additional 0.53 OMEs (95% confidence interval, 0.40-0.65; P less than .001), or 5.3 more pills, for every 10 extra pills prescribed. The larger the initial prescription, the more patients used, an association that persisted when the data were adjusted for procedure and patient-specific factors such as postoperative pain.

The study’s acknowledged limitations included an inability to estimate how many patients were contacted for patient-reported outcome collection, which obscures how representative this sample may be of the patient population in general. There was also no data gathered regarding preoperative opioid use, a near certainty in this cohort given a 3%-4% prevalence of chronic opioid use.

That said, the investigators noted that “intentionally keeping future recommendations liberal in quantity may ultimately aid with widespread adoption, especially for clinicians concerned that prescribing reductions may lead to increased pain and calls for refills after surgery.” They commended local efforts already underway to combat this issue– including their own work at the University of Michigan, where evidence-based prescribing recommendations resulted in a 63% reduction in opioid prescription size without an increase in refills or pain – but reiterated that more needs to be done at a state level.

The authors offered a possible reason for the link between prescription size and patient consumption. “A plausible explanation for the association between prescription size and medication use is the anchoring and adjustment heuristic. This is a psychologic heuristic wherein a piece of information serves as an anchor on which adjustments are made to reach an estimation or decision. For example, obesity literature has shown that food intake increases with portion size. In this case, a larger amount of opioids may serve as a mental anchor by which patients estimate their analgesic needs.”

Michael Englesbe, MD, Jennifer Waljee,MD, and Chad Brummett, MD, reported receiving funding from the Michigan Department of Health and Human Services and the National Institute on Drug Abuse. Joceline Vu, MD, reported receiving funding from the National Institutes of Health Ruth L. Kirschstein National Research Service Award; Jay Lee, MD, reported receiving funding from the National Cancer Institute.

SOURCE: Howard R et al. JAMA Surg. 2018 Nov 7. doi: 10.1001/jamasurg.2018.4234.

Opioids are still often overprescribed after surgery and the quantity of the prescription is associated with higher patient-reported consumption, according to a population-based study of surgery patients.

sdominick/iStock/Getty Images

Ryan Howard, MD, FACS, of the department of surgery at the University of Michigan, Ann Arbor, and his coauthors analyzed data from the Michigan Surgical Quality Collaborative and sampled 2,392 patients who underwent 1 of 12 common surgical procedures in Michigan between Jan. 1 and Sept. 30, 2017, and were prescribed opioids for pain. For all patients, the quantity of opioid prescribed – converted to oral morphine equivalents (OMEs) to adjust for varying potency – was considerably greater than the quantity actually consumed by the patient, wrote Dr. Howard and his colleagues in JAMA Surgery.

The study findings have troubling implications, the authors suggested. “Overprescribing was universally observed in this cohort, affecting each of the 12 procedures analyzed. This phenomenon was not limited to single, outlier institutions, but was widespread across many hospitals. This resulted in increased opioid consumption among patients who received larger prescriptions, as well as tens of thousands of leftover pills in 9 months that entered communities across the state of Michigan.”

The median amount prescribed was 150 OMEs, the equivalent of 30 pills of hydrocodone/acetaminophen, 5/325 mg. The median consumed, as reported by patients, was 45 OMEs, or 9 pills, meaning only 27% of the prescribed amount was used. Prescription size was also strongly associated with higher consumption; patients used an additional 0.53 OMEs (95% confidence interval, 0.40-0.65; P less than .001), or 5.3 more pills, for every 10 extra pills prescribed. The larger the initial prescription, the more patients used, an association that persisted when the data were adjusted for procedure and patient-specific factors such as postoperative pain.

The study’s acknowledged limitations included an inability to estimate how many patients were contacted for patient-reported outcome collection, which obscures how representative this sample may be of the patient population in general. There was also no data gathered regarding preoperative opioid use, a near certainty in this cohort given a 3%-4% prevalence of chronic opioid use.

That said, the investigators noted that “intentionally keeping future recommendations liberal in quantity may ultimately aid with widespread adoption, especially for clinicians concerned that prescribing reductions may lead to increased pain and calls for refills after surgery.” They commended local efforts already underway to combat this issue– including their own work at the University of Michigan, where evidence-based prescribing recommendations resulted in a 63% reduction in opioid prescription size without an increase in refills or pain – but reiterated that more needs to be done at a state level.

The authors offered a possible reason for the link between prescription size and patient consumption. “A plausible explanation for the association between prescription size and medication use is the anchoring and adjustment heuristic. This is a psychologic heuristic wherein a piece of information serves as an anchor on which adjustments are made to reach an estimation or decision. For example, obesity literature has shown that food intake increases with portion size. In this case, a larger amount of opioids may serve as a mental anchor by which patients estimate their analgesic needs.”

Michael Englesbe, MD, Jennifer Waljee,MD, and Chad Brummett, MD, reported receiving funding from the Michigan Department of Health and Human Services and the National Institute on Drug Abuse. Joceline Vu, MD, reported receiving funding from the National Institutes of Health Ruth L. Kirschstein National Research Service Award; Jay Lee, MD, reported receiving funding from the National Cancer Institute.

SOURCE: Howard R et al. JAMA Surg. 2018 Nov 7. doi: 10.1001/jamasurg.2018.4234.

BERLIN – In addition to the pain, motor and sensory impairments, and cognitive dysfunction that can stalk multiple sclerosis (MS) patients, for many, there’s also the challenge of an invisible, tough-to-quantify entity: fatigue.

©RusN/Thinkstock.com

“Approximately 80% of patients suffer from fatigue, so it’s an immense problem in MS. There’s no real clear relationship with disease severity,” Vincent de Groot, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. “Despite what a lot of people think, there’s no clear or strong relationship between fatigue and the amount of physical activity people undertake daily,” he noted.

“Patients all know what we are talking about when we ask about fatigue,” but there are a variety of definitions of fatigue used in research, a fact that has limited progress in the field, said Dr. de Groot.

Primary fatigue is related to the pathophysiology of MS itself, while secondary fatigue can result from MS symptoms, such as poor sleep from spasms. Secondary fatigue can also be a side effect of MS medications; baclofen, used for spasticity, is a good example, said Dr. de Groot. “We must not underestimate how many problems these drugs can give people.”

What’s the mechanism by which MS causes primary fatigue? “The simple answer is that we do not know,” said Dr. de Groot, a physiatrist and researcher at Vrije University, Amsterdam.

Though immune-mediated fatigue had been proposed as a factor for patients with MS, Dr. de Groot said that his own lab’s work has not found any connection between fatigue levels and any immune-related biomarkers. “So I don’t think the immune hypothesis has a lot of evidence.”

Similarly, though there might be mechanistic reasons to suspect the hypothalamic-pituitary-adrenal (HPA) axis as a culprit for MS fatigue, no consistent association has been found between any markers for HPA axis disruption and fatigue ratings, Dr. de Groot said.

Newer theories center on MS-related disruptions in brain connectivity, with imaging studies now able to detect some of these disruptions in functional connectivity that correlate with fatigue. “Right now, I think this is the hypothesis to bet money on,” Dr. de Groot said.

Many factors come into play, including environmental and psychological factors, he said.

“What can we do to treat MS-related fatigue?” Though several drugs have been used, “if you carefully look at the systematic reviews, the evidence is very, very disappointing,” Dr. de Groot said. For both amantadine and modafinil, “there is no evidence that these drugs are effective,” he said, citing a systematic review and meta-analysis that found a pooled effect size of 0.07 (95% confidence interval, –0.22 to 0.37) for medications (Mult Scler Int. 2014 May; doi: 10.1155/2014/798285).

Only two trials have looked at multidisciplinary rehabilitation for MS-related fatigue, Dr. de Groot said. Two studies that looked at multidisciplinary strategies that pulled in a variety of disciplines to help develop tailored fatigue management strategies saw no between-group effect when the multidisciplinary intervention was compared with nurse-provided information or with non–fatigue-related rehabilitation.

In an effort to determine whether MS-related fatigue is truly refractory to treatment, Dr. de Groot said that he and his colleagues decided to take “three steps back” to look at the individual interventions that make up a multidisciplinary approach to tackling fatigue. “So, we looked at exercise therapy, energy conservation management, and cognitive-behavioral therapy,” beginning with a literature review, he said.

Members of his research group found that effect sizes ranged from small to moderate for the three approaches, but there were methodologic problems with many of the studies; in the case of cognitive-behavioral therapy (CBT), the effect size waned over time, Dr. de Groot said. A newer randomized, controlled trial showed a relatively robust effect size of 0.52 for Internet-delivered CBT, which may provide a promising and practical approach (J Neurol Neurosurg Psychiatry. 2018 Sep;89[9]:970-6. doi: 10.1136/jnnp-2017-317463).

Looking at fatigue and societal participation, Dr. de Groot and his colleagues examined what effect aerobic training, energy conservation management, and CBT had on the two outcome measures. The three interventions were studied in three stand-alone trials, he said.

Patients were assessed at baseline, and at 8, 16, 26, and 52 weeks. The assessments were performed by a blinded researcher and were the same across trials: For fatigue, researchers used the Checklist Individual Strength–fatigue (CIS20R-fatigue), and for societal participation, they administered the Impact on Participation and Autonomy (IPA).

Each trial included 90 patients, randomized 1:1 to receive high- or low-intensity treatment. Patients had to have MS with no exacerbations within the prior 6 months and an Expanded Disability Status Scale score of 6 or less. However, the included patients had severe fatigue, with a CIS20R-fatigue subscore of 35 or higher, and the fatigue could not be attributable to such secondary causes as infection, depression, or thyroid or sleep problems. Finally, patients could not have been treated for fatigue in the 3 months prior to enrollment.

Those in the high-intensity treatment group received 12 sessions focused on the particular intervention over 4 months, provided by an expert therapist. Each type of intervention had a treatment protocol that was followed over the 4 months. Patients receiving low-intensity treatment saw an MS-specialized nurse three times over 4 months.

The aerobic training intervention had patients performing high-intensity exercise on a cycle ergometer for 30 minutes, three times weekly for 16 weeks. In addition to the 12 supervised sessions, patients also completed 36 home-based sessions. The level of intensity for each patient was personalized based on their baseline cardiopulmonary exercise test, Dr. de Groot said.

At the end of 1 year, patients in the high-intensity group and those in the low-intensity group reported virtually the same fatigue scores. Though there was an initial drop in fatigue for those in the high-intensity group, compared with baseline and with the low-intensity participants, values on the CIS20R never dropped below 35, the “severe fatigue” cutoff.

And, Dr. de Groot said, there was no effect on societal participation or in other fatigue scores. In sum, the effect size was barely significant at –0.54 (95% CI, –1.00 to –0.06), with a number needed to treat of 9.

Adherence to attempting the workouts was fairly good for participants in the high-intensity group; 74% completed the sessions, with 71% doing so at the prescribed workload. The median rate of perceived exertion on a 1-20 scale was 14.

However, the thrice-weekly exercise bouts didn’t improve aerobic fitness parameters: Neither V0₂peak, V0₂peak adjusted for body mass, nor anaerobic threshold changed for those in the high-intensity group. Peak power did increase by 11.7 watts (P = .048).

Energy conservation education, whether delivered in high- or low-intensity format, had almost no effect on fatigue scores, with a number needed to treat of 158 – a figure that is “neither significant nor clinically meaningful,” Dr. de Groot said. Other fatigue scores and societal participation levels also went unchanged.

However, CBT delivered in a series of 10 modules to address various beliefs and coping mechanisms about MS, fatigue, pain, and activity regulation did have a positive effect on fatigue. Here, the effect size was –0.79 (95% CI, –1.26 to –0.32). The number needed to treat was 3, and CIS20R values did dip below the “severe fatigue” threshold during treatment. A similar effect, Dr. de Groot said, was seen for other fatigue and quality of life measures, though societal participation scores didn’t change. No significant improvement was seen for the low-intensity CBT group.

“Severe MS-related fatigue can be reduced effectively with CBT in the short term. More research is needed on how to maintain this effect in the long term,” Dr. de Groot said. Still, “it’s currently the best treatment option,” he said.

The fact that patients reverted to their preintervention fatigue levels regardless of the intervention shows that effective treatment for MS-related fatigue should probably be ongoing, viewed more as a process than an occurrence, Dr. de Groot said.

To that end, Dr. de Groot and his colleagues are conducting a randomized, controlled trial that includes 166 MS patients with fatigue. The study has two arms: The first is a noninferiority trial comparing face-to-face CBT with e-learning delivery of the content, and the second looks at the efficacy of ongoing booster sessions after initial CBT.

An online database of randomized, controlled trials of rehabilitation for MS patients can be found at www.appeco.net.

The study was funded by Fonds NutsOhra, a private Dutch foundation. Dr. de Groot reported no relevant conflicts of interest.

[email protected]

SOURCE: de Groot V. Mult Scler. 2018;24(S2):83, Abstract 225.

BERLIN – In addition to the pain, motor and sensory impairments, and cognitive dysfunction that can stalk multiple sclerosis (MS) patients, for many, there’s also the challenge of an invisible, tough-to-quantify entity: fatigue.

©RusN/Thinkstock.com

“Approximately 80% of patients suffer from fatigue, so it’s an immense problem in MS. There’s no real clear relationship with disease severity,” Vincent de Groot, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. “Despite what a lot of people think, there’s no clear or strong relationship between fatigue and the amount of physical activity people undertake daily,” he noted.

“Patients all know what we are talking about when we ask about fatigue,” but there are a variety of definitions of fatigue used in research, a fact that has limited progress in the field, said Dr. de Groot.

Primary fatigue is related to the pathophysiology of MS itself, while secondary fatigue can result from MS symptoms, such as poor sleep from spasms. Secondary fatigue can also be a side effect of MS medications; baclofen, used for spasticity, is a good example, said Dr. de Groot. “We must not underestimate how many problems these drugs can give people.”

What’s the mechanism by which MS causes primary fatigue? “The simple answer is that we do not know,” said Dr. de Groot, a physiatrist and researcher at Vrije University, Amsterdam.

Though immune-mediated fatigue had been proposed as a factor for patients with MS, Dr. de Groot said that his own lab’s work has not found any connection between fatigue levels and any immune-related biomarkers. “So I don’t think the immune hypothesis has a lot of evidence.”

Similarly, though there might be mechanistic reasons to suspect the hypothalamic-pituitary-adrenal (HPA) axis as a culprit for MS fatigue, no consistent association has been found between any markers for HPA axis disruption and fatigue ratings, Dr. de Groot said.

Newer theories center on MS-related disruptions in brain connectivity, with imaging studies now able to detect some of these disruptions in functional connectivity that correlate with fatigue. “Right now, I think this is the hypothesis to bet money on,” Dr. de Groot said.

Many factors come into play, including environmental and psychological factors, he said.

“What can we do to treat MS-related fatigue?” Though several drugs have been used, “if you carefully look at the systematic reviews, the evidence is very, very disappointing,” Dr. de Groot said. For both amantadine and modafinil, “there is no evidence that these drugs are effective,” he said, citing a systematic review and meta-analysis that found a pooled effect size of 0.07 (95% confidence interval, –0.22 to 0.37) for medications (Mult Scler Int. 2014 May; doi: 10.1155/2014/798285).

Only two trials have looked at multidisciplinary rehabilitation for MS-related fatigue, Dr. de Groot said. Two studies that looked at multidisciplinary strategies that pulled in a variety of disciplines to help develop tailored fatigue management strategies saw no between-group effect when the multidisciplinary intervention was compared with nurse-provided information or with non–fatigue-related rehabilitation.

In an effort to determine whether MS-related fatigue is truly refractory to treatment, Dr. de Groot said that he and his colleagues decided to take “three steps back” to look at the individual interventions that make up a multidisciplinary approach to tackling fatigue. “So, we looked at exercise therapy, energy conservation management, and cognitive-behavioral therapy,” beginning with a literature review, he said.

Members of his research group found that effect sizes ranged from small to moderate for the three approaches, but there were methodologic problems with many of the studies; in the case of cognitive-behavioral therapy (CBT), the effect size waned over time, Dr. de Groot said. A newer randomized, controlled trial showed a relatively robust effect size of 0.52 for Internet-delivered CBT, which may provide a promising and practical approach (J Neurol Neurosurg Psychiatry. 2018 Sep;89[9]:970-6. doi: 10.1136/jnnp-2017-317463).

Looking at fatigue and societal participation, Dr. de Groot and his colleagues examined what effect aerobic training, energy conservation management, and CBT had on the two outcome measures. The three interventions were studied in three stand-alone trials, he said.

Patients were assessed at baseline, and at 8, 16, 26, and 52 weeks. The assessments were performed by a blinded researcher and were the same across trials: For fatigue, researchers used the Checklist Individual Strength–fatigue (CIS20R-fatigue), and for societal participation, they administered the Impact on Participation and Autonomy (IPA).

Each trial included 90 patients, randomized 1:1 to receive high- or low-intensity treatment. Patients had to have MS with no exacerbations within the prior 6 months and an Expanded Disability Status Scale score of 6 or less. However, the included patients had severe fatigue, with a CIS20R-fatigue subscore of 35 or higher, and the fatigue could not be attributable to such secondary causes as infection, depression, or thyroid or sleep problems. Finally, patients could not have been treated for fatigue in the 3 months prior to enrollment.

Those in the high-intensity treatment group received 12 sessions focused on the particular intervention over 4 months, provided by an expert therapist. Each type of intervention had a treatment protocol that was followed over the 4 months. Patients receiving low-intensity treatment saw an MS-specialized nurse three times over 4 months.

The aerobic training intervention had patients performing high-intensity exercise on a cycle ergometer for 30 minutes, three times weekly for 16 weeks. In addition to the 12 supervised sessions, patients also completed 36 home-based sessions. The level of intensity for each patient was personalized based on their baseline cardiopulmonary exercise test, Dr. de Groot said.

At the end of 1 year, patients in the high-intensity group and those in the low-intensity group reported virtually the same fatigue scores. Though there was an initial drop in fatigue for those in the high-intensity group, compared with baseline and with the low-intensity participants, values on the CIS20R never dropped below 35, the “severe fatigue” cutoff.

And, Dr. de Groot said, there was no effect on societal participation or in other fatigue scores. In sum, the effect size was barely significant at –0.54 (95% CI, –1.00 to –0.06), with a number needed to treat of 9.

Adherence to attempting the workouts was fairly good for participants in the high-intensity group; 74% completed the sessions, with 71% doing so at the prescribed workload. The median rate of perceived exertion on a 1-20 scale was 14.

However, the thrice-weekly exercise bouts didn’t improve aerobic fitness parameters: Neither V0₂peak, V0₂peak adjusted for body mass, nor anaerobic threshold changed for those in the high-intensity group. Peak power did increase by 11.7 watts (P = .048).

Energy conservation education, whether delivered in high- or low-intensity format, had almost no effect on fatigue scores, with a number needed to treat of 158 – a figure that is “neither significant nor clinically meaningful,” Dr. de Groot said. Other fatigue scores and societal participation levels also went unchanged.

However, CBT delivered in a series of 10 modules to address various beliefs and coping mechanisms about MS, fatigue, pain, and activity regulation did have a positive effect on fatigue. Here, the effect size was –0.79 (95% CI, –1.26 to –0.32). The number needed to treat was 3, and CIS20R values did dip below the “severe fatigue” threshold during treatment. A similar effect, Dr. de Groot said, was seen for other fatigue and quality of life measures, though societal participation scores didn’t change. No significant improvement was seen for the low-intensity CBT group.

“Severe MS-related fatigue can be reduced effectively with CBT in the short term. More research is needed on how to maintain this effect in the long term,” Dr. de Groot said. Still, “it’s currently the best treatment option,” he said.

The fact that patients reverted to their preintervention fatigue levels regardless of the intervention shows that effective treatment for MS-related fatigue should probably be ongoing, viewed more as a process than an occurrence, Dr. de Groot said.

To that end, Dr. de Groot and his colleagues are conducting a randomized, controlled trial that includes 166 MS patients with fatigue. The study has two arms: The first is a noninferiority trial comparing face-to-face CBT with e-learning delivery of the content, and the second looks at the efficacy of ongoing booster sessions after initial CBT.

An online database of randomized, controlled trials of rehabilitation for MS patients can be found at www.appeco.net.

The study was funded by Fonds NutsOhra, a private Dutch foundation. Dr. de Groot reported no relevant conflicts of interest.

[email protected]

SOURCE: de Groot V. Mult Scler. 2018;24(S2):83, Abstract 225.

BERLIN – In addition to the pain, motor and sensory impairments, and cognitive dysfunction that can stalk multiple sclerosis (MS) patients, for many, there’s also the challenge of an invisible, tough-to-quantify entity: fatigue.

©RusN/Thinkstock.com

“Approximately 80% of patients suffer from fatigue, so it’s an immense problem in MS. There’s no real clear relationship with disease severity,” Vincent de Groot, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. “Despite what a lot of people think, there’s no clear or strong relationship between fatigue and the amount of physical activity people undertake daily,” he noted.

“Patients all know what we are talking about when we ask about fatigue,” but there are a variety of definitions of fatigue used in research, a fact that has limited progress in the field, said Dr. de Groot.

Primary fatigue is related to the pathophysiology of MS itself, while secondary fatigue can result from MS symptoms, such as poor sleep from spasms. Secondary fatigue can also be a side effect of MS medications; baclofen, used for spasticity, is a good example, said Dr. de Groot. “We must not underestimate how many problems these drugs can give people.”

What’s the mechanism by which MS causes primary fatigue? “The simple answer is that we do not know,” said Dr. de Groot, a physiatrist and researcher at Vrije University, Amsterdam.

Though immune-mediated fatigue had been proposed as a factor for patients with MS, Dr. de Groot said that his own lab’s work has not found any connection between fatigue levels and any immune-related biomarkers. “So I don’t think the immune hypothesis has a lot of evidence.”

Similarly, though there might be mechanistic reasons to suspect the hypothalamic-pituitary-adrenal (HPA) axis as a culprit for MS fatigue, no consistent association has been found between any markers for HPA axis disruption and fatigue ratings, Dr. de Groot said.

Newer theories center on MS-related disruptions in brain connectivity, with imaging studies now able to detect some of these disruptions in functional connectivity that correlate with fatigue. “Right now, I think this is the hypothesis to bet money on,” Dr. de Groot said.

Many factors come into play, including environmental and psychological factors, he said.

“What can we do to treat MS-related fatigue?” Though several drugs have been used, “if you carefully look at the systematic reviews, the evidence is very, very disappointing,” Dr. de Groot said. For both amantadine and modafinil, “there is no evidence that these drugs are effective,” he said, citing a systematic review and meta-analysis that found a pooled effect size of 0.07 (95% confidence interval, –0.22 to 0.37) for medications (Mult Scler Int. 2014 May; doi: 10.1155/2014/798285).

Only two trials have looked at multidisciplinary rehabilitation for MS-related fatigue, Dr. de Groot said. Two studies that looked at multidisciplinary strategies that pulled in a variety of disciplines to help develop tailored fatigue management strategies saw no between-group effect when the multidisciplinary intervention was compared with nurse-provided information or with non–fatigue-related rehabilitation.

In an effort to determine whether MS-related fatigue is truly refractory to treatment, Dr. de Groot said that he and his colleagues decided to take “three steps back” to look at the individual interventions that make up a multidisciplinary approach to tackling fatigue. “So, we looked at exercise therapy, energy conservation management, and cognitive-behavioral therapy,” beginning with a literature review, he said.

Members of his research group found that effect sizes ranged from small to moderate for the three approaches, but there were methodologic problems with many of the studies; in the case of cognitive-behavioral therapy (CBT), the effect size waned over time, Dr. de Groot said. A newer randomized, controlled trial showed a relatively robust effect size of 0.52 for Internet-delivered CBT, which may provide a promising and practical approach (J Neurol Neurosurg Psychiatry. 2018 Sep;89[9]:970-6. doi: 10.1136/jnnp-2017-317463).

Looking at fatigue and societal participation, Dr. de Groot and his colleagues examined what effect aerobic training, energy conservation management, and CBT had on the two outcome measures. The three interventions were studied in three stand-alone trials, he said.

Patients were assessed at baseline, and at 8, 16, 26, and 52 weeks. The assessments were performed by a blinded researcher and were the same across trials: For fatigue, researchers used the Checklist Individual Strength–fatigue (CIS20R-fatigue), and for societal participation, they administered the Impact on Participation and Autonomy (IPA).

Each trial included 90 patients, randomized 1:1 to receive high- or low-intensity treatment. Patients had to have MS with no exacerbations within the prior 6 months and an Expanded Disability Status Scale score of 6 or less. However, the included patients had severe fatigue, with a CIS20R-fatigue subscore of 35 or higher, and the fatigue could not be attributable to such secondary causes as infection, depression, or thyroid or sleep problems. Finally, patients could not have been treated for fatigue in the 3 months prior to enrollment.

Those in the high-intensity treatment group received 12 sessions focused on the particular intervention over 4 months, provided by an expert therapist. Each type of intervention had a treatment protocol that was followed over the 4 months. Patients receiving low-intensity treatment saw an MS-specialized nurse three times over 4 months.

The aerobic training intervention had patients performing high-intensity exercise on a cycle ergometer for 30 minutes, three times weekly for 16 weeks. In addition to the 12 supervised sessions, patients also completed 36 home-based sessions. The level of intensity for each patient was personalized based on their baseline cardiopulmonary exercise test, Dr. de Groot said.

At the end of 1 year, patients in the high-intensity group and those in the low-intensity group reported virtually the same fatigue scores. Though there was an initial drop in fatigue for those in the high-intensity group, compared with baseline and with the low-intensity participants, values on the CIS20R never dropped below 35, the “severe fatigue” cutoff.

And, Dr. de Groot said, there was no effect on societal participation or in other fatigue scores. In sum, the effect size was barely significant at –0.54 (95% CI, –1.00 to –0.06), with a number needed to treat of 9.

Adherence to attempting the workouts was fairly good for participants in the high-intensity group; 74% completed the sessions, with 71% doing so at the prescribed workload. The median rate of perceived exertion on a 1-20 scale was 14.

However, the thrice-weekly exercise bouts didn’t improve aerobic fitness parameters: Neither V0₂peak, V0₂peak adjusted for body mass, nor anaerobic threshold changed for those in the high-intensity group. Peak power did increase by 11.7 watts (P = .048).

Energy conservation education, whether delivered in high- or low-intensity format, had almost no effect on fatigue scores, with a number needed to treat of 158 – a figure that is “neither significant nor clinically meaningful,” Dr. de Groot said. Other fatigue scores and societal participation levels also went unchanged.

However, CBT delivered in a series of 10 modules to address various beliefs and coping mechanisms about MS, fatigue, pain, and activity regulation did have a positive effect on fatigue. Here, the effect size was –0.79 (95% CI, –1.26 to –0.32). The number needed to treat was 3, and CIS20R values did dip below the “severe fatigue” threshold during treatment. A similar effect, Dr. de Groot said, was seen for other fatigue and quality of life measures, though societal participation scores didn’t change. No significant improvement was seen for the low-intensity CBT group.

“Severe MS-related fatigue can be reduced effectively with CBT in the short term. More research is needed on how to maintain this effect in the long term,” Dr. de Groot said. Still, “it’s currently the best treatment option,” he said.

The fact that patients reverted to their preintervention fatigue levels regardless of the intervention shows that effective treatment for MS-related fatigue should probably be ongoing, viewed more as a process than an occurrence, Dr. de Groot said.

To that end, Dr. de Groot and his colleagues are conducting a randomized, controlled trial that includes 166 MS patients with fatigue. The study has two arms: The first is a noninferiority trial comparing face-to-face CBT with e-learning delivery of the content, and the second looks at the efficacy of ongoing booster sessions after initial CBT.

An online database of randomized, controlled trials of rehabilitation for MS patients can be found at www.appeco.net.

The study was funded by Fonds NutsOhra, a private Dutch foundation. Dr. de Groot reported no relevant conflicts of interest.

[email protected]

SOURCE: de Groot V. Mult Scler. 2018;24(S2):83, Abstract 225.

BERLIN – The presence of infratentorial and deep white matter lesions early in the course of relapse-onset multiple sclerosis was associated with high levels of disability 30 years later in a study looking at MRI predictors.

Sara Freeman/MDedge News

Univariate predictors of an Expanded Disability Status Scale (EDSS) score of more than 3.5, which is indicative of impaired mobility after 30 years, were the presence of an IT lesion at baseline, with an odds ratio (OR) of 12.4 (95% confidence interval [CI], 3.35-3.46; P less than .001), the presence of a deep white matter (DWM) lesion 1 year after presenting with clinically-isolated syndrome (CIS; OR = 10.65; 95% CI, 2.84-38.84; P less than .001), and the presence of an infratentorial (IT) lesion 1 year post CIS presentation (OR = 11.1; 95% CI, 3.31-37.22; P less than .001). At 5 years after a CIS presentation, the EDSS score, EDSS score change, and a DWM lesion score of more than 5 were indicative of worse disability after 30 years.

There was no significant association with age of onset, gender, CIS type, baseline EDSS, or disease duration, study investigator Karen Chung, MBBS, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“As we know, approximately 85% of people with MS initially present with a clinically isolated syndrome,” said Dr. Chung, a clinical research associate at the Queen Square Multiple Sclerosis Centre in the UCL Institute of Neurology in London. She added that the long-term prognosis after CIS is very variable, with some patients developing little detectable disability over time, while others may experience considerable decline.

There have been few studies examining whether there are any MRI parameters that might help predict patients’ long-term outcomes, so the aim of the study Dr. Chung presented was to see if there were any MRI parameters that might be predictive of clinical outcome 30 years after the onset of CIS.

Dr. Chung and her coauthors examined data on 120 of 132 individuals from the First London CIS Cohort who were prospectively recruited between 1984 and 1987 and had known outcomes. They looked at prospectively gathered MRI data and EDSS data at baseline, 5, 10, 14, 20, and 30 years. MRI data were obtained for 1 year after the CIS event, and data on the lowest EDSS score after the CIS event were retrospectively determined from patient notes or recall. The cohort was predominantly female (61%), with a mean of 31.5 years at CIS onset. Around half (52%) presented with optic neuritis, 27% with a spinal cord syndrome, and 20% with a brainstem syndrome. The high percentage of patients presenting with optic neuritis may be due to the fact that one of the recruiting centers was a specialist eye hospital, Dr. Chung noted later during discussion.

The 2010 McDonald Criteria were used to determine whether patients had CIS, relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), or death related to MS.

“We looked at all the MRIs available to us and quantified the T2 lesion count for whole brain as well as by location,” Dr. Chung explained. The locations considered were juxtacortical, periventricular, infratentorial, and deep white matter.

“I think it is important to remind ourselves that we have come a long way with MRI technology in the 30 years timespan,” she added, noting that there was “clearly a difference in the quality.”

Clinical outcomes at 30 years were as follows: 80 patients (67%) developed MS, of whom 35 (44%) had RRMS, 26 (33%) had SPMS, 15 (20%) had died as a result of MS, and 3 (4%) had died for unknown or unrelated causes. Of the 40 patients (33%) who remained with CIS, 10 (25%) died without developing MS.

“This is a largely untreated cohort where, within the 80 people with MS, 11 (14%) were treated with a DMT [disease-modifying treatment] at some point,” Dr. Chung reported. All DMTs used were first-line injectable agents, she observed.

EDSS scores could be obtained for 107 patients. At 30 years, people with low EDSS scores were those who remained with CIS or RRMS, and as EDSS scores increased, the severity of MS increased.

“Overall, T2 lesions were better predictors of 30-year outcome than EDSS,” Dr. Chung said. For combinations of predictors, patients who had at least one IT and one DWM lesion within 1 year of a CIS had a higher probability (94%) of having an EDSS score of more than 3.5 at 30 years than when compared with those with neither lesion (13%) and those with one DWM but no IT lesions (49%).

Looking at the best independent predictors up to 5 years, the predicted probability of an EDSS score of more than 3.5 if there were no IT lesions and fewer than five DWM lesions was 18%. But if there were no IT but more than 5 DWM lesions, the probability of disability at 30 years rose to 52%. The probabilities rose even higher to 63% if there was one or more IT and five or less DWM lesions and 90% if there was one or more IT and more than five DWM lesions.

“In this cohort, the presence of early infratentorial and deep white matter lesions following a CIS are associated with higher level of disability 30 years later,” Dr. Chung concluded. “Early predictive models can add information to risk-benefit stratification.”

During discussion, one delegate expressed concerns that these data were “not generalizable to the current situation.” This was a cohort of patients that largely wasn’t treated or if they were, treatment was delayed by more than 10 years. These data were interesting “from a historical perspective,” he argued, “but I don’t understand, how in the absence of contemporary therapies this is applicable in a way that will allow us to use this information to make prognoses for the future.”

Dr. Chung agreed, noting that this was more of a natural history study. “However, I think it is applicable in clinical practice in my opinion.

“When you have a patient presenting with a CIS, at the time of diagnosis, especially now when we can diagnose patients earlier with the new 2017 criteria, it will be helpful for the patient and ourselves to apply some of the information I presented to help perhaps in aiding decisions regarding treatment.”

The study was funded by a grant from the MS Society of Great Britain. Dr. Chung disclosed receiving honoraria from Teva, Biogen, and Roche.

SOURCE: Chung K et al. Mult Scler. 2018;24(S2):58-59, Abstract 157.

BERLIN – The presence of infratentorial and deep white matter lesions early in the course of relapse-onset multiple sclerosis was associated with high levels of disability 30 years later in a study looking at MRI predictors.

Sara Freeman/MDedge News

Univariate predictors of an Expanded Disability Status Scale (EDSS) score of more than 3.5, which is indicative of impaired mobility after 30 years, were the presence of an IT lesion at baseline, with an odds ratio (OR) of 12.4 (95% confidence interval [CI], 3.35-3.46; P less than .001), the presence of a deep white matter (DWM) lesion 1 year after presenting with clinically-isolated syndrome (CIS; OR = 10.65; 95% CI, 2.84-38.84; P less than .001), and the presence of an infratentorial (IT) lesion 1 year post CIS presentation (OR = 11.1; 95% CI, 3.31-37.22; P less than .001). At 5 years after a CIS presentation, the EDSS score, EDSS score change, and a DWM lesion score of more than 5 were indicative of worse disability after 30 years.

There was no significant association with age of onset, gender, CIS type, baseline EDSS, or disease duration, study investigator Karen Chung, MBBS, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“As we know, approximately 85% of people with MS initially present with a clinically isolated syndrome,” said Dr. Chung, a clinical research associate at the Queen Square Multiple Sclerosis Centre in the UCL Institute of Neurology in London. She added that the long-term prognosis after CIS is very variable, with some patients developing little detectable disability over time, while others may experience considerable decline.

There have been few studies examining whether there are any MRI parameters that might help predict patients’ long-term outcomes, so the aim of the study Dr. Chung presented was to see if there were any MRI parameters that might be predictive of clinical outcome 30 years after the onset of CIS.

Dr. Chung and her coauthors examined data on 120 of 132 individuals from the First London CIS Cohort who were prospectively recruited between 1984 and 1987 and had known outcomes. They looked at prospectively gathered MRI data and EDSS data at baseline, 5, 10, 14, 20, and 30 years. MRI data were obtained for 1 year after the CIS event, and data on the lowest EDSS score after the CIS event were retrospectively determined from patient notes or recall. The cohort was predominantly female (61%), with a mean of 31.5 years at CIS onset. Around half (52%) presented with optic neuritis, 27% with a spinal cord syndrome, and 20% with a brainstem syndrome. The high percentage of patients presenting with optic neuritis may be due to the fact that one of the recruiting centers was a specialist eye hospital, Dr. Chung noted later during discussion.

The 2010 McDonald Criteria were used to determine whether patients had CIS, relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), or death related to MS.

“We looked at all the MRIs available to us and quantified the T2 lesion count for whole brain as well as by location,” Dr. Chung explained. The locations considered were juxtacortical, periventricular, infratentorial, and deep white matter.

“I think it is important to remind ourselves that we have come a long way with MRI technology in the 30 years timespan,” she added, noting that there was “clearly a difference in the quality.”

Clinical outcomes at 30 years were as follows: 80 patients (67%) developed MS, of whom 35 (44%) had RRMS, 26 (33%) had SPMS, 15 (20%) had died as a result of MS, and 3 (4%) had died for unknown or unrelated causes. Of the 40 patients (33%) who remained with CIS, 10 (25%) died without developing MS.

“This is a largely untreated cohort where, within the 80 people with MS, 11 (14%) were treated with a DMT [disease-modifying treatment] at some point,” Dr. Chung reported. All DMTs used were first-line injectable agents, she observed.

EDSS scores could be obtained for 107 patients. At 30 years, people with low EDSS scores were those who remained with CIS or RRMS, and as EDSS scores increased, the severity of MS increased.

“Overall, T2 lesions were better predictors of 30-year outcome than EDSS,” Dr. Chung said. For combinations of predictors, patients who had at least one IT and one DWM lesion within 1 year of a CIS had a higher probability (94%) of having an EDSS score of more than 3.5 at 30 years than when compared with those with neither lesion (13%) and those with one DWM but no IT lesions (49%).

Looking at the best independent predictors up to 5 years, the predicted probability of an EDSS score of more than 3.5 if there were no IT lesions and fewer than five DWM lesions was 18%. But if there were no IT but more than 5 DWM lesions, the probability of disability at 30 years rose to 52%. The probabilities rose even higher to 63% if there was one or more IT and five or less DWM lesions and 90% if there was one or more IT and more than five DWM lesions.

“In this cohort, the presence of early infratentorial and deep white matter lesions following a CIS are associated with higher level of disability 30 years later,” Dr. Chung concluded. “Early predictive models can add information to risk-benefit stratification.”

During discussion, one delegate expressed concerns that these data were “not generalizable to the current situation.” This was a cohort of patients that largely wasn’t treated or if they were, treatment was delayed by more than 10 years. These data were interesting “from a historical perspective,” he argued, “but I don’t understand, how in the absence of contemporary therapies this is applicable in a way that will allow us to use this information to make prognoses for the future.”

Dr. Chung agreed, noting that this was more of a natural history study. “However, I think it is applicable in clinical practice in my opinion.

“When you have a patient presenting with a CIS, at the time of diagnosis, especially now when we can diagnose patients earlier with the new 2017 criteria, it will be helpful for the patient and ourselves to apply some of the information I presented to help perhaps in aiding decisions regarding treatment.”

The study was funded by a grant from the MS Society of Great Britain. Dr. Chung disclosed receiving honoraria from Teva, Biogen, and Roche.

SOURCE: Chung K et al. Mult Scler. 2018;24(S2):58-59, Abstract 157.

BERLIN – The presence of infratentorial and deep white matter lesions early in the course of relapse-onset multiple sclerosis was associated with high levels of disability 30 years later in a study looking at MRI predictors.

Sara Freeman/MDedge News

Univariate predictors of an Expanded Disability Status Scale (EDSS) score of more than 3.5, which is indicative of impaired mobility after 30 years, were the presence of an IT lesion at baseline, with an odds ratio (OR) of 12.4 (95% confidence interval [CI], 3.35-3.46; P less than .001), the presence of a deep white matter (DWM) lesion 1 year after presenting with clinically-isolated syndrome (CIS; OR = 10.65; 95% CI, 2.84-38.84; P less than .001), and the presence of an infratentorial (IT) lesion 1 year post CIS presentation (OR = 11.1; 95% CI, 3.31-37.22; P less than .001). At 5 years after a CIS presentation, the EDSS score, EDSS score change, and a DWM lesion score of more than 5 were indicative of worse disability after 30 years.

There was no significant association with age of onset, gender, CIS type, baseline EDSS, or disease duration, study investigator Karen Chung, MBBS, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“As we know, approximately 85% of people with MS initially present with a clinically isolated syndrome,” said Dr. Chung, a clinical research associate at the Queen Square Multiple Sclerosis Centre in the UCL Institute of Neurology in London. She added that the long-term prognosis after CIS is very variable, with some patients developing little detectable disability over time, while others may experience considerable decline.

There have been few studies examining whether there are any MRI parameters that might help predict patients’ long-term outcomes, so the aim of the study Dr. Chung presented was to see if there were any MRI parameters that might be predictive of clinical outcome 30 years after the onset of CIS.

Dr. Chung and her coauthors examined data on 120 of 132 individuals from the First London CIS Cohort who were prospectively recruited between 1984 and 1987 and had known outcomes. They looked at prospectively gathered MRI data and EDSS data at baseline, 5, 10, 14, 20, and 30 years. MRI data were obtained for 1 year after the CIS event, and data on the lowest EDSS score after the CIS event were retrospectively determined from patient notes or recall. The cohort was predominantly female (61%), with a mean of 31.5 years at CIS onset. Around half (52%) presented with optic neuritis, 27% with a spinal cord syndrome, and 20% with a brainstem syndrome. The high percentage of patients presenting with optic neuritis may be due to the fact that one of the recruiting centers was a specialist eye hospital, Dr. Chung noted later during discussion.

The 2010 McDonald Criteria were used to determine whether patients had CIS, relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), or death related to MS.

“We looked at all the MRIs available to us and quantified the T2 lesion count for whole brain as well as by location,” Dr. Chung explained. The locations considered were juxtacortical, periventricular, infratentorial, and deep white matter.

“I think it is important to remind ourselves that we have come a long way with MRI technology in the 30 years timespan,” she added, noting that there was “clearly a difference in the quality.”

Clinical outcomes at 30 years were as follows: 80 patients (67%) developed MS, of whom 35 (44%) had RRMS, 26 (33%) had SPMS, 15 (20%) had died as a result of MS, and 3 (4%) had died for unknown or unrelated causes. Of the 40 patients (33%) who remained with CIS, 10 (25%) died without developing MS.

“This is a largely untreated cohort where, within the 80 people with MS, 11 (14%) were treated with a DMT [disease-modifying treatment] at some point,” Dr. Chung reported. All DMTs used were first-line injectable agents, she observed.

EDSS scores could be obtained for 107 patients. At 30 years, people with low EDSS scores were those who remained with CIS or RRMS, and as EDSS scores increased, the severity of MS increased.

“Overall, T2 lesions were better predictors of 30-year outcome than EDSS,” Dr. Chung said. For combinations of predictors, patients who had at least one IT and one DWM lesion within 1 year of a CIS had a higher probability (94%) of having an EDSS score of more than 3.5 at 30 years than when compared with those with neither lesion (13%) and those with one DWM but no IT lesions (49%).

Looking at the best independent predictors up to 5 years, the predicted probability of an EDSS score of more than 3.5 if there were no IT lesions and fewer than five DWM lesions was 18%. But if there were no IT but more than 5 DWM lesions, the probability of disability at 30 years rose to 52%. The probabilities rose even higher to 63% if there was one or more IT and five or less DWM lesions and 90% if there was one or more IT and more than five DWM lesions.

“In this cohort, the presence of early infratentorial and deep white matter lesions following a CIS are associated with higher level of disability 30 years later,” Dr. Chung concluded. “Early predictive models can add information to risk-benefit stratification.”

During discussion, one delegate expressed concerns that these data were “not generalizable to the current situation.” This was a cohort of patients that largely wasn’t treated or if they were, treatment was delayed by more than 10 years. These data were interesting “from a historical perspective,” he argued, “but I don’t understand, how in the absence of contemporary therapies this is applicable in a way that will allow us to use this information to make prognoses for the future.”

Dr. Chung agreed, noting that this was more of a natural history study. “However, I think it is applicable in clinical practice in my opinion.

“When you have a patient presenting with a CIS, at the time of diagnosis, especially now when we can diagnose patients earlier with the new 2017 criteria, it will be helpful for the patient and ourselves to apply some of the information I presented to help perhaps in aiding decisions regarding treatment.”

The study was funded by a grant from the MS Society of Great Britain. Dr. Chung disclosed receiving honoraria from Teva, Biogen, and Roche.

SOURCE: Chung K et al. Mult Scler. 2018;24(S2):58-59, Abstract 157.

Clinical question

In pediatric postoperative spinal fusion/adolescent idiopathic scoliosis patients, do alternatives to traditional opioid-based analgesic pain regimens lead to improved clinical outcomes?

Background

Traditional care for pediatric postoperative spinal fusion (PSF) patients has included late mobilization most often because of significant pain that requires significant opioid administration. This has led to side effects of heavy opioid use, primarily nausea/vomiting and sleepiness.

In the United States, prescribers have become more aware of the pitfalls of opioid use given that more people now die of opioid misuse than breast cancer. An approach of multimodal analgesia with early mobilization has been shown to have decreased length of stay (LOS) and improve patient satisfaction, but data on clinical outcomes have been lacking.

Study design

Single-center quality improvement (QI) project.

Setting

Urban, 527-bed, quaternary care, free-standing children’s hospital.

Synopsis

Based on the recognition that multiple “standards” of care were utilized in the postoperative management of PSF patients, a QI project was undertaken. The primary outcome measured was functional recovery, as measured by average LOS and pain scores at the first 6:00 am after surgery then on postoperative days 1, 2, and 3.

Process measures were: use of multimodal agents (gabapentin and ketorolac) and discontinuation of patient-controlled analgesia (PCA) before postoperative day 3. Balancing measures were 30-day readmissions or ED revisit. Patients were divided into three groups by analyzing outcomes in three consecutive time periods: conventional management (n = 134), transition period (n = 104), and rapid recovery pathway (n = 84). In the conventional management time period, patients received intraoperative methadone and postoperative morphine/hydromorphone PCA. During the transition period, plan-do-study-act (PDSA) cycles with ketorolac and gabapentin pilots were instituted and assessed. Finally, a rapid recovery pathway (RRP) was designed and published as a web-based algorithm. Standardized entry order sets were developed to maintain compliance and consistency among health care professionals, and a transition period was allowed to reach the highest possible percentage of patients adhering to multimodal analgesia regimen.

Adherence to the multimodal regimen led to 90% of patients receiving ketorolac on postoperative day 1, 100% receiving gabapentin on night of surgery, 86% off of IV PCA by postoperative day 3, and 100% order set adherence after full implementation of the RRP. LOS decreased from 5.7 to 4 days after RRP implementation. Pain scores also showed significant improvement on postoperative day 0 (average pain score, 3.8 vs. 4.9) and postoperative day 1 (3.8 vs. 5). Balancing measures of 30-day readmissions or ED visits after discharge was 2.9% and rose to 3.6% after full implementation.

Bottom line

Multimodal analgesia – including preoperative gabapentin and acetaminophen, intraoperative methadone and acetaminophen, and postoperative PCA diazepam, gabapentin, acetaminophen, and ketorolac – results in decreased length of stay and improved self-reported daily pain scores.

Citation

Muhly WT et al. Rapid recovery pathway after spinal fusion for idiopathic scoliosis. Pediatrics. 2016 Apr;137(4):e20151568.

Dr. Giordano is a pediatric neurosurgery hospitalist and assistant professor in pediatrics at Columbia University Irving Medical Center in New York.

Clinical question

In pediatric postoperative spinal fusion/adolescent idiopathic scoliosis patients, do alternatives to traditional opioid-based analgesic pain regimens lead to improved clinical outcomes?

Background

Traditional care for pediatric postoperative spinal fusion (PSF) patients has included late mobilization most often because of significant pain that requires significant opioid administration. This has led to side effects of heavy opioid use, primarily nausea/vomiting and sleepiness.

In the United States, prescribers have become more aware of the pitfalls of opioid use given that more people now die of opioid misuse than breast cancer. An approach of multimodal analgesia with early mobilization has been shown to have decreased length of stay (LOS) and improve patient satisfaction, but data on clinical outcomes have been lacking.

Study design

Single-center quality improvement (QI) project.

Setting

Urban, 527-bed, quaternary care, free-standing children’s hospital.

Synopsis

Based on the recognition that multiple “standards” of care were utilized in the postoperative management of PSF patients, a QI project was undertaken. The primary outcome measured was functional recovery, as measured by average LOS and pain scores at the first 6:00 am after surgery then on postoperative days 1, 2, and 3.

Process measures were: use of multimodal agents (gabapentin and ketorolac) and discontinuation of patient-controlled analgesia (PCA) before postoperative day 3. Balancing measures were 30-day readmissions or ED revisit. Patients were divided into three groups by analyzing outcomes in three consecutive time periods: conventional management (n = 134), transition period (n = 104), and rapid recovery pathway (n = 84). In the conventional management time period, patients received intraoperative methadone and postoperative morphine/hydromorphone PCA. During the transition period, plan-do-study-act (PDSA) cycles with ketorolac and gabapentin pilots were instituted and assessed. Finally, a rapid recovery pathway (RRP) was designed and published as a web-based algorithm. Standardized entry order sets were developed to maintain compliance and consistency among health care professionals, and a transition period was allowed to reach the highest possible percentage of patients adhering to multimodal analgesia regimen.

Adherence to the multimodal regimen led to 90% of patients receiving ketorolac on postoperative day 1, 100% receiving gabapentin on night of surgery, 86% off of IV PCA by postoperative day 3, and 100% order set adherence after full implementation of the RRP. LOS decreased from 5.7 to 4 days after RRP implementation. Pain scores also showed significant improvement on postoperative day 0 (average pain score, 3.8 vs. 4.9) and postoperative day 1 (3.8 vs. 5). Balancing measures of 30-day readmissions or ED visits after discharge was 2.9% and rose to 3.6% after full implementation.

Bottom line

Multimodal analgesia – including preoperative gabapentin and acetaminophen, intraoperative methadone and acetaminophen, and postoperative PCA diazepam, gabapentin, acetaminophen, and ketorolac – results in decreased length of stay and improved self-reported daily pain scores.

Citation

Muhly WT et al. Rapid recovery pathway after spinal fusion for idiopathic scoliosis. Pediatrics. 2016 Apr;137(4):e20151568.

Dr. Giordano is a pediatric neurosurgery hospitalist and assistant professor in pediatrics at Columbia University Irving Medical Center in New York.

Clinical question

In pediatric postoperative spinal fusion/adolescent idiopathic scoliosis patients, do alternatives to traditional opioid-based analgesic pain regimens lead to improved clinical outcomes?

Background

Traditional care for pediatric postoperative spinal fusion (PSF) patients has included late mobilization most often because of significant pain that requires significant opioid administration. This has led to side effects of heavy opioid use, primarily nausea/vomiting and sleepiness.

In the United States, prescribers have become more aware of the pitfalls of opioid use given that more people now die of opioid misuse than breast cancer. An approach of multimodal analgesia with early mobilization has been shown to have decreased length of stay (LOS) and improve patient satisfaction, but data on clinical outcomes have been lacking.

Study design

Single-center quality improvement (QI) project.

Setting

Urban, 527-bed, quaternary care, free-standing children’s hospital.

Synopsis

Based on the recognition that multiple “standards” of care were utilized in the postoperative management of PSF patients, a QI project was undertaken. The primary outcome measured was functional recovery, as measured by average LOS and pain scores at the first 6:00 am after surgery then on postoperative days 1, 2, and 3.

Process measures were: use of multimodal agents (gabapentin and ketorolac) and discontinuation of patient-controlled analgesia (PCA) before postoperative day 3. Balancing measures were 30-day readmissions or ED revisit. Patients were divided into three groups by analyzing outcomes in three consecutive time periods: conventional management (n = 134), transition period (n = 104), and rapid recovery pathway (n = 84). In the conventional management time period, patients received intraoperative methadone and postoperative morphine/hydromorphone PCA. During the transition period, plan-do-study-act (PDSA) cycles with ketorolac and gabapentin pilots were instituted and assessed. Finally, a rapid recovery pathway (RRP) was designed and published as a web-based algorithm. Standardized entry order sets were developed to maintain compliance and consistency among health care professionals, and a transition period was allowed to reach the highest possible percentage of patients adhering to multimodal analgesia regimen.

Adherence to the multimodal regimen led to 90% of patients receiving ketorolac on postoperative day 1, 100% receiving gabapentin on night of surgery, 86% off of IV PCA by postoperative day 3, and 100% order set adherence after full implementation of the RRP. LOS decreased from 5.7 to 4 days after RRP implementation. Pain scores also showed significant improvement on postoperative day 0 (average pain score, 3.8 vs. 4.9) and postoperative day 1 (3.8 vs. 5). Balancing measures of 30-day readmissions or ED visits after discharge was 2.9% and rose to 3.6% after full implementation.

Bottom line

Multimodal analgesia – including preoperative gabapentin and acetaminophen, intraoperative methadone and acetaminophen, and postoperative PCA diazepam, gabapentin, acetaminophen, and ketorolac – results in decreased length of stay and improved self-reported daily pain scores.

Citation

Muhly WT et al. Rapid recovery pathway after spinal fusion for idiopathic scoliosis. Pediatrics. 2016 Apr;137(4):e20151568.

Dr. Giordano is a pediatric neurosurgery hospitalist and assistant professor in pediatrics at Columbia University Irving Medical Center in New York.

ATLANTA – According to Peter Berlit, MD, clinicians should think of an underlying rheumatic disease in association with stroke when a patient has younger age, no risk factors, and accompanying headache and encephalopathy.

Other factors include combination of ischemic and hemorrhagic stroke, exclusive involvement of intracranial vessels, systemic signs, and lab tests indicating inflammation.

At the annual meeting of the American Neurological Association, Dr. Berlit, secretary general of the German Society of Neurology in Berlin, discussed the diagnosis and management of rare causes of stroke.

Giant cell arteritis (GCA)

One of the rare causes of stroke, GCA can be diagnosed when three of five criteria are met: being 50 years of age or older, having a newly developed headache, tenderness of the superficial temporal artery, elevated sedimentation rate of at least 50 mm per hour, and GCA in a biopsy specimen from the temporal artery.

“What we fear most is sudden blindness due to involvement of arteries serving the eyes, which appears in up to 30% of GCA patients,” said Dr. Berlit, who formerly chaired the department of neurology at Alfried Krupp Hospital, Essen, Germany. “Stroke occurs in approximately 2% of GCA patients, so it’s a lot rarer.” GCA can also be diagnosed by ultrasound. One meta-analysis of 23 studies using halo, stenosis, and occlusion as ultrasound criteria found a sensitivity of 87% and a specificity of 96% (Ann Intern Med. 2005;142[5]:359-69). “You can also use 3-Tesla MRI with the use of contrast agent, which shows inflammation of the temporal artery, but also other large vessels including the aortic arch,” he said. “The treatment of GCA has changed since the end of 2017 and involves starting with prednisolone 1 mg/kg body weight.” After a dose of 30 mg for 4 weeks, reduce the dose by 2.5 mg every 2 weeks. After reaching the dose of 15 mg daily, reduce by 1 mg per month. “The recommended steroid-sparing treatment is subcutaneous tocilizumab at a dose of 162 mg weekly or every other week, combined with a prednisone taper for a minimum of 26 weeks,” he said. Supportive therapies include pantoprazole 20 mg, aspirin 100 mg, calcium, vitamin D, and bisphosphonates.
 

Primary angiitis of the central nervous system (PACNS)

Next, Dr. Berlit discussed diagnostic criteria for PACNS, an acquired neurological deficit unexplained after complete evaluation. “You should have a diagnostic cerebral angiogram or biopsy demonstrating vasculitis,” he said. “There should be no evidence of systemic vasculitis or any other conditions that could mimic the angiogram findings. Usually you have abnormal CSF findings, including pleocytosis and protein elevation, and a biopsy demonstrating vasculitis.”

MRI studies in suspected vasculitis include fluid-attenuated inversion recovery (FLAIR), diffusion imaging with apparent diffusion coefficient (ADC) maps, gradient ECHO, MR angiography, and contrast-enhanced imaging. “These usually show multifocal lesions of different ages, and hemorrhages occur in about 10% of lesions,” Dr. Berlit said. “Leptomeningeal enhancement is an indicator of good treatment response.”

A brain and leptomeningeal biopsy demonstrating the angiitis remains the preferred method for diagnosis of PACNS. “Open biopsies out of recent MRI lesions are especially diagnostic,” he said. “If there are no lesions accessible for surgery in noneloquent brain areas, a biopsy from the right frontal lobe is recommended.” The histologic findings of PACNS consist of granulomatous inflammation, fibrinoid necrosis of vessel walls, or exclusively lymphocytic cellular infiltrates. “The treatment of choice in PACNS is the combination of steroids and cyclophosphamide pulse therapy,” he said. “There are also data showing that rituximab or methotrexate might be treatment options. With a relapse rate of 25% and a reduced survival rate, a close follow-up of suspected PACNS is mandatory.”
 

Reversible cerebral vasoconstriction syndrome (RCVS)

Another rare cause of stroke is RCVS, which typically presents as thunderclap headaches with or without neurologic symptoms. MRI may be normal, but symmetric border zone infarctions and small subarachnoid hemorrhages are possible. Catheter, CT, or MR angiography show segmental arterial vasoconstriction. “You always have to exclude cerebral aneurysm,” Dr. Berlit said. “There is reversibility of RCVS within 3 months.” RCVS is often associated with a long list of drugs, including phenylpropanolamine, Methergine (methylergonovine), bromocriptine, lisuride, SSRIs, triptans, isometheptene, tacrolimus, cyclophosphamide, erythropoietin, intravenous immunoglobulins, erythrocyte concentrates, nasal sprays, cocaine, ecstasy, amphetamines, cannabis, and LSD. “After stopping responsible medications, treatment involves a course of nimodipine,” he said.

Moyamoya disease (MMD)

Dr. Berlit closed his presentation by discussing MMD, a rare occlusive cerebrovascular disorder characterized by progressive stenosis or occlusion of the intracranial portion of the internal carotid artery and proximal cerebral arteries with an extensive network of fine collaterals. “This is an idiopathic vasculopathy with remarkable regional and racial differences worldwide; it’s most frequently found in Asians, especially in Japan and Korea,” he said. “In Europe, there is about one-tenth the incidence, compared with that of Japan. In Asian MMD, about 15% of cases follow an autosomal dominant inheritance. The collaterals in MMD present histologically as a thin media, a fragmented elastic laminae, and the formation of microaneurysms. There is no inflammation.”

MMD diagnostic criteria include stenosis or occlusion of the terminal portion of the internal carotid artery and at the proximal portion of the anterior and middle cerebral arteries. Abnormal vascular networks are present in the basal ganglia and angiographic findings present bilaterally. Cases with unilateral angiographic findings are considered probable. Clinicians should exclude the following conditions: arteriosclerosis, autoimmune disease, brain neoplasm, history of cranial irradiation, Down syndrome, head trauma, neurofibromatosis, and meningitis. “If the angiographic pattern is resembled by one of these conditions, this is called moyamoya syndrome,” Dr. Berlit noted. “MMD is a progressive disorder. Within a few months you can see occlusion of the middle cerebral artery and the anterior cerebral artery, so you have to treat these patients.”

In patients who are white, MMD presents with lower rates of hemorrhage, but in Asians, microbleeds occur in up to 44% of patients and hemorrhages in up to 65% patients. “Both subarachnoidal and intracerebral hemorrhages occur, especially in connection with pregnancy and delivery,” he said. “The risk of both cerebral ischemia and hemorrhagic complications increases with stages of MMD.”

Direct or indirect intracranial bypass surgery is recommended in stages 3 or more, and has been shown to significantly reduce the 5-year stroke risk. To date, Dr. Berlit and his associates have treated 86 hemispheres in 56 patients. The average age of the patients was 42 years, 70% were female, and the average follow-up was 39 months. All intracranial bypasses were open on follow-up, and a decrease of the typical moyamoya vessels was observed in 81% of patients.

Dr. Berlit reported having no financial disclosures.

[email protected]

ATLANTA – According to Peter Berlit, MD, clinicians should think of an underlying rheumatic disease in association with stroke when a patient has younger age, no risk factors, and accompanying headache and encephalopathy.

Other factors include combination of ischemic and hemorrhagic stroke, exclusive involvement of intracranial vessels, systemic signs, and lab tests indicating inflammation.

At the annual meeting of the American Neurological Association, Dr. Berlit, secretary general of the German Society of Neurology in Berlin, discussed the diagnosis and management of rare causes of stroke.

Giant cell arteritis (GCA)

One of the rare causes of stroke, GCA can be diagnosed when three of five criteria are met: being 50 years of age or older, having a newly developed headache, tenderness of the superficial temporal artery, elevated sedimentation rate of at least 50 mm per hour, and GCA in a biopsy specimen from the temporal artery.

“What we fear most is sudden blindness due to involvement of arteries serving the eyes, which appears in up to 30% of GCA patients,” said Dr. Berlit, who formerly chaired the department of neurology at Alfried Krupp Hospital, Essen, Germany. “Stroke occurs in approximately 2% of GCA patients, so it’s a lot rarer.” GCA can also be diagnosed by ultrasound. One meta-analysis of 23 studies using halo, stenosis, and occlusion as ultrasound criteria found a sensitivity of 87% and a specificity of 96% (Ann Intern Med. 2005;142[5]:359-69). “You can also use 3-Tesla MRI with the use of contrast agent, which shows inflammation of the temporal artery, but also other large vessels including the aortic arch,” he said. “The treatment of GCA has changed since the end of 2017 and involves starting with prednisolone 1 mg/kg body weight.” After a dose of 30 mg for 4 weeks, reduce the dose by 2.5 mg every 2 weeks. After reaching the dose of 15 mg daily, reduce by 1 mg per month. “The recommended steroid-sparing treatment is subcutaneous tocilizumab at a dose of 162 mg weekly or every other week, combined with a prednisone taper for a minimum of 26 weeks,” he said. Supportive therapies include pantoprazole 20 mg, aspirin 100 mg, calcium, vitamin D, and bisphosphonates.
 

Primary angiitis of the central nervous system (PACNS)

Next, Dr. Berlit discussed diagnostic criteria for PACNS, an acquired neurological deficit unexplained after complete evaluation. “You should have a diagnostic cerebral angiogram or biopsy demonstrating vasculitis,” he said. “There should be no evidence of systemic vasculitis or any other conditions that could mimic the angiogram findings. Usually you have abnormal CSF findings, including pleocytosis and protein elevation, and a biopsy demonstrating vasculitis.”

MRI studies in suspected vasculitis include fluid-attenuated inversion recovery (FLAIR), diffusion imaging with apparent diffusion coefficient (ADC) maps, gradient ECHO, MR angiography, and contrast-enhanced imaging. “These usually show multifocal lesions of different ages, and hemorrhages occur in about 10% of lesions,” Dr. Berlit said. “Leptomeningeal enhancement is an indicator of good treatment response.”

A brain and leptomeningeal biopsy demonstrating the angiitis remains the preferred method for diagnosis of PACNS. “Open biopsies out of recent MRI lesions are especially diagnostic,” he said. “If there are no lesions accessible for surgery in noneloquent brain areas, a biopsy from the right frontal lobe is recommended.” The histologic findings of PACNS consist of granulomatous inflammation, fibrinoid necrosis of vessel walls, or exclusively lymphocytic cellular infiltrates. “The treatment of choice in PACNS is the combination of steroids and cyclophosphamide pulse therapy,” he said. “There are also data showing that rituximab or methotrexate might be treatment options. With a relapse rate of 25% and a reduced survival rate, a close follow-up of suspected PACNS is mandatory.”
 

Reversible cerebral vasoconstriction syndrome (RCVS)

Another rare cause of stroke is RCVS, which typically presents as thunderclap headaches with or without neurologic symptoms. MRI may be normal, but symmetric border zone infarctions and small subarachnoid hemorrhages are possible. Catheter, CT, or MR angiography show segmental arterial vasoconstriction. “You always have to exclude cerebral aneurysm,” Dr. Berlit said. “There is reversibility of RCVS within 3 months.” RCVS is often associated with a long list of drugs, including phenylpropanolamine, Methergine (methylergonovine), bromocriptine, lisuride, SSRIs, triptans, isometheptene, tacrolimus, cyclophosphamide, erythropoietin, intravenous immunoglobulins, erythrocyte concentrates, nasal sprays, cocaine, ecstasy, amphetamines, cannabis, and LSD. “After stopping responsible medications, treatment involves a course of nimodipine,” he said.

Moyamoya disease (MMD)

Dr. Berlit closed his presentation by discussing MMD, a rare occlusive cerebrovascular disorder characterized by progressive stenosis or occlusion of the intracranial portion of the internal carotid artery and proximal cerebral arteries with an extensive network of fine collaterals. “This is an idiopathic vasculopathy with remarkable regional and racial differences worldwide; it’s most frequently found in Asians, especially in Japan and Korea,” he said. “In Europe, there is about one-tenth the incidence, compared with that of Japan. In Asian MMD, about 15% of cases follow an autosomal dominant inheritance. The collaterals in MMD present histologically as a thin media, a fragmented elastic laminae, and the formation of microaneurysms. There is no inflammation.”

MMD diagnostic criteria include stenosis or occlusion of the terminal portion of the internal carotid artery and at the proximal portion of the anterior and middle cerebral arteries. Abnormal vascular networks are present in the basal ganglia and angiographic findings present bilaterally. Cases with unilateral angiographic findings are considered probable. Clinicians should exclude the following conditions: arteriosclerosis, autoimmune disease, brain neoplasm, history of cranial irradiation, Down syndrome, head trauma, neurofibromatosis, and meningitis. “If the angiographic pattern is resembled by one of these conditions, this is called moyamoya syndrome,” Dr. Berlit noted. “MMD is a progressive disorder. Within a few months you can see occlusion of the middle cerebral artery and the anterior cerebral artery, so you have to treat these patients.”

In patients who are white, MMD presents with lower rates of hemorrhage, but in Asians, microbleeds occur in up to 44% of patients and hemorrhages in up to 65% patients. “Both subarachnoidal and intracerebral hemorrhages occur, especially in connection with pregnancy and delivery,” he said. “The risk of both cerebral ischemia and hemorrhagic complications increases with stages of MMD.”

Direct or indirect intracranial bypass surgery is recommended in stages 3 or more, and has been shown to significantly reduce the 5-year stroke risk. To date, Dr. Berlit and his associates have treated 86 hemispheres in 56 patients. The average age of the patients was 42 years, 70% were female, and the average follow-up was 39 months. All intracranial bypasses were open on follow-up, and a decrease of the typical moyamoya vessels was observed in 81% of patients.

Dr. Berlit reported having no financial disclosures.

[email protected]

ATLANTA – According to Peter Berlit, MD, clinicians should think of an underlying rheumatic disease in association with stroke when a patient has younger age, no risk factors, and accompanying headache and encephalopathy.

Other factors include combination of ischemic and hemorrhagic stroke, exclusive involvement of intracranial vessels, systemic signs, and lab tests indicating inflammation.

At the annual meeting of the American Neurological Association, Dr. Berlit, secretary general of the German Society of Neurology in Berlin, discussed the diagnosis and management of rare causes of stroke.

Giant cell arteritis (GCA)

One of the rare causes of stroke, GCA can be diagnosed when three of five criteria are met: being 50 years of age or older, having a newly developed headache, tenderness of the superficial temporal artery, elevated sedimentation rate of at least 50 mm per hour, and GCA in a biopsy specimen from the temporal artery.

“What we fear most is sudden blindness due to involvement of arteries serving the eyes, which appears in up to 30% of GCA patients,” said Dr. Berlit, who formerly chaired the department of neurology at Alfried Krupp Hospital, Essen, Germany. “Stroke occurs in approximately 2% of GCA patients, so it’s a lot rarer.” GCA can also be diagnosed by ultrasound. One meta-analysis of 23 studies using halo, stenosis, and occlusion as ultrasound criteria found a sensitivity of 87% and a specificity of 96% (Ann Intern Med. 2005;142[5]:359-69). “You can also use 3-Tesla MRI with the use of contrast agent, which shows inflammation of the temporal artery, but also other large vessels including the aortic arch,” he said. “The treatment of GCA has changed since the end of 2017 and involves starting with prednisolone 1 mg/kg body weight.” After a dose of 30 mg for 4 weeks, reduce the dose by 2.5 mg every 2 weeks. After reaching the dose of 15 mg daily, reduce by 1 mg per month. “The recommended steroid-sparing treatment is subcutaneous tocilizumab at a dose of 162 mg weekly or every other week, combined with a prednisone taper for a minimum of 26 weeks,” he said. Supportive therapies include pantoprazole 20 mg, aspirin 100 mg, calcium, vitamin D, and bisphosphonates.
 

Primary angiitis of the central nervous system (PACNS)

Next, Dr. Berlit discussed diagnostic criteria for PACNS, an acquired neurological deficit unexplained after complete evaluation. “You should have a diagnostic cerebral angiogram or biopsy demonstrating vasculitis,” he said. “There should be no evidence of systemic vasculitis or any other conditions that could mimic the angiogram findings. Usually you have abnormal CSF findings, including pleocytosis and protein elevation, and a biopsy demonstrating vasculitis.”

MRI studies in suspected vasculitis include fluid-attenuated inversion recovery (FLAIR), diffusion imaging with apparent diffusion coefficient (ADC) maps, gradient ECHO, MR angiography, and contrast-enhanced imaging. “These usually show multifocal lesions of different ages, and hemorrhages occur in about 10% of lesions,” Dr. Berlit said. “Leptomeningeal enhancement is an indicator of good treatment response.”

A brain and leptomeningeal biopsy demonstrating the angiitis remains the preferred method for diagnosis of PACNS. “Open biopsies out of recent MRI lesions are especially diagnostic,” he said. “If there are no lesions accessible for surgery in noneloquent brain areas, a biopsy from the right frontal lobe is recommended.” The histologic findings of PACNS consist of granulomatous inflammation, fibrinoid necrosis of vessel walls, or exclusively lymphocytic cellular infiltrates. “The treatment of choice in PACNS is the combination of steroids and cyclophosphamide pulse therapy,” he said. “There are also data showing that rituximab or methotrexate might be treatment options. With a relapse rate of 25% and a reduced survival rate, a close follow-up of suspected PACNS is mandatory.”
 

Reversible cerebral vasoconstriction syndrome (RCVS)

Another rare cause of stroke is RCVS, which typically presents as thunderclap headaches with or without neurologic symptoms. MRI may be normal, but symmetric border zone infarctions and small subarachnoid hemorrhages are possible. Catheter, CT, or MR angiography show segmental arterial vasoconstriction. “You always have to exclude cerebral aneurysm,” Dr. Berlit said. “There is reversibility of RCVS within 3 months.” RCVS is often associated with a long list of drugs, including phenylpropanolamine, Methergine (methylergonovine), bromocriptine, lisuride, SSRIs, triptans, isometheptene, tacrolimus, cyclophosphamide, erythropoietin, intravenous immunoglobulins, erythrocyte concentrates, nasal sprays, cocaine, ecstasy, amphetamines, cannabis, and LSD. “After stopping responsible medications, treatment involves a course of nimodipine,” he said.

Moyamoya disease (MMD)

Dr. Berlit closed his presentation by discussing MMD, a rare occlusive cerebrovascular disorder characterized by progressive stenosis or occlusion of the intracranial portion of the internal carotid artery and proximal cerebral arteries with an extensive network of fine collaterals. “This is an idiopathic vasculopathy with remarkable regional and racial differences worldwide; it’s most frequently found in Asians, especially in Japan and Korea,” he said. “In Europe, there is about one-tenth the incidence, compared with that of Japan. In Asian MMD, about 15% of cases follow an autosomal dominant inheritance. The collaterals in MMD present histologically as a thin media, a fragmented elastic laminae, and the formation of microaneurysms. There is no inflammation.”

MMD diagnostic criteria include stenosis or occlusion of the terminal portion of the internal carotid artery and at the proximal portion of the anterior and middle cerebral arteries. Abnormal vascular networks are present in the basal ganglia and angiographic findings present bilaterally. Cases with unilateral angiographic findings are considered probable. Clinicians should exclude the following conditions: arteriosclerosis, autoimmune disease, brain neoplasm, history of cranial irradiation, Down syndrome, head trauma, neurofibromatosis, and meningitis. “If the angiographic pattern is resembled by one of these conditions, this is called moyamoya syndrome,” Dr. Berlit noted. “MMD is a progressive disorder. Within a few months you can see occlusion of the middle cerebral artery and the anterior cerebral artery, so you have to treat these patients.”

In patients who are white, MMD presents with lower rates of hemorrhage, but in Asians, microbleeds occur in up to 44% of patients and hemorrhages in up to 65% patients. “Both subarachnoidal and intracerebral hemorrhages occur, especially in connection with pregnancy and delivery,” he said. “The risk of both cerebral ischemia and hemorrhagic complications increases with stages of MMD.”

Direct or indirect intracranial bypass surgery is recommended in stages 3 or more, and has been shown to significantly reduce the 5-year stroke risk. To date, Dr. Berlit and his associates have treated 86 hemispheres in 56 patients. The average age of the patients was 42 years, 70% were female, and the average follow-up was 39 months. All intracranial bypasses were open on follow-up, and a decrease of the typical moyamoya vessels was observed in 81% of patients.

Dr. Berlit reported having no financial disclosures.

[email protected]

The updated guidance on managing acute flaccid myelitis is unlikely to relieve the frustrations of physicians struggling to treat the condition.

After reviewing the extant data on the baffling disorder, the Centers for Disease Control and Prevention found no evidence that corticosteroids, interferon, antivirals, or any other immunologic or biologic therapy is an effective treatment.

All of the treatments mentioned in the guidance have been used anecdotally, and often for cases proven to be associated with enterovirus-related cases. However, there are no well validated studies confirming benefit for any of these approaches, the agency said in its clinical management document.

Acute flaccid myelitis (AFM) has stricken 90 patients in the United States this year and another 252 cases are being investigated, according to new data from the CDC. The number of confirmed cases is triple that seen in 2017. Whether the disease is an infectious or autoimmune process, or something else entirely, remains unknown.

In response to the outbreak – the largest since 2014 – an expert panel of 4 CDC staff physicians reviewed the literature to find what, if any, treatments were effective; another 14 external experts provided input on the recommendations. At this point, nothing can be officially recommended, the agency said.

Corticosteroids

Corticosteroids should not be administered to most patients with AFM. In addition to “a theoretical concern” about the potential adverse effects of these drugs in acute infections, there is some hard evidence that they are associated with worse outcomes in enteroviral neuroinvasive diseases, particularly those caused by EV-71.

This observation, following a 2012 outbreak in Cambodia, led a World Health Organization commission to conclude that corticosteroids were contraindicated in the management of EV-71–associated neuroinvasive disease. This year, there has been an uptick in EV-A71-associated neurologic disease.

The CDC did hedge its advice on corticosteroids a bit in the setting of AFM, however. “There may be theoretical benefit for steroids in the setting of severe cord swelling or long tract signs suggesting white matter involvement, where steroids may salvage tissue that may be harmed due to an ongoing immune/inflammatory response. While AFM is clinically and radiographically defined by the predominance of gray matter damage in the spinal cord, some patients may have some white matter involvement. It is not clear if these different patterns are important relative to therapeutic considerations.”

Nevertheless, the agency does not recommend corticosteroid use for these patients. “The possible benefits of the use of corticosteroids to manage spinal cord edema or white matter involvement in AFM should be balanced with the possible harm due to immunosuppression in the setting of possible viral infection.”
 

IVIG

While IVIG holds some theoretical benefit for AFM, there are no high-level human data, the guidelines state. The treatment is generally safe and well tolerated, but the few reports of its use in AFM did not show clear benefit. These include two case series. One suggested an acute improvement of neurologic status, but no long-term resolution of deficits. The other indicated neither significant improvement nor deterioration.

However, current practice at Children’s Hospital of Philadelphia is to initiate IVIG therapy at AFM diagnosis in hopes of boosting humoral immunity.

Nevertheless, the CDC said, “For IVIG to modify disease in an active viral infectious process, early administration is likely required, and possibly prior to exposure,” and the treatment cannot be recommended.
 

Plasma exchange

Plasma exchange in combination with IVIG and corticosteroids was ineffective in a case series of four Argentinian children, although a single case published last year found that the combination was associated with significant improvement. However, there are not enough data to recommend this approach.

Fluoxetine

Fluoxetine’s antiviral potential turned up in a high-throughput screening project to identify novel compounds with antiviral efficacy against enteroviruses. In 2012, researchers from the University of California, Los Angeles, tested more than 1,000 compounds and found that the SSRI is a potent inhibitor of coxsackievirus. A later project at the National Institutes of Health replicated this finding, and determined that fluoxetine inhibited several enteroviruses, including the AFM suspect, EV-D68.

Fluoxetine concentrates more highly in the central nervous system than it does in plasma, but its antiviral properties have nothing to do with neurotransmitter activity. Rather, it appears to inhibit protein 2C, a highly conserved nonstructural protein that’s crucial to the assembly of RNA into virion particles.

In early November, a retrospective study examined fluoxetine’s use in 30 AFM patients, compared with 26 who did not receive it. The primary outcome was change in summative limb strength score. The study did little to clarify any benefit, however. The authors concluded that fluoxetine was preferentially given to patients with EDV-68 infections. They had more severe impairment at nadir, and at the last follow-up of about 1 year, they had worse outcomes.

“There is no clear human evidence for efficacy of fluoxetine in the treatment of AFM based on a single retrospective evaluation conducted in patients with AFM, and data from a mouse model also did not support efficacy,” the CDC said.
 

Antiviral medications

The CDC is quite clear on its recommendation that these drugs are not indicated in AFM, since it is not yet proven to be an infectious process.

“Any guidance regarding antiviral medications should be interpreted with great caution, given the unknowns about the pathogenesis of this illness at present ... Testing has been conducted at CDC for antiviral activity of compounds pleconaril, pocapavir, and vapendavir and none have significant activity against currently circulating strains of EV-D68 at clinically relevant concentrations.”
 

Interferon

There is some anecdotal evidence that interferon alpha-2b was beneficial in treating a polio-like syndrome associated with West Nile virus and Saint Louis encephalitis. “Although there are limited in vitro, animal, and anecdotal human data suggesting activity of some interferons against viral infections, sufficient data are lacking in the setting of AFM,” the agency said. “There is no indication that interferon should be used for the treatment of AFM, and there is concern about the potential for harm from the use of interferon given the immunomodulatory effects in the setting of possible ongoing viral replication.”

[email protected]

SOURCE: CDC Acute Flaccid Myelitis: Interim Considerations for Clinical Management

The updated guidance on managing acute flaccid myelitis is unlikely to relieve the frustrations of physicians struggling to treat the condition.

After reviewing the extant data on the baffling disorder, the Centers for Disease Control and Prevention found no evidence that corticosteroids, interferon, antivirals, or any other immunologic or biologic therapy is an effective treatment.

All of the treatments mentioned in the guidance have been used anecdotally, and often for cases proven to be associated with enterovirus-related cases. However, there are no well validated studies confirming benefit for any of these approaches, the agency said in its clinical management document.

Acute flaccid myelitis (AFM) has stricken 90 patients in the United States this year and another 252 cases are being investigated, according to new data from the CDC. The number of confirmed cases is triple that seen in 2017. Whether the disease is an infectious or autoimmune process, or something else entirely, remains unknown.

In response to the outbreak – the largest since 2014 – an expert panel of 4 CDC staff physicians reviewed the literature to find what, if any, treatments were effective; another 14 external experts provided input on the recommendations. At this point, nothing can be officially recommended, the agency said.

Corticosteroids

Corticosteroids should not be administered to most patients with AFM. In addition to “a theoretical concern” about the potential adverse effects of these drugs in acute infections, there is some hard evidence that they are associated with worse outcomes in enteroviral neuroinvasive diseases, particularly those caused by EV-71.

This observation, following a 2012 outbreak in Cambodia, led a World Health Organization commission to conclude that corticosteroids were contraindicated in the management of EV-71–associated neuroinvasive disease. This year, there has been an uptick in EV-A71-associated neurologic disease.

The CDC did hedge its advice on corticosteroids a bit in the setting of AFM, however. “There may be theoretical benefit for steroids in the setting of severe cord swelling or long tract signs suggesting white matter involvement, where steroids may salvage tissue that may be harmed due to an ongoing immune/inflammatory response. While AFM is clinically and radiographically defined by the predominance of gray matter damage in the spinal cord, some patients may have some white matter involvement. It is not clear if these different patterns are important relative to therapeutic considerations.”

Nevertheless, the agency does not recommend corticosteroid use for these patients. “The possible benefits of the use of corticosteroids to manage spinal cord edema or white matter involvement in AFM should be balanced with the possible harm due to immunosuppression in the setting of possible viral infection.”
 

IVIG

While IVIG holds some theoretical benefit for AFM, there are no high-level human data, the guidelines state. The treatment is generally safe and well tolerated, but the few reports of its use in AFM did not show clear benefit. These include two case series. One suggested an acute improvement of neurologic status, but no long-term resolution of deficits. The other indicated neither significant improvement nor deterioration.

However, current practice at Children’s Hospital of Philadelphia is to initiate IVIG therapy at AFM diagnosis in hopes of boosting humoral immunity.

Nevertheless, the CDC said, “For IVIG to modify disease in an active viral infectious process, early administration is likely required, and possibly prior to exposure,” and the treatment cannot be recommended.
 

Plasma exchange

Plasma exchange in combination with IVIG and corticosteroids was ineffective in a case series of four Argentinian children, although a single case published last year found that the combination was associated with significant improvement. However, there are not enough data to recommend this approach.

Fluoxetine

Fluoxetine’s antiviral potential turned up in a high-throughput screening project to identify novel compounds with antiviral efficacy against enteroviruses. In 2012, researchers from the University of California, Los Angeles, tested more than 1,000 compounds and found that the SSRI is a potent inhibitor of coxsackievirus. A later project at the National Institutes of Health replicated this finding, and determined that fluoxetine inhibited several enteroviruses, including the AFM suspect, EV-D68.

Fluoxetine concentrates more highly in the central nervous system than it does in plasma, but its antiviral properties have nothing to do with neurotransmitter activity. Rather, it appears to inhibit protein 2C, a highly conserved nonstructural protein that’s crucial to the assembly of RNA into virion particles.

In early November, a retrospective study examined fluoxetine’s use in 30 AFM patients, compared with 26 who did not receive it. The primary outcome was change in summative limb strength score. The study did little to clarify any benefit, however. The authors concluded that fluoxetine was preferentially given to patients with EDV-68 infections. They had more severe impairment at nadir, and at the last follow-up of about 1 year, they had worse outcomes.

“There is no clear human evidence for efficacy of fluoxetine in the treatment of AFM based on a single retrospective evaluation conducted in patients with AFM, and data from a mouse model also did not support efficacy,” the CDC said.
 

Antiviral medications

The CDC is quite clear on its recommendation that these drugs are not indicated in AFM, since it is not yet proven to be an infectious process.

“Any guidance regarding antiviral medications should be interpreted with great caution, given the unknowns about the pathogenesis of this illness at present ... Testing has been conducted at CDC for antiviral activity of compounds pleconaril, pocapavir, and vapendavir and none have significant activity against currently circulating strains of EV-D68 at clinically relevant concentrations.”
 

Interferon

There is some anecdotal evidence that interferon alpha-2b was beneficial in treating a polio-like syndrome associated with West Nile virus and Saint Louis encephalitis. “Although there are limited in vitro, animal, and anecdotal human data suggesting activity of some interferons against viral infections, sufficient data are lacking in the setting of AFM,” the agency said. “There is no indication that interferon should be used for the treatment of AFM, and there is concern about the potential for harm from the use of interferon given the immunomodulatory effects in the setting of possible ongoing viral replication.”

[email protected]

SOURCE: CDC Acute Flaccid Myelitis: Interim Considerations for Clinical Management

The updated guidance on managing acute flaccid myelitis is unlikely to relieve the frustrations of physicians struggling to treat the condition.

After reviewing the extant data on the baffling disorder, the Centers for Disease Control and Prevention found no evidence that corticosteroids, interferon, antivirals, or any other immunologic or biologic therapy is an effective treatment.

All of the treatments mentioned in the guidance have been used anecdotally, and often for cases proven to be associated with enterovirus-related cases. However, there are no well validated studies confirming benefit for any of these approaches, the agency said in its clinical management document.

Acute flaccid myelitis (AFM) has stricken 90 patients in the United States this year and another 252 cases are being investigated, according to new data from the CDC. The number of confirmed cases is triple that seen in 2017. Whether the disease is an infectious or autoimmune process, or something else entirely, remains unknown.

In response to the outbreak – the largest since 2014 – an expert panel of 4 CDC staff physicians reviewed the literature to find what, if any, treatments were effective; another 14 external experts provided input on the recommendations. At this point, nothing can be officially recommended, the agency said.

Corticosteroids

Corticosteroids should not be administered to most patients with AFM. In addition to “a theoretical concern” about the potential adverse effects of these drugs in acute infections, there is some hard evidence that they are associated with worse outcomes in enteroviral neuroinvasive diseases, particularly those caused by EV-71.

This observation, following a 2012 outbreak in Cambodia, led a World Health Organization commission to conclude that corticosteroids were contraindicated in the management of EV-71–associated neuroinvasive disease. This year, there has been an uptick in EV-A71-associated neurologic disease.

The CDC did hedge its advice on corticosteroids a bit in the setting of AFM, however. “There may be theoretical benefit for steroids in the setting of severe cord swelling or long tract signs suggesting white matter involvement, where steroids may salvage tissue that may be harmed due to an ongoing immune/inflammatory response. While AFM is clinically and radiographically defined by the predominance of gray matter damage in the spinal cord, some patients may have some white matter involvement. It is not clear if these different patterns are important relative to therapeutic considerations.”

Nevertheless, the agency does not recommend corticosteroid use for these patients. “The possible benefits of the use of corticosteroids to manage spinal cord edema or white matter involvement in AFM should be balanced with the possible harm due to immunosuppression in the setting of possible viral infection.”
 

IVIG

While IVIG holds some theoretical benefit for AFM, there are no high-level human data, the guidelines state. The treatment is generally safe and well tolerated, but the few reports of its use in AFM did not show clear benefit. These include two case series. One suggested an acute improvement of neurologic status, but no long-term resolution of deficits. The other indicated neither significant improvement nor deterioration.

However, current practice at Children’s Hospital of Philadelphia is to initiate IVIG therapy at AFM diagnosis in hopes of boosting humoral immunity.

Nevertheless, the CDC said, “For IVIG to modify disease in an active viral infectious process, early administration is likely required, and possibly prior to exposure,” and the treatment cannot be recommended.
 

Plasma exchange

Plasma exchange in combination with IVIG and corticosteroids was ineffective in a case series of four Argentinian children, although a single case published last year found that the combination was associated with significant improvement. However, there are not enough data to recommend this approach.

Fluoxetine

Fluoxetine’s antiviral potential turned up in a high-throughput screening project to identify novel compounds with antiviral efficacy against enteroviruses. In 2012, researchers from the University of California, Los Angeles, tested more than 1,000 compounds and found that the SSRI is a potent inhibitor of coxsackievirus. A later project at the National Institutes of Health replicated this finding, and determined that fluoxetine inhibited several enteroviruses, including the AFM suspect, EV-D68.

Fluoxetine concentrates more highly in the central nervous system than it does in plasma, but its antiviral properties have nothing to do with neurotransmitter activity. Rather, it appears to inhibit protein 2C, a highly conserved nonstructural protein that’s crucial to the assembly of RNA into virion particles.

In early November, a retrospective study examined fluoxetine’s use in 30 AFM patients, compared with 26 who did not receive it. The primary outcome was change in summative limb strength score. The study did little to clarify any benefit, however. The authors concluded that fluoxetine was preferentially given to patients with EDV-68 infections. They had more severe impairment at nadir, and at the last follow-up of about 1 year, they had worse outcomes.

“There is no clear human evidence for efficacy of fluoxetine in the treatment of AFM based on a single retrospective evaluation conducted in patients with AFM, and data from a mouse model also did not support efficacy,” the CDC said.
 

Antiviral medications

The CDC is quite clear on its recommendation that these drugs are not indicated in AFM, since it is not yet proven to be an infectious process.

“Any guidance regarding antiviral medications should be interpreted with great caution, given the unknowns about the pathogenesis of this illness at present ... Testing has been conducted at CDC for antiviral activity of compounds pleconaril, pocapavir, and vapendavir and none have significant activity against currently circulating strains of EV-D68 at clinically relevant concentrations.”
 

Interferon

There is some anecdotal evidence that interferon alpha-2b was beneficial in treating a polio-like syndrome associated with West Nile virus and Saint Louis encephalitis. “Although there are limited in vitro, animal, and anecdotal human data suggesting activity of some interferons against viral infections, sufficient data are lacking in the setting of AFM,” the agency said. “There is no indication that interferon should be used for the treatment of AFM, and there is concern about the potential for harm from the use of interferon given the immunomodulatory effects in the setting of possible ongoing viral replication.”

[email protected]

SOURCE: CDC Acute Flaccid Myelitis: Interim Considerations for Clinical Management

Clinical question: Is the combination of aspirin and clopidogrel effective in reducing stroke recurrence?

Background: The risk of recurrent stroke varies from 3% to 15% in the 3 months after a minor ischemic stroke (NIH Stroke Scale score of 3 or less) or high-risk transient ischemic attack (ABCD2 score of 4 or less). Dual-antiplatelet therapy with aspirin and clopidogrel reduces recurrent coronary syndrome; therefore, this strategy can prevent recurrent stroke.

Study design: Prospective, randomized, double-blind, multicenter, placebo-controlled trial.

Setting: 269 sites in 10 countries, mostly in the United States, from May 28, 2010, to Dec. 19, 2017.

Synopsis: The POINT (­Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) trial enrolled 4,881 patients older than 18 years of age randomized to a loading dose of 600 mg of clopidogrel followed by 75 mg per day or placebo, and aspirin 162 mg daily for 5 days followed by 81 mg daily. The primary outcome was the risk of major ischemic events, including ischemic stroke, myocardial infarction, or death from ischemic vascular causes. Major ischemic events were observed in 5.0% receiving dual therapy and in 6.5% of those receiving aspirin alone (hazard ratio, 0.75; 95% confidence interval, 0.59-0.95; P = .02) with most occurring within a week after the initial stroke. Major hemorrhage occurred in only 23 patients (0.9%), most of which were extracranial and nonfatal. One of the main limitations is the difficulty in objectively diagnosing TIAs, accounting for 43% of the patients in the study.

Bottom line: Dual-antiplatelet therapy with aspirin and clopidogrel is beneficial, mainly in the first week after a minor stroke or high-risk TIA with low risk of major bleeding.

Citation: Johnston SC et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med. 2018;379:215-25.

Dr. Vela-Duarte is assistant professor of neurology at the University of Colorado, Denver.

Clinical question: Is the combination of aspirin and clopidogrel effective in reducing stroke recurrence?

Background: The risk of recurrent stroke varies from 3% to 15% in the 3 months after a minor ischemic stroke (NIH Stroke Scale score of 3 or less) or high-risk transient ischemic attack (ABCD2 score of 4 or less). Dual-antiplatelet therapy with aspirin and clopidogrel reduces recurrent coronary syndrome; therefore, this strategy can prevent recurrent stroke.

Study design: Prospective, randomized, double-blind, multicenter, placebo-controlled trial.

Setting: 269 sites in 10 countries, mostly in the United States, from May 28, 2010, to Dec. 19, 2017.

Synopsis: The POINT (­Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) trial enrolled 4,881 patients older than 18 years of age randomized to a loading dose of 600 mg of clopidogrel followed by 75 mg per day or placebo, and aspirin 162 mg daily for 5 days followed by 81 mg daily. The primary outcome was the risk of major ischemic events, including ischemic stroke, myocardial infarction, or death from ischemic vascular causes. Major ischemic events were observed in 5.0% receiving dual therapy and in 6.5% of those receiving aspirin alone (hazard ratio, 0.75; 95% confidence interval, 0.59-0.95; P = .02) with most occurring within a week after the initial stroke. Major hemorrhage occurred in only 23 patients (0.9%), most of which were extracranial and nonfatal. One of the main limitations is the difficulty in objectively diagnosing TIAs, accounting for 43% of the patients in the study.

Bottom line: Dual-antiplatelet therapy with aspirin and clopidogrel is beneficial, mainly in the first week after a minor stroke or high-risk TIA with low risk of major bleeding.

Citation: Johnston SC et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med. 2018;379:215-25.

Dr. Vela-Duarte is assistant professor of neurology at the University of Colorado, Denver.

Clinical question: Is the combination of aspirin and clopidogrel effective in reducing stroke recurrence?

Background: The risk of recurrent stroke varies from 3% to 15% in the 3 months after a minor ischemic stroke (NIH Stroke Scale score of 3 or less) or high-risk transient ischemic attack (ABCD2 score of 4 or less). Dual-antiplatelet therapy with aspirin and clopidogrel reduces recurrent coronary syndrome; therefore, this strategy can prevent recurrent stroke.

Study design: Prospective, randomized, double-blind, multicenter, placebo-controlled trial.

Setting: 269 sites in 10 countries, mostly in the United States, from May 28, 2010, to Dec. 19, 2017.

Synopsis: The POINT (­Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) trial enrolled 4,881 patients older than 18 years of age randomized to a loading dose of 600 mg of clopidogrel followed by 75 mg per day or placebo, and aspirin 162 mg daily for 5 days followed by 81 mg daily. The primary outcome was the risk of major ischemic events, including ischemic stroke, myocardial infarction, or death from ischemic vascular causes. Major ischemic events were observed in 5.0% receiving dual therapy and in 6.5% of those receiving aspirin alone (hazard ratio, 0.75; 95% confidence interval, 0.59-0.95; P = .02) with most occurring within a week after the initial stroke. Major hemorrhage occurred in only 23 patients (0.9%), most of which were extracranial and nonfatal. One of the main limitations is the difficulty in objectively diagnosing TIAs, accounting for 43% of the patients in the study.

Bottom line: Dual-antiplatelet therapy with aspirin and clopidogrel is beneficial, mainly in the first week after a minor stroke or high-risk TIA with low risk of major bleeding.

Citation: Johnston SC et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med. 2018;379:215-25.

Dr. Vela-Duarte is assistant professor of neurology at the University of Colorado, Denver.

Clinical question: Does rivaroxaban prevent recurrent ischemic stroke in patients with embolic stroke from undetermined source?

Background: Embolic stroke of undetermined source (ESUS) represents approximately 20% of ischemic strokes. Rivaroxaban inhibits factor Xa and is shown to be effective for secondary stroke prevention in patients with nonvalvular atrial fibrillation. Strategies to prevent cryptogenic stroke caused by mechanisms other than cardioembolic sources are lacking.

Study design: International, double-blind, event-­driven, randomized, phase III trial.

Recurrent stroke was observed in 158 in the rivaroxaban group and 156 in the aspirin group, mostly ischemic. The trial was terminated early because of a higher incidence of intracranial hemorrhage and major bleeding among patients assigned to rivaroxaban at an annual rate of 1.8%, compared with 0.7% (hazard ratio, 2.72; 95% confidence interval, 1.68-4.39; P less than .001). Although the study utilized strict criteria to define ESUS, it is feasible that the lack of benefit may be due to heterogeneous arterial, cardiogenic, and paradoxical emboli with diverse composition and poor response to rivaroxaban.

Bottom line: Rivaroxaban does not confer protection from recurrent stroke in patients with embolic stroke of unknown origin and increases risk for intracranial hemorrhage and major bleeding.

Citation: Hart RG et al. Rivaroxaban for stroke prevention after embolic stroke of undetermined source. N Engl J Med. 2018;378(23):2191-201.

Dr. Vela-Duarte is assistant professor of neurology at the University of Colorado, Denver

Clinical question: Does rivaroxaban prevent recurrent ischemic stroke in patients with embolic stroke from undetermined source?

Background: Embolic stroke of undetermined source (ESUS) represents approximately 20% of ischemic strokes. Rivaroxaban inhibits factor Xa and is shown to be effective for secondary stroke prevention in patients with nonvalvular atrial fibrillation. Strategies to prevent cryptogenic stroke caused by mechanisms other than cardioembolic sources are lacking.

Study design: International, double-blind, event-­driven, randomized, phase III trial.

Recurrent stroke was observed in 158 in the rivaroxaban group and 156 in the aspirin group, mostly ischemic. The trial was terminated early because of a higher incidence of intracranial hemorrhage and major bleeding among patients assigned to rivaroxaban at an annual rate of 1.8%, compared with 0.7% (hazard ratio, 2.72; 95% confidence interval, 1.68-4.39; P less than .001). Although the study utilized strict criteria to define ESUS, it is feasible that the lack of benefit may be due to heterogeneous arterial, cardiogenic, and paradoxical emboli with diverse composition and poor response to rivaroxaban.

Bottom line: Rivaroxaban does not confer protection from recurrent stroke in patients with embolic stroke of unknown origin and increases risk for intracranial hemorrhage and major bleeding.

Citation: Hart RG et al. Rivaroxaban for stroke prevention after embolic stroke of undetermined source. N Engl J Med. 2018;378(23):2191-201.

Dr. Vela-Duarte is assistant professor of neurology at the University of Colorado, Denver

Clinical question: Does rivaroxaban prevent recurrent ischemic stroke in patients with embolic stroke from undetermined source?

Background: Embolic stroke of undetermined source (ESUS) represents approximately 20% of ischemic strokes. Rivaroxaban inhibits factor Xa and is shown to be effective for secondary stroke prevention in patients with nonvalvular atrial fibrillation. Strategies to prevent cryptogenic stroke caused by mechanisms other than cardioembolic sources are lacking.

Study design: International, double-blind, event-­driven, randomized, phase III trial.

Recurrent stroke was observed in 158 in the rivaroxaban group and 156 in the aspirin group, mostly ischemic. The trial was terminated early because of a higher incidence of intracranial hemorrhage and major bleeding among patients assigned to rivaroxaban at an annual rate of 1.8%, compared with 0.7% (hazard ratio, 2.72; 95% confidence interval, 1.68-4.39; P less than .001). Although the study utilized strict criteria to define ESUS, it is feasible that the lack of benefit may be due to heterogeneous arterial, cardiogenic, and paradoxical emboli with diverse composition and poor response to rivaroxaban.

Bottom line: Rivaroxaban does not confer protection from recurrent stroke in patients with embolic stroke of unknown origin and increases risk for intracranial hemorrhage and major bleeding.

Citation: Hart RG et al. Rivaroxaban for stroke prevention after embolic stroke of undetermined source. N Engl J Med. 2018;378(23):2191-201.

Dr. Vela-Duarte is assistant professor of neurology at the University of Colorado, Denver

Adults with Down syndrome and dementia had a risk of death five times higher than those without dementia, according to results of a recent prospective study.

More than 70% of the individuals with Down syndrome who died over the course of follow-up had a clinical diagnosis of dementia in this longitudinal study of community dwelling participants, many of whom had factors associated with dementia such as the apolipoprotein E (APOE) genotype.

The findings of this study support an “urgent need” for clinical trials of treatment that might delay or prevent dementia in individuals with Down syndrome, said the investigators, led by Rosalyn Hithersay, MSc, of the department of forensic and neurodevelopmental sciences in the Institute of Psychiatry, Psychology, and Neuroscience at King’s College London (United Kingdom).

“We hope that our findings can improve clinical care by identifying factors associated with increased risk for dementia and mortality risk in this population, suggesting the potentially beneficial effects of existing medication options and helping clinicians provide prognostic information for their patients,” the authors wrote in JAMA Neurology.

The risk of dementia in individuals with Down syndrome has grown to “exceptional” levels, alongside a dramatic increase in life expectancy in these patients, from just 10 years of age some 50 years ago, to nearly 64 years today, investigators said.

Although other research has confirmed that dementia is frequently recorded as a contributory factor in Down syndrome deaths in recent years, this latest study provides crude mortality rates and exploratory analyses of factors that may modify mortality and dementia risk, according to the researchers.

Their study included 211 individuals with Down syndrome who were aged at least 36 years at study entry and followed for a total of 503.92 person-years, the investigators reported.

A total of 27 individuals died during follow-up, with a median age at death of 57 years; of those individuals, 19 (70.37%) had a clinical diagnosis of dementia, according to the report.

The crude mortality rate for individuals with dementia was nearly 1,192 deaths per 10,000 person-years, compared with 232 deaths per 10,000 person-years for those with no dementia diagnosis, the investigators found.

Further analysis showed that factors independently associated with mortality in those with a dementia diagnosis included APOE genotype, dementia medication status, early-onset epilepsy, and presence of two or more comorbid conditions.

In a combined model, APOE genotype was significantly associated with mortality risk, they added.

Among the eight individuals with Down syndrome who died without a dementia diagnosis, one reportedly had early signs of cognitive decline, and two had late-onset epilepsy.

Late-onset epilepsy, identified in seven individuals (4.8%) with no dementia diagnosis in this study, was the only factor associated with mortality in individuals without dementia, conferring a 10-fold increase in risk of that outcome, according to the analysis.

“This raises the question of whether seizures can begin in the absence of other features of dementia in individuals with Down syndrome or whether these seven individuals had significant AD pathology and neurological symptoms but had yet to receive a formal dementia diagnosis,” the researchers wrote in a discussion of results.

The authors reported no conflict of interest disclosures related to the study. Their research was supported by UK National Institute for Health Research networks and participating National Health Services trusts, as well as a Wellcome Trust Strategic Award to the London Down Syndrome Consortium.

SOURCE: Hithersay R et al. JAMA Neurol. 2018 Nov 19. doi: 10.1001/jamaneurol.2018.3616

Adults with Down syndrome and dementia had a risk of death five times higher than those without dementia, according to results of a recent prospective study.

More than 70% of the individuals with Down syndrome who died over the course of follow-up had a clinical diagnosis of dementia in this longitudinal study of community dwelling participants, many of whom had factors associated with dementia such as the apolipoprotein E (APOE) genotype.

The findings of this study support an “urgent need” for clinical trials of treatment that might delay or prevent dementia in individuals with Down syndrome, said the investigators, led by Rosalyn Hithersay, MSc, of the department of forensic and neurodevelopmental sciences in the Institute of Psychiatry, Psychology, and Neuroscience at King’s College London (United Kingdom).

“We hope that our findings can improve clinical care by identifying factors associated with increased risk for dementia and mortality risk in this population, suggesting the potentially beneficial effects of existing medication options and helping clinicians provide prognostic information for their patients,” the authors wrote in JAMA Neurology.

The risk of dementia in individuals with Down syndrome has grown to “exceptional” levels, alongside a dramatic increase in life expectancy in these patients, from just 10 years of age some 50 years ago, to nearly 64 years today, investigators said.

Although other research has confirmed that dementia is frequently recorded as a contributory factor in Down syndrome deaths in recent years, this latest study provides crude mortality rates and exploratory analyses of factors that may modify mortality and dementia risk, according to the researchers.

Their study included 211 individuals with Down syndrome who were aged at least 36 years at study entry and followed for a total of 503.92 person-years, the investigators reported.

A total of 27 individuals died during follow-up, with a median age at death of 57 years; of those individuals, 19 (70.37%) had a clinical diagnosis of dementia, according to the report.

The crude mortality rate for individuals with dementia was nearly 1,192 deaths per 10,000 person-years, compared with 232 deaths per 10,000 person-years for those with no dementia diagnosis, the investigators found.

Further analysis showed that factors independently associated with mortality in those with a dementia diagnosis included APOE genotype, dementia medication status, early-onset epilepsy, and presence of two or more comorbid conditions.

In a combined model, APOE genotype was significantly associated with mortality risk, they added.

Among the eight individuals with Down syndrome who died without a dementia diagnosis, one reportedly had early signs of cognitive decline, and two had late-onset epilepsy.

Late-onset epilepsy, identified in seven individuals (4.8%) with no dementia diagnosis in this study, was the only factor associated with mortality in individuals without dementia, conferring a 10-fold increase in risk of that outcome, according to the analysis.

“This raises the question of whether seizures can begin in the absence of other features of dementia in individuals with Down syndrome or whether these seven individuals had significant AD pathology and neurological symptoms but had yet to receive a formal dementia diagnosis,” the researchers wrote in a discussion of results.

The authors reported no conflict of interest disclosures related to the study. Their research was supported by UK National Institute for Health Research networks and participating National Health Services trusts, as well as a Wellcome Trust Strategic Award to the London Down Syndrome Consortium.

SOURCE: Hithersay R et al. JAMA Neurol. 2018 Nov 19. doi: 10.1001/jamaneurol.2018.3616

Adults with Down syndrome and dementia had a risk of death five times higher than those without dementia, according to results of a recent prospective study.

More than 70% of the individuals with Down syndrome who died over the course of follow-up had a clinical diagnosis of dementia in this longitudinal study of community dwelling participants, many of whom had factors associated with dementia such as the apolipoprotein E (APOE) genotype.

The findings of this study support an “urgent need” for clinical trials of treatment that might delay or prevent dementia in individuals with Down syndrome, said the investigators, led by Rosalyn Hithersay, MSc, of the department of forensic and neurodevelopmental sciences in the Institute of Psychiatry, Psychology, and Neuroscience at King’s College London (United Kingdom).

“We hope that our findings can improve clinical care by identifying factors associated with increased risk for dementia and mortality risk in this population, suggesting the potentially beneficial effects of existing medication options and helping clinicians provide prognostic information for their patients,” the authors wrote in JAMA Neurology.

The risk of dementia in individuals with Down syndrome has grown to “exceptional” levels, alongside a dramatic increase in life expectancy in these patients, from just 10 years of age some 50 years ago, to nearly 64 years today, investigators said.

Although other research has confirmed that dementia is frequently recorded as a contributory factor in Down syndrome deaths in recent years, this latest study provides crude mortality rates and exploratory analyses of factors that may modify mortality and dementia risk, according to the researchers.

Their study included 211 individuals with Down syndrome who were aged at least 36 years at study entry and followed for a total of 503.92 person-years, the investigators reported.

A total of 27 individuals died during follow-up, with a median age at death of 57 years; of those individuals, 19 (70.37%) had a clinical diagnosis of dementia, according to the report.

The crude mortality rate for individuals with dementia was nearly 1,192 deaths per 10,000 person-years, compared with 232 deaths per 10,000 person-years for those with no dementia diagnosis, the investigators found.

Further analysis showed that factors independently associated with mortality in those with a dementia diagnosis included APOE genotype, dementia medication status, early-onset epilepsy, and presence of two or more comorbid conditions.

In a combined model, APOE genotype was significantly associated with mortality risk, they added.

Among the eight individuals with Down syndrome who died without a dementia diagnosis, one reportedly had early signs of cognitive decline, and two had late-onset epilepsy.

Late-onset epilepsy, identified in seven individuals (4.8%) with no dementia diagnosis in this study, was the only factor associated with mortality in individuals without dementia, conferring a 10-fold increase in risk of that outcome, according to the analysis.

“This raises the question of whether seizures can begin in the absence of other features of dementia in individuals with Down syndrome or whether these seven individuals had significant AD pathology and neurological symptoms but had yet to receive a formal dementia diagnosis,” the researchers wrote in a discussion of results.

The authors reported no conflict of interest disclosures related to the study. Their research was supported by UK National Institute for Health Research networks and participating National Health Services trusts, as well as a Wellcome Trust Strategic Award to the London Down Syndrome Consortium.

SOURCE: Hithersay R et al. JAMA Neurol. 2018 Nov 19. doi: 10.1001/jamaneurol.2018.3616