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AANEM Annual Meeting

Access daily, concise peer-reviewed reports from the AANEM Annual Meeting selected by the Neurology Today editors.

Monday, October 12, 2020

A novel technology for assessing eye movements may provide a less invasive alternative to repetitive nerve stimulation for diagnosing myasthenia gravis, a research team suggested in a presentation at the American Association of Neuromuscular & Electrodiagnostic Medicine 2020 Virtual Annual Meeting.

The scientists used videonystagmography (VNG)—video goggles with mini-cameras—to record voluntary eye movements in patients with myasthenia gravis and healthy controls. They found that patients with MG had a decrement in extraocular muscle activity compared with healthy controls.

The change was only a few seconds, but the scientists believe that the technology is accurate enough to help in the diagnosis of MG.        

"When we encounter patients with ptosis in the outpatient clinic, ocular MG is one of the diagnoses," said Goknur Kocak, MD, a neurology resident at the Istanbul University-Cerrahpasa Faculty of Medicine, who with colleagues at her institution collaborated with Andrea Corse, MD, associate professor of neurology and neurosurgery at Johns Hopkins University School of Medicine.

"However, sometimes we cannot find any evidence to support the diagnosis other than anamnesis. Ocular myasthenia gravis is characterized by ptosis and oculomotor paresis, but a technique to directly evaluate the extraocular movement activity hasn't been used. Developing a non-invasive tool led us to use VNG to record eye movement."

The research team recruited 13 patients with ocular MG and 21 with generalized MG as well as 23 healthy volunteers. All were asked to wear video goggles while the scientists recorded the velocity of their eye movements as they followed a moving target. They put visual targets in the horizontal planes so that the eye excursion of a person three feet away would be 20 degrees from the primary gaze (center gaze). All participants sat in an upright position three feet away from the visual display. The recording lasted for 60 seconds per eye, and the investigators administered the test to the two eyes separately.

Dr. Kocak told Neurology Today that she fixed the eyelids with medical tape to prevent ptosis that might occur during the test.                             

The MG patients showed significant eye muscle fatigue during the exercise, but the patients quickly recovered. By contrast, there was no decrement in fatigue in the healthy volunteers.

An increment response started within one to two seconds, which "is critically important for neuromuscular junction disorders," Dr. Kocak said, adding: "It was so similar to the so-called U-shaped decrement that is demonstrated in diagnostic repetitive nerve stimulation studies."

She said that VNG is used as a primary diagnostic tool for investigating the source of vestibular disorders such as vertigo and balance disturbances.               

"During the VNG assessment, the patient only wears goggles, which is more comfortable, and VNG is less operator-dependent compared with other tests, increasing test reliability. You can achieve a diagnosis in less time than other techniques as it takes one minute per eye to carry out the test." 

Dr. Kocak, whose abstract earned her the AANEM 2020 Golseth Young Investigator Award, said that this is the first study to utilize VNG to demonstrate extraocular movement activity indirectly. "Further research is necessary to confirm the diagnostic accuracy of VNG compared with currently used diagnostic tests," she said.

Robert L. Ruff, MD, PhD, FAAN, professor emeritus at Case Western Reserve University of Medicine, said that other studies have measured velocity of eye movements in MG patients and identified abnormalities unique to MG.

"What the researchers did that was new was to use easily available technology to record eye movements," said Dr. Ruff, who was not involved with the study. "They used current, inexpensive, and readily available technology to be able to detect abnormalities in eye movements associated with MG."

Dr. Ruff noted that the technology could be used without needing special labs or expensive equipment. The advance implements and applies available engineering technology to enable people to perform diagnostic noninvasive procedures, he said.

He added: "If I were a patient with MG, I would much prefer undergoing a video study of my eye movements rather than any form of EMG."

Drs. Kocak and Ruff had no relevant disclosures.

AANEM 2020 Abstract 1: Kocak G, Dolek B, Tutuncu M, et al. A novel diagnostic method for myasthenia gravis.

Monday, October 12, 2020

Ataluren, a drug that targets nonsense mutations, combined with standard of care seemed to delay low pulmonary function in patients with Duchenne muscular dystrophy, according to findings presented at the American Association of Neuromuscular and Electrodiagnostic Medicine 2020 Virtual Annual Meeting.

Ataluren is designed to promote read-through of a premature stop codon so that full-length dystrophin protein is produced. It has previously been found in natural history studies to delay loss of ambulation, and currently has orphan drug designation in the US.

 "These data suggest that ataluren plus standard of care treatment slow pulmonary disease progression in non-ambulatory patients with nonsense mutation Duchenne muscular dystrophy," Andres Nascimento Osorio, MD, a pediatric neurologist and researcher at Barcelona Children's Hospital, said in his presentation of the findings, sponsored by the drug's developer, PTC Therapeutics.

Researchers assessed pulmonary function in 22 patients receiving ataluren, who were non-ambulatory at their last assessment, in the Strategic Targeting of Registries and International Database of Excellence (STRIDE) registry. They compared those data to 22 matched controls, who were not receiving ataluren—only standard of care—in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study.

Non-ambulatory patients were matched for age at first symptoms, age at first corticosteroid use, and duration of corticosteroid use.

The median age at loss of ambulation was 12.4 years for the ataluren group and 11.1 for the non-ataluren group. Up to the time of lost ambulation, the mean ataluren exposure was 302 days.

In the ataluren group, patients reached a predicted forced vital capacity (FVC) of less than 60 percent at age 18.7-years-old, compared with age 15.6-years-old for the non-ataluren patients. The average ataluren exposure for those receiving ataluren, through to the point when FVC was less than 60 percent, was 661 days.

Dr. Osorio said researchers are continuing to assess ataluren's effects.

"We are waiting for results in the dystrophin quantification and follow-up (over the) long term in the real world from the STRIDE registry," he said.

Oscar Mayer, MD, director of the pulmonary function laboratory at the University of Pennsylvania, said the results would appear to be meaningful to patients, noting the sizable difference between the treatment group and the standard of care group in when they reached the lung-impairment outcome in the study.

"That, I think, for the most part is highly significant," he said. He added that "anything you can do" to delay the need for a ventilator would make a significant difference in the quality of life of patients with breathing challenges, he said. In this case, the age of the ataluren patients reaching a forced vital capacity of less than 60 percent surpasses age 18, meaning these patients reached adulthood before that level of impairment was recorded.

Whether pulmonary function is as important a measure to patients, in terms of quality of life, is another question, he said. If patients were asked whether they would prefer to keep walking or to preserve a percentage of lung function, they would likely tend to choose the ability to walk. Nonetheless, ataluren's effects on lung function could have an important impact on patients' lives, he said.

But he wondered, "Is the rate of decline the same, or is the rate of decline slower?" If the drug brings about a slower rate of lung-function decline, its impact in the end would be greater than if it simply delays the onset of lung-function decline, Dr. Mayer said.

Dr. Nascimento Osorio has received fees as a speaker and consultant for Biogen, PTC Therapeutics and Sarepta Therapeutics, and is an investigator on clinical trials sponsored by Biogen, F. Hoffmann-La Roche, Italfarmaco, Sarepta Therapeutics, and TAMDMD.

Link Up for Related Information

AANEM Abstract 9: Nascimento Osorio A, Tulinius M, Buccella F, et al. Pulmonary function in non-ambulatory patients with nonsense mutation Duchenne muscular dystrophy: STRIDE  Registry and CINRG Duchenne National History Study: A matched cohort analysis.

Nascimento Osorio A, Tulinius M, Buccella F, et al, on behalf of the STRIDE and CINRG DNHS Investigators. Pulmonary function in non-ambulatory patients with nmDMD from the STRIDE ataluren Registry and CINRG Duchenne National History Study.

Monday, October 12, 2020

Intravenous immunoglobulin (IVIG) is safe and effective as maintenance therapy for patients with chronic inflammatory demyelinating polyneuropathy (CIDP) when administered at 1.0 g/kg, according to a double-blind, randomized, parallel-group, phase 3 study presented at the American Association of Neuromuscular & Electrodiagnostic Medicine 2020 Virtual Annual Meeting.

The findings also highlighted a potential dose-dependent response to IVIG maintenance treatment.

The research team randomized 142 patients with probable or definite CIDP 1:2:1 to receive 0.5 g/kg, 1.0 g/kg, or 2.0 g/kg IVIG, respectively, as maintenance therapy every three weeks for up to 24 weeks.

 "In general, IVIG has been studied in the clinical setting, which involves an induction dose of 2.0 g/kg followed by 1.0 g/kg dosing every three weeks," said the lead study author David Cornblath, MD, professor of neurology at the Johns Hopkins University School of Medicine in Baltimore.

"What the [current] ProCID study did that was unique was to systematically study a higher maintenance dose of 2.0 g/kg every three weeks and a lower maintenance dose of 0.5 g/kg every three weeks. So that provided us with an opportunity to evaluate a dose-response."

The response rate in the 1.0 g/kg cohort—indicated by a decrease of at least one point in the adjusted Inflammatory Neuropathy Cause and Treatment Disability (INCAT) score from baseline to week 24—was met among 79.7 percent of responders in the intention-to-treat group, the researchers found.

Treatment response seemed to be dose-dependent, reflected by the increased proportions of responders as measured by the adjusted INCAT score as the doses rose: 64.7 percent, 79.7 percent, and 91.7 percent, respectively, in the 0.5, 1.0 and 2.0 g/kg dose cohorts, the authors noted.

Other outcome measures such as grip strength, muscle strength, social participation and activity limitations also suggested a dose-dependent response with a higher proportion of responders in the 2.0 g/kg cohort compared to the 1.0 and 5.0 g/kg maintenance therapy doses.

"We have confirmed, which theoretically is no surprise to anybody, that 1.0g/kg as a maintenance dose following the induction dose works for people previously diagnosed with CIDP who were taken off their current medication," Dr. Cornblath said.

Dr. Cornblath added that the current study and others have shown that even with the induction dose, about half the people will improve by a single point on the INCAT scale, which is easily measured and is considered to be an objective measure of improvement.

"For neurologists, it's very helpful to begin to make the INCAT exam part of the standard examination in patients with CIDP," he said.

Corticosteroids, IVIG, and plasma exchange are three approved therapies for CIDP, noted Dr. Cornblath. "In our study, the study patients were mainly on corticosteroids, and then restarted on IVIG," Dr. Cornblath noted.

"We don't yet know whether there's a statistical dose-response that might change therapy," Dr. Cornblath told Neurology Today. "We are in the process of analyzing that data."

"Based on the findings of this study, neurologists may consider escalating the dose of IVIG from 1 to 2 g/kg in patients that do not improve on the lower dose," said Norman Latov, MD, PhD, professor of neurology and director of the Peripheral Neuropathy Center at Weill Cornell Medical Center in NY. "Such patients are currently considered treatment failures, but they might respond to higher doses," said Dr. Latov, who was not involved in the study. 

"Current protocols recommend maintenance on 1 g/kg every three weeks, based on a pivotal single-dose trial," Dr. Latov noted, "but higher doses were not tested, and further analysis indicated ongoing demyelinating activity, even in patients that appeared to be clinically stable."

This investigation also raises the question of whether some patients with a limited response may be under-treated; in these instances, increasing the dose may provide greater improvement, Dr. Latov noted.

"Most studies measure the rate of response, but we also need to assess the magnitude of improvement, ongoing demyelinating activity, and rate of subsequent relapses. There is a need for research into more sensitive markers of disease activity to help guide treatment decisions," he added.

These findings support our current clinical practice of administering 1 g/kg IVIG as maintenance therapy in CIDP every three weeks, added Eva L. Feldman, MD, PhD, FAAN, the Russell N. DeJong Professor of Neurology and director of NeuroNetwork for Emerging Therapies at the University of Michigan. "The data confirm our clinical 'suspicion' and practice: that IVIG is dose-dependent and a lower dose is less effective, while a higher dose is more effective." 

This study provides us with the evidence we need to practice evidence-based medicine, Dr. Feldman told Neurology Today.

Dr. Cornblath disclosed relationships with  Mitsubishi Tanabe Pharma Corporation, Alnylam Pharmaceuticals, Inc, Hansa Medical AB, PledPharma, Momenta Pharmaceuticals, Inc.Consultant for CSL Behring, Sanofi-Aventis Recherche & Development,  INC, Seattle Genetics, Octapharma AG, Grifols, S.A., Cigna Corporation, Pharnext SA, Annexon Biosciences, UCB Pharma Inc., Boehringer Ingelheim Therapeutics, Biotest Pharmaceuticals, Inc., Argenx, CytomX Therapeutics, PassageBio Pharma, and financial interests with Genentech Corp, Merrimack Pharmaceuticals, Disarm Therapeutics, Inc, Levicept Ltd., Amgen Inc., and Syntimmune, Inc. (sold to Alexion Pharma). Dr. Latov disclosed relationships with Polyneuron Pharmaceuticals, Therapath LLC, Cornell University, and Takeda. Dr. Feldman did not report any disclosures.

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AANEM 2020 Abstract 3: Cornblath D, Van Doorn P, Hartung HP, et al. The ProCID Study: Efficacy and safety of 3 different dosages of IVIG (Panzyga) in patients with chronic inflammatory demyelinating polyneuropathy. 

Monday, October 12, 2020

Long-term exposure to patisiran was both safe and effective for patients with hereditary transthyretin-mediated (hATTR) amyloidosis, according to an interim analysis of an international open-label extension study presented at the American Association of Neuromuscular & Electrodiagnostic Medicine 2020 Virtual Annual Meeting.

Patisiran, an RNA interference therapeutic acts to significantly reduce the production of wild type and mutant TTR in the liver.

The current analysis showed patisiran halted the disease progression and improved symptoms and quality of life among patients with hATTR, a life-threatening, progressive condition. The safety profile remained consistent with prior phase 2 open-label extension and phase 3 APOLLO studies.

Elizabeth Mauricio, MD, assistant professor of neurology at the Mayo Clinic in Jacksonville, FL, and colleagues set out to characterize the two-year safety and efficacy analyses from the ongoing Global OLE study.

The study team assessed 137 patients who were randomized to patisiran, 49 to the placebo cohort, and 25 to phase 2 open-label extension studies. The researchers reported on the first 24-months of the extension period. Some patients have been receiving patisiran for more than five years. The evaluations include assessments of strength, sensation, reflexes, nerve conduction studies, and autonomic function. Patients also completed questionnaires assessing quality of life.

Dr. Mauricio said that there have been no new safety concerns during the global open-label extension. Patients treated with patisiran have experienced sustained and durable improvements in their peripheral neuropathy and quality of life, she said. 

The researchers observed improvements in the modified Neuropathy Impairment Score as indicated by a mean change of -5.9 in the phase 2 OLE cohort and a -4.9 mean change in patisiran/APOLLO compared with parent study baselines, after 24 months of additional therapy.

After an additional 24 months of therapy, patisiran/APOLLO patients continued to demonstrate improvements on the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy scale.

In the Global OLE, APOLLO/placebo patients experienced better quality of life and halting of disease progression compared to Global OLE baseline after 24-months therapy .

"It is amazing that we now have medications that can halt this deadly disease," Dr. Mauricio said. "Early recognition of hATTR amyloidosis has never been more important. The sooner we can offer treatment, the better outcomes will be for our patients."

"The open label extension by Dr. Mauricio and colleagues provides strong evidence that patisiran prevents worsening of hereditary amyloidosis polyneuropathy for a further period of two years beyond the controlled trial period of 15 months," said Peter J. Dyck, MD, FAAN, director of the Peripheral Nerve Research Laboratory at the Mayo Clinic in Rochester, MN. "The lack of worsening of amyloidosis polyneuropathy for an observation period of three plus years (the control trial and the open label extension period) is noteworthy because survival is generally estimated to have a mean period of from four  to seven years in cohorts of untreated patients."

"Patisiran, inhibits the formation of both mutant and wild transthyretin in this disorder," Dr. Dyck told Neurology Today At the Meetings. "Although the authors emphasize improvement of neuropathy in some of the patients, it is lack of worsening I emphasize because the drug is not known to have a regenerative effect.  It remains to be determined whether patisiran or inotersen—another oligonucleotide treatment also showing a favorable effect on transthyretin amyloidosis polyneuropathy—affect longevity of hereditary amyloidosis polyneuropathy patients," he added.

"It is an important study," added Dr. Dyck, who was part of consortium that published a study in 2013 showing that the anti-inflammatory drug diflunisal significantly improved the short-term course of transthyretin amyloidosis polyneuropathy.

Drs. Mauricio and Dyck reported no relevant disclosures.

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AANEM Abstract 6: Mauricio E, Gonzalez-Duarte A, Adams D, et al. Global open-label extension: 24-month data of patisiran in patients with HATTR amyloidosis.

Adams D, Gonzalez-Duarte A, Mauricio E, et al. Global open-label extension: 24-month data of patisiran in patients with hATTR amyloidosis.


Monday, October 12, 2020

Nusinersen (Spinraza), an antisense oligonucleotide, was well-tolerated in adults with spinal muscular atrophy (SMA) type 2/3, according to findings from an interim analysis presented at the American Association of Neuromuscular & Electrodiagnostic Medicine 2020 Virtual Annual Meeting.

Four of the 10 patients included in the analysis showed improvement and did not decline in muscle strength by at least three points on the Revised Hammersmith Scale, which is used to assess physical abilities in patients with SMA type 2 and 3.

All ten showed stability within two points in the Revised Upper Limb Module. Four patients also showed reduced disease burden, and none declined by at least 10 points measured on the SMA-Health Index.

Craig Zaidman, MD, a neurologist at Washington University School of Medicine and the trial's principal investigator, said that the drug, an injection administered into the cerebrospinal fluid, was well-tolerated. In addition, pulmonary function tests were also stable.

SMA is caused by homozygous deletions/mutations in the SMN1 gene. Humans have a backup copy, the SMN2 gene, but in the absence of the normal SMN1 gene, babies are dependent on the SMN2 gene, which is not identical to SMN1. It differs in one critical place: a single nucleotide substitution that alters splicing and usually excludes exon 7 in the mRNA. The result is that there isn't enough normal SMN protein produced.

The US Food and Drug Administration fast-tracked nusinersen in 2016 based on significant findings from clinical trials with infants and young children; they began to reach developmental milestones, including assisted sitting up, standing and walking that had not been seen before.

But there is a lot of variability in symptoms among patients, and not much is known about the drug's safety and efficacy for adults with the disorder.

None of the patients in the study have discontinued treatment, although one patient developed pancreatitis and the other pneumonia. There has been a total of 2,490 cumulative treatment days and 95 injections. The study will be complete after all patients are followed and assessed for up to 30 months.

Dr. Zaidman's group hopes to enroll a total of 73 patients with SMA 2/3and are continuing to recruit people age 18 to 70-years old who are ambulatory or non-ambulatory. Biogen, which is funding the study, is not providing the drug free to patients or paying for costs associated with standard clinical care. The trial consists of visits timed to coincide with nusinersen treatment—at baseline, the 15th day after the first infusion, day 60, day 240, and then every eight months throughout the study period.                            

Some of the tests include the 6-Minute Walk Test for ambulatory patients to see whether the treatment enhances mobility and ambulation in patients who can walk.  They also look for changes on the Revised Upper Limb Module. 

The treatment requires multiple and ongoing intrathecal doses, with an estimated cost of $750,000 for the first year of treatment, with subsequent annual treatments dropping to $375,000 per year per patient.

Commenting on the study, Kathryn J. Swoboda, MD, the Katherine B. Sims endowed chair in neurogenetics at the Center for Genomic Medicine at Massachusetts General Hospital in Boston, said: "This study expands upon observations from smaller case series, and is another milestone for our SMA community. Nusinersen was well tolerated, and most adult SMA patients who participated demonstrated stabilization or improved motor function. The power of hope for a stable future for these adults should not be underestimated." 

Dr. Zaidman received research support from Biogen. Dr. Swoboda had no relevant disclosures.

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AANEM 2020 Abstract 8: Zaidman C, Proud C, Chu ML, et al. Preliminary results of the Spinraza in Adults with Spinal Muscular Atrophy (SAS) Study.