TBD Meeting (3895-19)

AUSTIN, TEX. – Postural orthostatic tachycardia syndrome (POTS) is not a single disorder, but rather includes multiple overlapping subtypes, according to Steven Vernino, MD, PhD, a professor of neurology at the University of Texas, Dallas.

“It’s pretty well established that there’s a heterogeneous spectrum of disorders that can present this way,” Dr. Vernino told attendees at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine. “Investigation is somewhat difficult because we have limited tools.”

In his overview of POTS, Dr. Vernino defined it as a chronic condition with an “inappropriate orthostatic increase in heart rate” and symptoms that persist for at least 6 months. The heart rate increase should be at least 30 beats per minute – or 40 bpm in those aged 12-19 years – within 5-10 minutes of quiet standing or an upright tilt, but the patient lacks orthostatic hypotension. Often, however, other symptoms continue even if the tachycardia is not always present.

These symptoms range widely, including fainting, shortness of breath, headaches, fatigue, fibromyalgia, dizziness, brain fog, chest tightens, sensitivity to light or sound, tingling, heat intolerance, and gastrointestinal problems. Pain is particularly common.

Though peak incidence occurs around age 14 years, the average age of patients with POTS is 30 years. Women comprise 86% of those with POTS and 93% of patients are white, though this last figure may result from multiple reporting biases. A quarter of patients are disabled to a degree similar to heart failure or chronic obstructive pulmonary disease, he said.

Prevalence estimates are all over the map, ranging in academic literature from “up to 1% of teens” to “millions of Americans,” Dr. Vernino said. A commonly accepted range puts the estimate at 500,000 to 3 million Americans, the number used by Dysautonomia International.

Key to treatment of POTS is assessing possible underlying causes and individualizing treatment based on likely contributing etiologies, such as hypovolemia, deconditioning, and autoimmunity, Dr. Vernino said.

Classifications and etiologies of POTS

With its various possible etiologies, “it’s our job as physicians to try to understand, if you can, what the underlying the etiology is and try to address that,” Dr. Vernino said. About 11% of patients have a family history of POTS, and some research has suggested genes that may be involved, including the one that encodes the norepinephrine transporter and alpha tryptase.

Patients with neuropathic POTS have a mild or partial peripheral autonomic neuropathy “that causes a problem with the vasomotor function so that when patients stand, they don’t have an adequate increase in vascular tone, blood pools in the feet and they develop relative hypovolemia, and the autonomic nervous system compensates with tachycardia,” he said. The Quantitative Sudomotor Axon Reflex Test may show distal sweating, and a skin biopsy can be done to assess intraepidermal nerve fiber density.

Hyperadrenergic POTS involves “the presence of a dramatic, excessive rise of norepinephrine” and can involve tremor, nausea, sweating, and headache when patients are upright, Dr. Vernino said.

“These are patients who appear, clinically and in laboratory testing, to have inappropriate sympathetic response to standing up,” he said, and they may have orthostatic hypertension along with an increased heart rate.

Other subtypes of POTS can overlap neuropathic and hyperadrenergic types, which can also overlap one another. About 30% of patients appear hypovolemic, with a 13%-17% volume deficit, even with copious intake of water and sodium, he said. Despite this deficit, renin levels are typically normal in these patients, and aldosterone levels may be paradoxically low. Reduced red blood cell mass may be present, too (Circulation. 2005 Apr 5;111[13]:1574-82).

“What causes that and how that’s related to the other features is a bit unclear, and then, either as a primary or as a secondary component of POTS, there can be cardiac deconditioning,” Dr. Vernino said, requiring quantitative ECG. “It’s unclear whether that deconditioning happens as a consequence of disability from POTS or as a primary part of it.”

Questions still exist regarding whether autoimmunity is one of the underpinnings of POTS, Dr. Vernino said. It’s associated with elevated inflammatory biomarker levels and systemic autoimmune disorders such as Sjögren’s syndrome, as well as with antiphospholipid antibodies.

“More recently there’s been evidence on specific autoantibodies that have been found in POTS patients, and we’re still working through what all that means,” he said. “The real question is whether these antibodies are the cause of POTS” versus an effect or an epiphenomenon.

These antibodies include some G protein–coupled receptor antibodies, such as adrenergic receptor autoantibodies, angiotensin II type 1 receptor antibodies, and muscarinic acetylcholine receptor M3 antibodies. Others include thyroid autoantibodies, ganglionic acetylcholine receptor antibodies, and IgG antibodies, as well as several dozen cardiac membrane proteins.

Comorbidities and risk factors

Although 41% of patients with POTS report some health event preceding onset of symptoms, it’s unclear which, if any, of these events may be related to the condition. The most common antecedent event is infection, reported by 41% of patients in the “Big POTS Survey” conducted by Dysautonomia International, Dr. Vernino said. Other antecedent events reported included surgery (12%), pregnancy (9%), an accident (6%), vaccination (6%), puberty (5%), concussion (4%), and emotional trauma (3%). Research has found associations with migraine, concussion, and infection.

Comorbidities are also common, reported by 84% of patients in the same survey. Migraine, vitamin D deficiency, and joint hypermobility (Ehlers-Danlos syndrome type 3) top the list of comorbidities, and various autoimmune conditions, particularly Sjögren’s syndrome, may co-occur with POTS. Other comorbidities include small fiber neuropathy, mast-cell activation syndrome, chronic fatigue, gastrointestinal problems, vasovagal syncope, and sleeping difficulties.

Joint hypermobility appears to be a “pretty strong risk factor for development” of POTS, Dr. Vernino said, and patients may even be involved in activities where that’s helpful, such as gymnastics. “You can make this diagnosis clinically – there isn’t a genetic test for joint hypermobility syndrome – and you usually don’t have the other features of Marfan syndrome,” he told attendees.

Other risk factors include low body mass, mitral valve prolapse, migraine, anxiety, irritable bowel syndrome, prolonged bed rest after an illness, and mast-cell activation syndrome.

Prognosis and treatment

POTS is very common but often still unrecognized, Dr. Vernino said, “because the symptoms are somewhat diverse and broad and vague.” Even providers who recognize POTS can become preoccupied with “the heart rate increase being the whole picture, but there are many other symptoms, and that leads to a significant impact on the quality of life of these patients.”

The course of POTS varies across patients. In about half of patients, symptoms persist but the severity improves, and one in five patients fully resolve. Severity only tends to worsen over time in about 3.5% of patients, and severity remains constant in 8.7% (J Pediatr. 2016 Jun;173:149-53. doi: 10.1016/j.jpeds.2016.02.035).

“It would probably be simpler if POTS was a single entity that had a single etiology that we could target,” Dr. Vernino said. But its heterogeneity means “we have to investigate patients individually and understand their particular situation, individualize their treatment, whether it be nonpharmacological or pharmacological, to their particular potential etiologies.”

Dr. Vernino has received research support from Genentech, Grifols, Athena/Quest, Biohaven Pharmaceutical, Dysautonomia International, and the Rex Griswold Foundation.

AUSTIN, TEX. – Postural orthostatic tachycardia syndrome (POTS) is not a single disorder, but rather includes multiple overlapping subtypes, according to Steven Vernino, MD, PhD, a professor of neurology at the University of Texas, Dallas.

“It’s pretty well established that there’s a heterogeneous spectrum of disorders that can present this way,” Dr. Vernino told attendees at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine. “Investigation is somewhat difficult because we have limited tools.”

In his overview of POTS, Dr. Vernino defined it as a chronic condition with an “inappropriate orthostatic increase in heart rate” and symptoms that persist for at least 6 months. The heart rate increase should be at least 30 beats per minute – or 40 bpm in those aged 12-19 years – within 5-10 minutes of quiet standing or an upright tilt, but the patient lacks orthostatic hypotension. Often, however, other symptoms continue even if the tachycardia is not always present.

These symptoms range widely, including fainting, shortness of breath, headaches, fatigue, fibromyalgia, dizziness, brain fog, chest tightens, sensitivity to light or sound, tingling, heat intolerance, and gastrointestinal problems. Pain is particularly common.

Though peak incidence occurs around age 14 years, the average age of patients with POTS is 30 years. Women comprise 86% of those with POTS and 93% of patients are white, though this last figure may result from multiple reporting biases. A quarter of patients are disabled to a degree similar to heart failure or chronic obstructive pulmonary disease, he said.

Prevalence estimates are all over the map, ranging in academic literature from “up to 1% of teens” to “millions of Americans,” Dr. Vernino said. A commonly accepted range puts the estimate at 500,000 to 3 million Americans, the number used by Dysautonomia International.

Key to treatment of POTS is assessing possible underlying causes and individualizing treatment based on likely contributing etiologies, such as hypovolemia, deconditioning, and autoimmunity, Dr. Vernino said.

Classifications and etiologies of POTS

With its various possible etiologies, “it’s our job as physicians to try to understand, if you can, what the underlying the etiology is and try to address that,” Dr. Vernino said. About 11% of patients have a family history of POTS, and some research has suggested genes that may be involved, including the one that encodes the norepinephrine transporter and alpha tryptase.

Patients with neuropathic POTS have a mild or partial peripheral autonomic neuropathy “that causes a problem with the vasomotor function so that when patients stand, they don’t have an adequate increase in vascular tone, blood pools in the feet and they develop relative hypovolemia, and the autonomic nervous system compensates with tachycardia,” he said. The Quantitative Sudomotor Axon Reflex Test may show distal sweating, and a skin biopsy can be done to assess intraepidermal nerve fiber density.

Hyperadrenergic POTS involves “the presence of a dramatic, excessive rise of norepinephrine” and can involve tremor, nausea, sweating, and headache when patients are upright, Dr. Vernino said.

“These are patients who appear, clinically and in laboratory testing, to have inappropriate sympathetic response to standing up,” he said, and they may have orthostatic hypertension along with an increased heart rate.

Other subtypes of POTS can overlap neuropathic and hyperadrenergic types, which can also overlap one another. About 30% of patients appear hypovolemic, with a 13%-17% volume deficit, even with copious intake of water and sodium, he said. Despite this deficit, renin levels are typically normal in these patients, and aldosterone levels may be paradoxically low. Reduced red blood cell mass may be present, too (Circulation. 2005 Apr 5;111[13]:1574-82).

“What causes that and how that’s related to the other features is a bit unclear, and then, either as a primary or as a secondary component of POTS, there can be cardiac deconditioning,” Dr. Vernino said, requiring quantitative ECG. “It’s unclear whether that deconditioning happens as a consequence of disability from POTS or as a primary part of it.”

Questions still exist regarding whether autoimmunity is one of the underpinnings of POTS, Dr. Vernino said. It’s associated with elevated inflammatory biomarker levels and systemic autoimmune disorders such as Sjögren’s syndrome, as well as with antiphospholipid antibodies.

“More recently there’s been evidence on specific autoantibodies that have been found in POTS patients, and we’re still working through what all that means,” he said. “The real question is whether these antibodies are the cause of POTS” versus an effect or an epiphenomenon.

These antibodies include some G protein–coupled receptor antibodies, such as adrenergic receptor autoantibodies, angiotensin II type 1 receptor antibodies, and muscarinic acetylcholine receptor M3 antibodies. Others include thyroid autoantibodies, ganglionic acetylcholine receptor antibodies, and IgG antibodies, as well as several dozen cardiac membrane proteins.

Comorbidities and risk factors

Although 41% of patients with POTS report some health event preceding onset of symptoms, it’s unclear which, if any, of these events may be related to the condition. The most common antecedent event is infection, reported by 41% of patients in the “Big POTS Survey” conducted by Dysautonomia International, Dr. Vernino said. Other antecedent events reported included surgery (12%), pregnancy (9%), an accident (6%), vaccination (6%), puberty (5%), concussion (4%), and emotional trauma (3%). Research has found associations with migraine, concussion, and infection.

Comorbidities are also common, reported by 84% of patients in the same survey. Migraine, vitamin D deficiency, and joint hypermobility (Ehlers-Danlos syndrome type 3) top the list of comorbidities, and various autoimmune conditions, particularly Sjögren’s syndrome, may co-occur with POTS. Other comorbidities include small fiber neuropathy, mast-cell activation syndrome, chronic fatigue, gastrointestinal problems, vasovagal syncope, and sleeping difficulties.

Joint hypermobility appears to be a “pretty strong risk factor for development” of POTS, Dr. Vernino said, and patients may even be involved in activities where that’s helpful, such as gymnastics. “You can make this diagnosis clinically – there isn’t a genetic test for joint hypermobility syndrome – and you usually don’t have the other features of Marfan syndrome,” he told attendees.

Other risk factors include low body mass, mitral valve prolapse, migraine, anxiety, irritable bowel syndrome, prolonged bed rest after an illness, and mast-cell activation syndrome.

Prognosis and treatment

POTS is very common but often still unrecognized, Dr. Vernino said, “because the symptoms are somewhat diverse and broad and vague.” Even providers who recognize POTS can become preoccupied with “the heart rate increase being the whole picture, but there are many other symptoms, and that leads to a significant impact on the quality of life of these patients.”

The course of POTS varies across patients. In about half of patients, symptoms persist but the severity improves, and one in five patients fully resolve. Severity only tends to worsen over time in about 3.5% of patients, and severity remains constant in 8.7% (J Pediatr. 2016 Jun;173:149-53. doi: 10.1016/j.jpeds.2016.02.035).

“It would probably be simpler if POTS was a single entity that had a single etiology that we could target,” Dr. Vernino said. But its heterogeneity means “we have to investigate patients individually and understand their particular situation, individualize their treatment, whether it be nonpharmacological or pharmacological, to their particular potential etiologies.”

Dr. Vernino has received research support from Genentech, Grifols, Athena/Quest, Biohaven Pharmaceutical, Dysautonomia International, and the Rex Griswold Foundation.

AUSTIN, TEX. – Postural orthostatic tachycardia syndrome (POTS) is not a single disorder, but rather includes multiple overlapping subtypes, according to Steven Vernino, MD, PhD, a professor of neurology at the University of Texas, Dallas.

“It’s pretty well established that there’s a heterogeneous spectrum of disorders that can present this way,” Dr. Vernino told attendees at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine. “Investigation is somewhat difficult because we have limited tools.”

In his overview of POTS, Dr. Vernino defined it as a chronic condition with an “inappropriate orthostatic increase in heart rate” and symptoms that persist for at least 6 months. The heart rate increase should be at least 30 beats per minute – or 40 bpm in those aged 12-19 years – within 5-10 minutes of quiet standing or an upright tilt, but the patient lacks orthostatic hypotension. Often, however, other symptoms continue even if the tachycardia is not always present.

These symptoms range widely, including fainting, shortness of breath, headaches, fatigue, fibromyalgia, dizziness, brain fog, chest tightens, sensitivity to light or sound, tingling, heat intolerance, and gastrointestinal problems. Pain is particularly common.

Though peak incidence occurs around age 14 years, the average age of patients with POTS is 30 years. Women comprise 86% of those with POTS and 93% of patients are white, though this last figure may result from multiple reporting biases. A quarter of patients are disabled to a degree similar to heart failure or chronic obstructive pulmonary disease, he said.

Prevalence estimates are all over the map, ranging in academic literature from “up to 1% of teens” to “millions of Americans,” Dr. Vernino said. A commonly accepted range puts the estimate at 500,000 to 3 million Americans, the number used by Dysautonomia International.

Key to treatment of POTS is assessing possible underlying causes and individualizing treatment based on likely contributing etiologies, such as hypovolemia, deconditioning, and autoimmunity, Dr. Vernino said.

Classifications and etiologies of POTS

With its various possible etiologies, “it’s our job as physicians to try to understand, if you can, what the underlying the etiology is and try to address that,” Dr. Vernino said. About 11% of patients have a family history of POTS, and some research has suggested genes that may be involved, including the one that encodes the norepinephrine transporter and alpha tryptase.

Patients with neuropathic POTS have a mild or partial peripheral autonomic neuropathy “that causes a problem with the vasomotor function so that when patients stand, they don’t have an adequate increase in vascular tone, blood pools in the feet and they develop relative hypovolemia, and the autonomic nervous system compensates with tachycardia,” he said. The Quantitative Sudomotor Axon Reflex Test may show distal sweating, and a skin biopsy can be done to assess intraepidermal nerve fiber density.

Hyperadrenergic POTS involves “the presence of a dramatic, excessive rise of norepinephrine” and can involve tremor, nausea, sweating, and headache when patients are upright, Dr. Vernino said.

“These are patients who appear, clinically and in laboratory testing, to have inappropriate sympathetic response to standing up,” he said, and they may have orthostatic hypertension along with an increased heart rate.

Other subtypes of POTS can overlap neuropathic and hyperadrenergic types, which can also overlap one another. About 30% of patients appear hypovolemic, with a 13%-17% volume deficit, even with copious intake of water and sodium, he said. Despite this deficit, renin levels are typically normal in these patients, and aldosterone levels may be paradoxically low. Reduced red blood cell mass may be present, too (Circulation. 2005 Apr 5;111[13]:1574-82).

“What causes that and how that’s related to the other features is a bit unclear, and then, either as a primary or as a secondary component of POTS, there can be cardiac deconditioning,” Dr. Vernino said, requiring quantitative ECG. “It’s unclear whether that deconditioning happens as a consequence of disability from POTS or as a primary part of it.”

Questions still exist regarding whether autoimmunity is one of the underpinnings of POTS, Dr. Vernino said. It’s associated with elevated inflammatory biomarker levels and systemic autoimmune disorders such as Sjögren’s syndrome, as well as with antiphospholipid antibodies.

“More recently there’s been evidence on specific autoantibodies that have been found in POTS patients, and we’re still working through what all that means,” he said. “The real question is whether these antibodies are the cause of POTS” versus an effect or an epiphenomenon.

These antibodies include some G protein–coupled receptor antibodies, such as adrenergic receptor autoantibodies, angiotensin II type 1 receptor antibodies, and muscarinic acetylcholine receptor M3 antibodies. Others include thyroid autoantibodies, ganglionic acetylcholine receptor antibodies, and IgG antibodies, as well as several dozen cardiac membrane proteins.

Comorbidities and risk factors

Although 41% of patients with POTS report some health event preceding onset of symptoms, it’s unclear which, if any, of these events may be related to the condition. The most common antecedent event is infection, reported by 41% of patients in the “Big POTS Survey” conducted by Dysautonomia International, Dr. Vernino said. Other antecedent events reported included surgery (12%), pregnancy (9%), an accident (6%), vaccination (6%), puberty (5%), concussion (4%), and emotional trauma (3%). Research has found associations with migraine, concussion, and infection.

Comorbidities are also common, reported by 84% of patients in the same survey. Migraine, vitamin D deficiency, and joint hypermobility (Ehlers-Danlos syndrome type 3) top the list of comorbidities, and various autoimmune conditions, particularly Sjögren’s syndrome, may co-occur with POTS. Other comorbidities include small fiber neuropathy, mast-cell activation syndrome, chronic fatigue, gastrointestinal problems, vasovagal syncope, and sleeping difficulties.

Joint hypermobility appears to be a “pretty strong risk factor for development” of POTS, Dr. Vernino said, and patients may even be involved in activities where that’s helpful, such as gymnastics. “You can make this diagnosis clinically – there isn’t a genetic test for joint hypermobility syndrome – and you usually don’t have the other features of Marfan syndrome,” he told attendees.

Other risk factors include low body mass, mitral valve prolapse, migraine, anxiety, irritable bowel syndrome, prolonged bed rest after an illness, and mast-cell activation syndrome.

Prognosis and treatment

POTS is very common but often still unrecognized, Dr. Vernino said, “because the symptoms are somewhat diverse and broad and vague.” Even providers who recognize POTS can become preoccupied with “the heart rate increase being the whole picture, but there are many other symptoms, and that leads to a significant impact on the quality of life of these patients.”

The course of POTS varies across patients. In about half of patients, symptoms persist but the severity improves, and one in five patients fully resolve. Severity only tends to worsen over time in about 3.5% of patients, and severity remains constant in 8.7% (J Pediatr. 2016 Jun;173:149-53. doi: 10.1016/j.jpeds.2016.02.035).

“It would probably be simpler if POTS was a single entity that had a single etiology that we could target,” Dr. Vernino said. But its heterogeneity means “we have to investigate patients individually and understand their particular situation, individualize their treatment, whether it be nonpharmacological or pharmacological, to their particular potential etiologies.”

Dr. Vernino has received research support from Genentech, Grifols, Athena/Quest, Biohaven Pharmaceutical, Dysautonomia International, and the Rex Griswold Foundation.

AUSTIN, TEX. – Neuromuscular complications from immunotherapy for cancer are rare, but they occur often enough that it is helpful to know which ones can result from different immunotherapies and how to distinguish them from non–adverse event conditions, according to Christopher Trevino, MD, a neuro-oncologist at Tulane University in New Orleans.

At the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine, Dr. Trevino reviewed immunotherapy types, particularly immune checkpoint inhibitors, and the most common neuromuscular complications – primarily neuropathy, myasthenia gravis (MG), myositis, and encephalitis or meningitis.

“Timing of onset is a critical component to assist in identifying immune checkpoint inhibitor–associated versus non–immune checkpoint inhibitor–associated neuromuscular disease,” Dr. Trevino told attendees. Prompt recognition can be particularly urgent for MG because crisis and death rates are higher when induced by immunotherapy and require quick treatment. “Understanding the mechanisms of action sets a foundation for treatment approach,” he added.

Any part of the nervous system can be affected by immunotherapy toxicity, he said, and syndromes often overlap, with the peripheral nervous system typically more often affected than the central nervous system. Neurologic immune-related adverse events typically occur within four cycles of therapy – about 12 weeks after therapy initiation – but should always involve a work-up to exclude effects from the cancer itself, other neuromuscular diagnoses unrelated to therapy, and other toxicities from chemotherapy.

Recommended first-line treatment is halting immunotherapy with or without corticosteroids, after which most patients improve, often with “rapid, complete resolution of symptoms,” Dr. Trevino said. Restarting immunotherapy treatment is possible in some patients, though.
 

CAR T-cell and dendritic cell vaccine therapies

Four main types of immunotherapy exist: viral therapy, vaccine therapy, immune checkpoint inhibitors, and adoptive cell transfer, such as chimeric antigen receptor (CAR) T-cell therapy. Dr. Trevino focused on checkpoint inhibitors and adoptive cell transfer.

CAR T-cell therapy is a multistep treatment process that involves first removing blood from the patient to obtain their T cells. These are used to create and grow CAR T cells in the lab so that they can be infused back into the patient. The cells then bind to cancer cells and destroy them. Examples of approved CAR T-cell therapy include Yescarta (axicabtagene ciloleucel) for some types of non-Hodgkin lymphoma and Kymriah (tisagenlecleucel) for acute lymphoblastic leukemia (ALL).

Dendritic cell vaccines are similar to CAR T-cell therapy in that they also use the patient’s own immune cells to create cancer-killing cells that the patient then receives back. The only currently approved dendritic cell vaccine is Provenge (sipuleucel-T) for advanced prostate cancer.

The main toxicity to watch for from CAR T-cell therapy and dendritic cell vaccines is cytokine release syndrome (CRS). It can begin anywhere from 1-14 days after the infusion and involves T-cell expansion in the body that leads to a cytokine storm. Symptoms are wide ranging, including fatigue, fever, loss of appetite, tachycardia, hypotension, pain, rash, diarrhea, headache, confusion, seizures, muscle and joint pain, tachypnea, hypoxia and hallucinations, among others.

Specific central neurotoxicities that can result from CAR T-cell therapy include encephalopathy, cerebral edema, seizures and status epilepticus, cerebral vasospasm, and aphasia.
 

Immune checkpoint inhibitor toxicities

Immune checkpoint inhibitors are drugs that interrupt a cancer’s ability to hijack the immune system; they block the proteins that hold back T-cells from attacking the cancer, thereby releasing the immune system to go after the malignant cells.

The two most common types of immune checkpoint inhibitors are those targeting the programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathways. The three currently approved PD-1 inhibitors are pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo), which can treat nearly a dozen malignancies affecting different organs. Atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi) are the three currently approved PD-L1 inhibitors, indicated for urothelial carcinoma and a handful of other cancers, such as small-cell and non–small cell lung cancer and triple negative breast cancer.

The only other type of approved checkpoint inhibitor is ipilimumab (Yervoy), which targets the CTLA-4 protein. A number of other checkpoint inhibitors are in trials, however, such as ones targeting pathways involving OX40, ICOS, TIM3, and LAG-3 (J Hematol Oncol. 2018. doi: 10.1186/s13045-018-0582-8).

Immune-related adverse events are less common with PD-1 or PD-L1 inhibitors – a rate of 5%-10% – compared with adverse events from CTLA-4 inhibitors, which occur in about 15% of patients. Neurologic complications occur even more rarely – about 1%-4% of all immune checkpoint inhibitor therapies – and primarily include MG, Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and inflammatory myositis (Muscle Nerve. 2018;58[1]:10-22).

Treatment with multiple checkpoint inhibitors increases the likelihood of severe adverse events, with rates of up to 30%-50% of patients with dual treatment.
 

Distinguishing features of neuromuscular immunotherapy-related adverse events

MG is the most common neuromuscular immune-related adverse event from immune checkpoint inhibitors and tends to occur 3-12 weeks after beginning treatment, frequently comorbid with inflammatory myopathy or cardiomyopathy, Dr. Trevino said. About two-thirds of cases are de novo, while the remaining one-third involve preexisting MG; no reports of Lambert-Eaton myasthenic syndrome have been linked to checkpoint inhibitors.

Several characteristics distinguish checkpoint inhibitor–associated MG from standard MG. Standard MG can be ocular with or without bulbar or appendicular weakness, whereas immunotherapy-related MG is rarely only ocular (about 18% of cases). Immunotherapy-related MG involves an MG crisis at diagnosis in up to 50% of cases and has high mortality, both of which are rarer with standard MG.

While standard MG can be seronegative or involve AChR, MuSK, or LRP4 antibodies, about two-thirds of immunotherapy-related MG cases are positive for AChR antibodies. LRP4 antibodies are rare with MG from checkpoint inhibitors, and no MuSK antibodies have been reported in these cases. Creatine kinase (CK) or troponin I (TnI) elevation occurs in about 87% of patients with checkpoint inhibitor-induced MG, but standard MG doesn’t typically involve increased CK levels.

Inflammatory myositis (IM), the second most common neuromuscular adverse event from immunotherapy, tends to occur 2-15 weeks after immune checkpoint inhibitor therapy and can involve polymyositis, necrotizing autoimmune myopathy, dermatomyositis, granulomatous myositis, or other nonspecific myositis and myopathies.

Though proximal weakness occurs with IM both associated with immunotherapy and not, ocular symptoms are unique to cases associated with therapy and occur in about half of them. Myalgia, dyspnea, and dysphagia can all occur with checkpoint inhibitor–associated IM but don’t generally occur with standard IM. Immunotherapy-related IM is usually seronegative for myositis antibodies and doesn’t generally cause abnormalities in electromyography, compared with increased exertional activity and early recruitment of myopathic motor units in electromyography with standard IM.

GBS and CIDP are the third most common cause of neuromuscular complications from checkpoint inhibitors. The main distinguishing feature of these conditions from those not related to immunotherapy is that they occur anywhere from 4 to 68 weeks after therapy begins. Presentation is otherwise similar whether related to checkpoint inhibitors or not.

Aside from GBS and CIDP, other neuropathies that can result from immunotherapy complications include acute cranial neuropathies, axonal or demyelinating neuropathies, motor polyradiculopathy, vasculitic neuropathy, and plexopathy.

Neuromuscular complications other than those described above can also occur from checkpoint inhibitor therapy, such as enteric neuropathy, polyradiculitis, and meningo-radiculo-neuritis, but these are much rarer.

Four organizations have developed consensus guidelines for immune checkpoint inhibitor toxicities: the European Society for Medical Oncology (ESMO, 2017), Society for Immunotherapy of Cancer (SITC, 2017), American Society of Clinical Oncology (ASCO, 2018), and National Comprehensive Cancer Network (NCCN, 2019).

Dr Trevino had no disclosures.

AUSTIN, TEX. – Neuromuscular complications from immunotherapy for cancer are rare, but they occur often enough that it is helpful to know which ones can result from different immunotherapies and how to distinguish them from non–adverse event conditions, according to Christopher Trevino, MD, a neuro-oncologist at Tulane University in New Orleans.

At the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine, Dr. Trevino reviewed immunotherapy types, particularly immune checkpoint inhibitors, and the most common neuromuscular complications – primarily neuropathy, myasthenia gravis (MG), myositis, and encephalitis or meningitis.

“Timing of onset is a critical component to assist in identifying immune checkpoint inhibitor–associated versus non–immune checkpoint inhibitor–associated neuromuscular disease,” Dr. Trevino told attendees. Prompt recognition can be particularly urgent for MG because crisis and death rates are higher when induced by immunotherapy and require quick treatment. “Understanding the mechanisms of action sets a foundation for treatment approach,” he added.

Any part of the nervous system can be affected by immunotherapy toxicity, he said, and syndromes often overlap, with the peripheral nervous system typically more often affected than the central nervous system. Neurologic immune-related adverse events typically occur within four cycles of therapy – about 12 weeks after therapy initiation – but should always involve a work-up to exclude effects from the cancer itself, other neuromuscular diagnoses unrelated to therapy, and other toxicities from chemotherapy.

Recommended first-line treatment is halting immunotherapy with or without corticosteroids, after which most patients improve, often with “rapid, complete resolution of symptoms,” Dr. Trevino said. Restarting immunotherapy treatment is possible in some patients, though.
 

CAR T-cell and dendritic cell vaccine therapies

Four main types of immunotherapy exist: viral therapy, vaccine therapy, immune checkpoint inhibitors, and adoptive cell transfer, such as chimeric antigen receptor (CAR) T-cell therapy. Dr. Trevino focused on checkpoint inhibitors and adoptive cell transfer.

CAR T-cell therapy is a multistep treatment process that involves first removing blood from the patient to obtain their T cells. These are used to create and grow CAR T cells in the lab so that they can be infused back into the patient. The cells then bind to cancer cells and destroy them. Examples of approved CAR T-cell therapy include Yescarta (axicabtagene ciloleucel) for some types of non-Hodgkin lymphoma and Kymriah (tisagenlecleucel) for acute lymphoblastic leukemia (ALL).

Dendritic cell vaccines are similar to CAR T-cell therapy in that they also use the patient’s own immune cells to create cancer-killing cells that the patient then receives back. The only currently approved dendritic cell vaccine is Provenge (sipuleucel-T) for advanced prostate cancer.

The main toxicity to watch for from CAR T-cell therapy and dendritic cell vaccines is cytokine release syndrome (CRS). It can begin anywhere from 1-14 days after the infusion and involves T-cell expansion in the body that leads to a cytokine storm. Symptoms are wide ranging, including fatigue, fever, loss of appetite, tachycardia, hypotension, pain, rash, diarrhea, headache, confusion, seizures, muscle and joint pain, tachypnea, hypoxia and hallucinations, among others.

Specific central neurotoxicities that can result from CAR T-cell therapy include encephalopathy, cerebral edema, seizures and status epilepticus, cerebral vasospasm, and aphasia.
 

Immune checkpoint inhibitor toxicities

Immune checkpoint inhibitors are drugs that interrupt a cancer’s ability to hijack the immune system; they block the proteins that hold back T-cells from attacking the cancer, thereby releasing the immune system to go after the malignant cells.

The two most common types of immune checkpoint inhibitors are those targeting the programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathways. The three currently approved PD-1 inhibitors are pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo), which can treat nearly a dozen malignancies affecting different organs. Atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi) are the three currently approved PD-L1 inhibitors, indicated for urothelial carcinoma and a handful of other cancers, such as small-cell and non–small cell lung cancer and triple negative breast cancer.

The only other type of approved checkpoint inhibitor is ipilimumab (Yervoy), which targets the CTLA-4 protein. A number of other checkpoint inhibitors are in trials, however, such as ones targeting pathways involving OX40, ICOS, TIM3, and LAG-3 (J Hematol Oncol. 2018. doi: 10.1186/s13045-018-0582-8).

Immune-related adverse events are less common with PD-1 or PD-L1 inhibitors – a rate of 5%-10% – compared with adverse events from CTLA-4 inhibitors, which occur in about 15% of patients. Neurologic complications occur even more rarely – about 1%-4% of all immune checkpoint inhibitor therapies – and primarily include MG, Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and inflammatory myositis (Muscle Nerve. 2018;58[1]:10-22).

Treatment with multiple checkpoint inhibitors increases the likelihood of severe adverse events, with rates of up to 30%-50% of patients with dual treatment.
 

Distinguishing features of neuromuscular immunotherapy-related adverse events

MG is the most common neuromuscular immune-related adverse event from immune checkpoint inhibitors and tends to occur 3-12 weeks after beginning treatment, frequently comorbid with inflammatory myopathy or cardiomyopathy, Dr. Trevino said. About two-thirds of cases are de novo, while the remaining one-third involve preexisting MG; no reports of Lambert-Eaton myasthenic syndrome have been linked to checkpoint inhibitors.

Several characteristics distinguish checkpoint inhibitor–associated MG from standard MG. Standard MG can be ocular with or without bulbar or appendicular weakness, whereas immunotherapy-related MG is rarely only ocular (about 18% of cases). Immunotherapy-related MG involves an MG crisis at diagnosis in up to 50% of cases and has high mortality, both of which are rarer with standard MG.

While standard MG can be seronegative or involve AChR, MuSK, or LRP4 antibodies, about two-thirds of immunotherapy-related MG cases are positive for AChR antibodies. LRP4 antibodies are rare with MG from checkpoint inhibitors, and no MuSK antibodies have been reported in these cases. Creatine kinase (CK) or troponin I (TnI) elevation occurs in about 87% of patients with checkpoint inhibitor-induced MG, but standard MG doesn’t typically involve increased CK levels.

Inflammatory myositis (IM), the second most common neuromuscular adverse event from immunotherapy, tends to occur 2-15 weeks after immune checkpoint inhibitor therapy and can involve polymyositis, necrotizing autoimmune myopathy, dermatomyositis, granulomatous myositis, or other nonspecific myositis and myopathies.

Though proximal weakness occurs with IM both associated with immunotherapy and not, ocular symptoms are unique to cases associated with therapy and occur in about half of them. Myalgia, dyspnea, and dysphagia can all occur with checkpoint inhibitor–associated IM but don’t generally occur with standard IM. Immunotherapy-related IM is usually seronegative for myositis antibodies and doesn’t generally cause abnormalities in electromyography, compared with increased exertional activity and early recruitment of myopathic motor units in electromyography with standard IM.

GBS and CIDP are the third most common cause of neuromuscular complications from checkpoint inhibitors. The main distinguishing feature of these conditions from those not related to immunotherapy is that they occur anywhere from 4 to 68 weeks after therapy begins. Presentation is otherwise similar whether related to checkpoint inhibitors or not.

Aside from GBS and CIDP, other neuropathies that can result from immunotherapy complications include acute cranial neuropathies, axonal or demyelinating neuropathies, motor polyradiculopathy, vasculitic neuropathy, and plexopathy.

Neuromuscular complications other than those described above can also occur from checkpoint inhibitor therapy, such as enteric neuropathy, polyradiculitis, and meningo-radiculo-neuritis, but these are much rarer.

Four organizations have developed consensus guidelines for immune checkpoint inhibitor toxicities: the European Society for Medical Oncology (ESMO, 2017), Society for Immunotherapy of Cancer (SITC, 2017), American Society of Clinical Oncology (ASCO, 2018), and National Comprehensive Cancer Network (NCCN, 2019).

Dr Trevino had no disclosures.

AUSTIN, TEX. – Neuromuscular complications from immunotherapy for cancer are rare, but they occur often enough that it is helpful to know which ones can result from different immunotherapies and how to distinguish them from non–adverse event conditions, according to Christopher Trevino, MD, a neuro-oncologist at Tulane University in New Orleans.

At the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine, Dr. Trevino reviewed immunotherapy types, particularly immune checkpoint inhibitors, and the most common neuromuscular complications – primarily neuropathy, myasthenia gravis (MG), myositis, and encephalitis or meningitis.

“Timing of onset is a critical component to assist in identifying immune checkpoint inhibitor–associated versus non–immune checkpoint inhibitor–associated neuromuscular disease,” Dr. Trevino told attendees. Prompt recognition can be particularly urgent for MG because crisis and death rates are higher when induced by immunotherapy and require quick treatment. “Understanding the mechanisms of action sets a foundation for treatment approach,” he added.

Any part of the nervous system can be affected by immunotherapy toxicity, he said, and syndromes often overlap, with the peripheral nervous system typically more often affected than the central nervous system. Neurologic immune-related adverse events typically occur within four cycles of therapy – about 12 weeks after therapy initiation – but should always involve a work-up to exclude effects from the cancer itself, other neuromuscular diagnoses unrelated to therapy, and other toxicities from chemotherapy.

Recommended first-line treatment is halting immunotherapy with or without corticosteroids, after which most patients improve, often with “rapid, complete resolution of symptoms,” Dr. Trevino said. Restarting immunotherapy treatment is possible in some patients, though.
 

CAR T-cell and dendritic cell vaccine therapies

Four main types of immunotherapy exist: viral therapy, vaccine therapy, immune checkpoint inhibitors, and adoptive cell transfer, such as chimeric antigen receptor (CAR) T-cell therapy. Dr. Trevino focused on checkpoint inhibitors and adoptive cell transfer.

CAR T-cell therapy is a multistep treatment process that involves first removing blood from the patient to obtain their T cells. These are used to create and grow CAR T cells in the lab so that they can be infused back into the patient. The cells then bind to cancer cells and destroy them. Examples of approved CAR T-cell therapy include Yescarta (axicabtagene ciloleucel) for some types of non-Hodgkin lymphoma and Kymriah (tisagenlecleucel) for acute lymphoblastic leukemia (ALL).

Dendritic cell vaccines are similar to CAR T-cell therapy in that they also use the patient’s own immune cells to create cancer-killing cells that the patient then receives back. The only currently approved dendritic cell vaccine is Provenge (sipuleucel-T) for advanced prostate cancer.

The main toxicity to watch for from CAR T-cell therapy and dendritic cell vaccines is cytokine release syndrome (CRS). It can begin anywhere from 1-14 days after the infusion and involves T-cell expansion in the body that leads to a cytokine storm. Symptoms are wide ranging, including fatigue, fever, loss of appetite, tachycardia, hypotension, pain, rash, diarrhea, headache, confusion, seizures, muscle and joint pain, tachypnea, hypoxia and hallucinations, among others.

Specific central neurotoxicities that can result from CAR T-cell therapy include encephalopathy, cerebral edema, seizures and status epilepticus, cerebral vasospasm, and aphasia.
 

Immune checkpoint inhibitor toxicities

Immune checkpoint inhibitors are drugs that interrupt a cancer’s ability to hijack the immune system; they block the proteins that hold back T-cells from attacking the cancer, thereby releasing the immune system to go after the malignant cells.

The two most common types of immune checkpoint inhibitors are those targeting the programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathways. The three currently approved PD-1 inhibitors are pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo), which can treat nearly a dozen malignancies affecting different organs. Atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi) are the three currently approved PD-L1 inhibitors, indicated for urothelial carcinoma and a handful of other cancers, such as small-cell and non–small cell lung cancer and triple negative breast cancer.

The only other type of approved checkpoint inhibitor is ipilimumab (Yervoy), which targets the CTLA-4 protein. A number of other checkpoint inhibitors are in trials, however, such as ones targeting pathways involving OX40, ICOS, TIM3, and LAG-3 (J Hematol Oncol. 2018. doi: 10.1186/s13045-018-0582-8).

Immune-related adverse events are less common with PD-1 or PD-L1 inhibitors – a rate of 5%-10% – compared with adverse events from CTLA-4 inhibitors, which occur in about 15% of patients. Neurologic complications occur even more rarely – about 1%-4% of all immune checkpoint inhibitor therapies – and primarily include MG, Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and inflammatory myositis (Muscle Nerve. 2018;58[1]:10-22).

Treatment with multiple checkpoint inhibitors increases the likelihood of severe adverse events, with rates of up to 30%-50% of patients with dual treatment.
 

Distinguishing features of neuromuscular immunotherapy-related adverse events

MG is the most common neuromuscular immune-related adverse event from immune checkpoint inhibitors and tends to occur 3-12 weeks after beginning treatment, frequently comorbid with inflammatory myopathy or cardiomyopathy, Dr. Trevino said. About two-thirds of cases are de novo, while the remaining one-third involve preexisting MG; no reports of Lambert-Eaton myasthenic syndrome have been linked to checkpoint inhibitors.

Several characteristics distinguish checkpoint inhibitor–associated MG from standard MG. Standard MG can be ocular with or without bulbar or appendicular weakness, whereas immunotherapy-related MG is rarely only ocular (about 18% of cases). Immunotherapy-related MG involves an MG crisis at diagnosis in up to 50% of cases and has high mortality, both of which are rarer with standard MG.

While standard MG can be seronegative or involve AChR, MuSK, or LRP4 antibodies, about two-thirds of immunotherapy-related MG cases are positive for AChR antibodies. LRP4 antibodies are rare with MG from checkpoint inhibitors, and no MuSK antibodies have been reported in these cases. Creatine kinase (CK) or troponin I (TnI) elevation occurs in about 87% of patients with checkpoint inhibitor-induced MG, but standard MG doesn’t typically involve increased CK levels.

Inflammatory myositis (IM), the second most common neuromuscular adverse event from immunotherapy, tends to occur 2-15 weeks after immune checkpoint inhibitor therapy and can involve polymyositis, necrotizing autoimmune myopathy, dermatomyositis, granulomatous myositis, or other nonspecific myositis and myopathies.

Though proximal weakness occurs with IM both associated with immunotherapy and not, ocular symptoms are unique to cases associated with therapy and occur in about half of them. Myalgia, dyspnea, and dysphagia can all occur with checkpoint inhibitor–associated IM but don’t generally occur with standard IM. Immunotherapy-related IM is usually seronegative for myositis antibodies and doesn’t generally cause abnormalities in electromyography, compared with increased exertional activity and early recruitment of myopathic motor units in electromyography with standard IM.

GBS and CIDP are the third most common cause of neuromuscular complications from checkpoint inhibitors. The main distinguishing feature of these conditions from those not related to immunotherapy is that they occur anywhere from 4 to 68 weeks after therapy begins. Presentation is otherwise similar whether related to checkpoint inhibitors or not.

Aside from GBS and CIDP, other neuropathies that can result from immunotherapy complications include acute cranial neuropathies, axonal or demyelinating neuropathies, motor polyradiculopathy, vasculitic neuropathy, and plexopathy.

Neuromuscular complications other than those described above can also occur from checkpoint inhibitor therapy, such as enteric neuropathy, polyradiculitis, and meningo-radiculo-neuritis, but these are much rarer.

Four organizations have developed consensus guidelines for immune checkpoint inhibitor toxicities: the European Society for Medical Oncology (ESMO, 2017), Society for Immunotherapy of Cancer (SITC, 2017), American Society of Clinical Oncology (ASCO, 2018), and National Comprehensive Cancer Network (NCCN, 2019).

Dr Trevino had no disclosures.

AUSTIN, TEX. – Real-world effectiveness of ataluren for the treatment of Duchenne muscular dystrophy (DMD) with nonsense mutation was similar to the benefit seen in the randomized controlled trial that led to its European approval, according to new data.

“Participants in the STRIDE Registry [real-world patients] showed a reduction in functional decline over 48 weeks, compared with patients receiving placebo” in the trial, reported Abdallah Delage of PTC Therapeutics in Zug, Switzerland, and his associates.

Duchenne muscular dystrophy affects an estimated 1 in 3,600-6,000 male births globally, about 10%-15% of whom have nonsense mutation DMD. This mutation causes a truncated, nonfunctional dystrophin protein due to a premature stop codon, the authors explained. Ataluren “promotes ribosomal read-through of the premature stop codon to produce a full-length dystrophin protein,” they explained.

Ataluren is currently approved for ambulatory patients age 2 and older with nonsense mutation DMD in the European Union and several other European countries. Israel, Korea, Chile, and Ukraine have approved it for patients aged 5 and older.

The Strategic Targeting of Registries and International Database of Excellence (STRIDE) Registry contains real-world data from patients using ataluren as part of an ongoing multicenter observational postapproval safety study. The investigators are tracking patients for at least 5 years after enrollment in 14 countries where ataluren is approved or commercially available through early-access programs. Patients take 40 mg/kg daily: 10 mg/kg in the morning, 10 mg/kg midday, and 20 mg/kg in the evening.

The researchers compared outcomes in 216 patients in the STRIDE Registry with participants in a randomized controlled phase 3 study of ataluren involving 228 boys, aged 7-16, who received ataluren (n = 114) or placebo (n = 114) for 48 weeks. Patients were an average 9 years old in STRIDE and in both arms of the randomized controlled trial.

The STRIDE Registry participants, comprising 184 ambulatory and 26 nonambulatory patients at enrollment, had at least 48 weeks between their first and last assessment. All of the patients in the phase 3 study and 88.6% of the STRIDE Registry patients were receiving corticosteroids along with ataluren. The researchers compared the 184 ambulatory STRIDE participants with the participants of the randomized controlled trial for one primary and four secondary endpoints from baseline to 48 weeks.

For the primary endpoint, 6-minute walk distance, average distance was 35 meters shorter than baseline in STRIDE Registry participants (n = 66), 42.2 meters shorter in the patients receiving ataluren in the phase 3 study (n = 109), and 57.6 meters shorter in RCT patients receiving placebo in the phase 3 trial (n = 109).

A secondary endpoint, the time it took patients to walk or run 10 meters, increased 1.6 seconds from baseline to 48 weeks in STRIDE Registry participants (n = 61), 2.3 seconds in participants receiving ataluren in the phase 3 trial (n = 109), and 3.5 seconds in study participants receiving placebo (n = 110).

Another secondary endpoint, the change in time it took for patients to stand from supine position from baseline to 48 weeks, was 2.9 additional seconds for STRIDE participants (n = 55), 3.8 additional seconds in study participants receiving ataluren (n = 101), and 3.9 additional seconds in study participants receiving placebo (n = 96).

Two final secondary endpoints were the changes in time to climb four stairs and to descend four stairs from baseline to 48 weeks. STRIDE participants (n = 47) climbed four stairs 1.2 seconds more slowly at 48 weeks, compared with 2.7 seconds more slowly in the participants who received ataluren in the phase 3 trial (n = 105) and 4.5 seconds more slowly in those who received placebo. Descending four stairs took 0.5 more seconds at 48 weeks in STRIDE participants (n = 40), 2.2 more seconds in participants who received ataluren in the phase 3 trial (n = 106), and 4.0 more seconds in those who received placebo (n = 100).

At least one adverse event occurred in 20.7% of registry participants; seven of these were considered treatment related. Treatment-related side effects included abdominal pain, vomiting, headache, stomach ache, diarrhea, and increased serum lipids.

The study and STRIDE Registry is funded by PTC Therapeutics with TREAT-NMD and the Cooperative International Neuromuscular Research Group. Mr. Delage and five other authors are employees of PTC Therapeutics, and six authors had received speaker or consultancy fees or served on the advisory board of a variety of companies.

SOURCE: Delage A et al. AANEM 2019, Abstract 115.
 

AUSTIN, TEX. – Real-world effectiveness of ataluren for the treatment of Duchenne muscular dystrophy (DMD) with nonsense mutation was similar to the benefit seen in the randomized controlled trial that led to its European approval, according to new data.

“Participants in the STRIDE Registry [real-world patients] showed a reduction in functional decline over 48 weeks, compared with patients receiving placebo” in the trial, reported Abdallah Delage of PTC Therapeutics in Zug, Switzerland, and his associates.

Duchenne muscular dystrophy affects an estimated 1 in 3,600-6,000 male births globally, about 10%-15% of whom have nonsense mutation DMD. This mutation causes a truncated, nonfunctional dystrophin protein due to a premature stop codon, the authors explained. Ataluren “promotes ribosomal read-through of the premature stop codon to produce a full-length dystrophin protein,” they explained.

Ataluren is currently approved for ambulatory patients age 2 and older with nonsense mutation DMD in the European Union and several other European countries. Israel, Korea, Chile, and Ukraine have approved it for patients aged 5 and older.

The Strategic Targeting of Registries and International Database of Excellence (STRIDE) Registry contains real-world data from patients using ataluren as part of an ongoing multicenter observational postapproval safety study. The investigators are tracking patients for at least 5 years after enrollment in 14 countries where ataluren is approved or commercially available through early-access programs. Patients take 40 mg/kg daily: 10 mg/kg in the morning, 10 mg/kg midday, and 20 mg/kg in the evening.

The researchers compared outcomes in 216 patients in the STRIDE Registry with participants in a randomized controlled phase 3 study of ataluren involving 228 boys, aged 7-16, who received ataluren (n = 114) or placebo (n = 114) for 48 weeks. Patients were an average 9 years old in STRIDE and in both arms of the randomized controlled trial.

The STRIDE Registry participants, comprising 184 ambulatory and 26 nonambulatory patients at enrollment, had at least 48 weeks between their first and last assessment. All of the patients in the phase 3 study and 88.6% of the STRIDE Registry patients were receiving corticosteroids along with ataluren. The researchers compared the 184 ambulatory STRIDE participants with the participants of the randomized controlled trial for one primary and four secondary endpoints from baseline to 48 weeks.

For the primary endpoint, 6-minute walk distance, average distance was 35 meters shorter than baseline in STRIDE Registry participants (n = 66), 42.2 meters shorter in the patients receiving ataluren in the phase 3 study (n = 109), and 57.6 meters shorter in RCT patients receiving placebo in the phase 3 trial (n = 109).

A secondary endpoint, the time it took patients to walk or run 10 meters, increased 1.6 seconds from baseline to 48 weeks in STRIDE Registry participants (n = 61), 2.3 seconds in participants receiving ataluren in the phase 3 trial (n = 109), and 3.5 seconds in study participants receiving placebo (n = 110).

Another secondary endpoint, the change in time it took for patients to stand from supine position from baseline to 48 weeks, was 2.9 additional seconds for STRIDE participants (n = 55), 3.8 additional seconds in study participants receiving ataluren (n = 101), and 3.9 additional seconds in study participants receiving placebo (n = 96).

Two final secondary endpoints were the changes in time to climb four stairs and to descend four stairs from baseline to 48 weeks. STRIDE participants (n = 47) climbed four stairs 1.2 seconds more slowly at 48 weeks, compared with 2.7 seconds more slowly in the participants who received ataluren in the phase 3 trial (n = 105) and 4.5 seconds more slowly in those who received placebo. Descending four stairs took 0.5 more seconds at 48 weeks in STRIDE participants (n = 40), 2.2 more seconds in participants who received ataluren in the phase 3 trial (n = 106), and 4.0 more seconds in those who received placebo (n = 100).

At least one adverse event occurred in 20.7% of registry participants; seven of these were considered treatment related. Treatment-related side effects included abdominal pain, vomiting, headache, stomach ache, diarrhea, and increased serum lipids.

The study and STRIDE Registry is funded by PTC Therapeutics with TREAT-NMD and the Cooperative International Neuromuscular Research Group. Mr. Delage and five other authors are employees of PTC Therapeutics, and six authors had received speaker or consultancy fees or served on the advisory board of a variety of companies.

SOURCE: Delage A et al. AANEM 2019, Abstract 115.
 

AUSTIN, TEX. – Real-world effectiveness of ataluren for the treatment of Duchenne muscular dystrophy (DMD) with nonsense mutation was similar to the benefit seen in the randomized controlled trial that led to its European approval, according to new data.

“Participants in the STRIDE Registry [real-world patients] showed a reduction in functional decline over 48 weeks, compared with patients receiving placebo” in the trial, reported Abdallah Delage of PTC Therapeutics in Zug, Switzerland, and his associates.

Duchenne muscular dystrophy affects an estimated 1 in 3,600-6,000 male births globally, about 10%-15% of whom have nonsense mutation DMD. This mutation causes a truncated, nonfunctional dystrophin protein due to a premature stop codon, the authors explained. Ataluren “promotes ribosomal read-through of the premature stop codon to produce a full-length dystrophin protein,” they explained.

Ataluren is currently approved for ambulatory patients age 2 and older with nonsense mutation DMD in the European Union and several other European countries. Israel, Korea, Chile, and Ukraine have approved it for patients aged 5 and older.

The Strategic Targeting of Registries and International Database of Excellence (STRIDE) Registry contains real-world data from patients using ataluren as part of an ongoing multicenter observational postapproval safety study. The investigators are tracking patients for at least 5 years after enrollment in 14 countries where ataluren is approved or commercially available through early-access programs. Patients take 40 mg/kg daily: 10 mg/kg in the morning, 10 mg/kg midday, and 20 mg/kg in the evening.

The researchers compared outcomes in 216 patients in the STRIDE Registry with participants in a randomized controlled phase 3 study of ataluren involving 228 boys, aged 7-16, who received ataluren (n = 114) or placebo (n = 114) for 48 weeks. Patients were an average 9 years old in STRIDE and in both arms of the randomized controlled trial.

The STRIDE Registry participants, comprising 184 ambulatory and 26 nonambulatory patients at enrollment, had at least 48 weeks between their first and last assessment. All of the patients in the phase 3 study and 88.6% of the STRIDE Registry patients were receiving corticosteroids along with ataluren. The researchers compared the 184 ambulatory STRIDE participants with the participants of the randomized controlled trial for one primary and four secondary endpoints from baseline to 48 weeks.

For the primary endpoint, 6-minute walk distance, average distance was 35 meters shorter than baseline in STRIDE Registry participants (n = 66), 42.2 meters shorter in the patients receiving ataluren in the phase 3 study (n = 109), and 57.6 meters shorter in RCT patients receiving placebo in the phase 3 trial (n = 109).

A secondary endpoint, the time it took patients to walk or run 10 meters, increased 1.6 seconds from baseline to 48 weeks in STRIDE Registry participants (n = 61), 2.3 seconds in participants receiving ataluren in the phase 3 trial (n = 109), and 3.5 seconds in study participants receiving placebo (n = 110).

Another secondary endpoint, the change in time it took for patients to stand from supine position from baseline to 48 weeks, was 2.9 additional seconds for STRIDE participants (n = 55), 3.8 additional seconds in study participants receiving ataluren (n = 101), and 3.9 additional seconds in study participants receiving placebo (n = 96).

Two final secondary endpoints were the changes in time to climb four stairs and to descend four stairs from baseline to 48 weeks. STRIDE participants (n = 47) climbed four stairs 1.2 seconds more slowly at 48 weeks, compared with 2.7 seconds more slowly in the participants who received ataluren in the phase 3 trial (n = 105) and 4.5 seconds more slowly in those who received placebo. Descending four stairs took 0.5 more seconds at 48 weeks in STRIDE participants (n = 40), 2.2 more seconds in participants who received ataluren in the phase 3 trial (n = 106), and 4.0 more seconds in those who received placebo (n = 100).

At least one adverse event occurred in 20.7% of registry participants; seven of these were considered treatment related. Treatment-related side effects included abdominal pain, vomiting, headache, stomach ache, diarrhea, and increased serum lipids.

The study and STRIDE Registry is funded by PTC Therapeutics with TREAT-NMD and the Cooperative International Neuromuscular Research Group. Mr. Delage and five other authors are employees of PTC Therapeutics, and six authors had received speaker or consultancy fees or served on the advisory board of a variety of companies.

SOURCE: Delage A et al. AANEM 2019, Abstract 115.
 

AUSTIN, TEX. – When testing for acetylcholine receptor (AChR) autoantibodies in patients with suspected myasthenia gravis, testing for binding antibodies and for modulating antibodies is more accurate than testing for either subtype alone, researchers reported at the annual meeting of the American Association of Neuromuscular and Electrodiagnostic Medicine. Testing for both subtypes may be the most accurate approach, regardless of whether patients have coexisting neuromuscular disorders, the researchers said.

“The advent of improved methods of detecting AChR autoantibodies has greatly facilitated the diagnosis of myasthenia gravis,” said Pritikanta Paul, MBBS, a neuromuscular fellow at Mayo Clinic in Rochester, Minn., and his colleagues. AChR antibody assays frequently are part of evaluations for myasthenia gravis, but clinicians lack consensus as to which antibody subtypes – binding, blocking, or modulating – should be tested. Clinicians test for binding antibodies most commonly, while studies have found blocking antibodies to be “least useful as an initial diagnostic test,” Dr. Paul and his colleagues said.

To assess how combinatorial antibody testing and the presence of coexisting neuromuscular disorders affect testing’s sensitivity and specificity, the researchers reviewed clinical and electrophysiologic testing data from 360 patients with suspected myasthenia gravis who underwent serologic autoantibody testing between 2012 and 2015.

Titers of AChR binding antibodies greater than 0.02 nmol/L were considered positive, as were AChR modulating antibodies more than 20%. The researchers used a greater than 10% decrement of the compound muscle action potential to repetitive nerve stimulation at 2 Hz or positive response on single-fiber EMG as electrophysiologic confirmation of myasthenia gravis.

In all, 123 of the 360 patients had a final clinical and electrophysiologic diagnosis of myasthenia gravis, including 23 with ocular myasthenia gravis and 100 with generalized myasthenia gravis.

The sensitivity of testing for AChR binding autoantibodies was 92%, and the sensitivity of testing for modulating autoantibodies was 90%. In comparison, the sensitivity of testing for either antibody subtype or both was 94%.

Among 45 patients with myasthenia gravis and coexisting neuromuscular disorders, including peripheral neuropathy, mononeuropathies, radiculopathy, and motor neuron disease, the sensitivities of testing for binding antibodies, modulating antibodies, and either or both were 96%, 91%, and 96%, respectively.

Of the 237 patients who did not have myasthenia gravis, 89 had electrophysiologic confirmation of alternative diagnoses. Among these 89 patients, AChR autoantibody testing yielded 11 false positives. Three patients tested positive for both binding and modulating antibodies, six for binding antibodies only, and two for modulating antibodies only. Those with false-positive results had diagnoses that were “diverse and clinically distinguishable from myasthenia gravis,” including myalgia, neuropathy, blurred vision, epilepsy, encephalopathy, and hemifacial spasm, the researchers said.

The researchers had no relevant disclosures.

jremaly@mdedge.com

SOURCE: Paul P et al. AANEM 2019, Abstract 236.

AUSTIN, TEX. – When testing for acetylcholine receptor (AChR) autoantibodies in patients with suspected myasthenia gravis, testing for binding antibodies and for modulating antibodies is more accurate than testing for either subtype alone, researchers reported at the annual meeting of the American Association of Neuromuscular and Electrodiagnostic Medicine. Testing for both subtypes may be the most accurate approach, regardless of whether patients have coexisting neuromuscular disorders, the researchers said.

“The advent of improved methods of detecting AChR autoantibodies has greatly facilitated the diagnosis of myasthenia gravis,” said Pritikanta Paul, MBBS, a neuromuscular fellow at Mayo Clinic in Rochester, Minn., and his colleagues. AChR antibody assays frequently are part of evaluations for myasthenia gravis, but clinicians lack consensus as to which antibody subtypes – binding, blocking, or modulating – should be tested. Clinicians test for binding antibodies most commonly, while studies have found blocking antibodies to be “least useful as an initial diagnostic test,” Dr. Paul and his colleagues said.

To assess how combinatorial antibody testing and the presence of coexisting neuromuscular disorders affect testing’s sensitivity and specificity, the researchers reviewed clinical and electrophysiologic testing data from 360 patients with suspected myasthenia gravis who underwent serologic autoantibody testing between 2012 and 2015.

Titers of AChR binding antibodies greater than 0.02 nmol/L were considered positive, as were AChR modulating antibodies more than 20%. The researchers used a greater than 10% decrement of the compound muscle action potential to repetitive nerve stimulation at 2 Hz or positive response on single-fiber EMG as electrophysiologic confirmation of myasthenia gravis.

In all, 123 of the 360 patients had a final clinical and electrophysiologic diagnosis of myasthenia gravis, including 23 with ocular myasthenia gravis and 100 with generalized myasthenia gravis.

The sensitivity of testing for AChR binding autoantibodies was 92%, and the sensitivity of testing for modulating autoantibodies was 90%. In comparison, the sensitivity of testing for either antibody subtype or both was 94%.

Among 45 patients with myasthenia gravis and coexisting neuromuscular disorders, including peripheral neuropathy, mononeuropathies, radiculopathy, and motor neuron disease, the sensitivities of testing for binding antibodies, modulating antibodies, and either or both were 96%, 91%, and 96%, respectively.

Of the 237 patients who did not have myasthenia gravis, 89 had electrophysiologic confirmation of alternative diagnoses. Among these 89 patients, AChR autoantibody testing yielded 11 false positives. Three patients tested positive for both binding and modulating antibodies, six for binding antibodies only, and two for modulating antibodies only. Those with false-positive results had diagnoses that were “diverse and clinically distinguishable from myasthenia gravis,” including myalgia, neuropathy, blurred vision, epilepsy, encephalopathy, and hemifacial spasm, the researchers said.

The researchers had no relevant disclosures.

jremaly@mdedge.com

SOURCE: Paul P et al. AANEM 2019, Abstract 236.

AUSTIN, TEX. – When testing for acetylcholine receptor (AChR) autoantibodies in patients with suspected myasthenia gravis, testing for binding antibodies and for modulating antibodies is more accurate than testing for either subtype alone, researchers reported at the annual meeting of the American Association of Neuromuscular and Electrodiagnostic Medicine. Testing for both subtypes may be the most accurate approach, regardless of whether patients have coexisting neuromuscular disorders, the researchers said.

“The advent of improved methods of detecting AChR autoantibodies has greatly facilitated the diagnosis of myasthenia gravis,” said Pritikanta Paul, MBBS, a neuromuscular fellow at Mayo Clinic in Rochester, Minn., and his colleagues. AChR antibody assays frequently are part of evaluations for myasthenia gravis, but clinicians lack consensus as to which antibody subtypes – binding, blocking, or modulating – should be tested. Clinicians test for binding antibodies most commonly, while studies have found blocking antibodies to be “least useful as an initial diagnostic test,” Dr. Paul and his colleagues said.

To assess how combinatorial antibody testing and the presence of coexisting neuromuscular disorders affect testing’s sensitivity and specificity, the researchers reviewed clinical and electrophysiologic testing data from 360 patients with suspected myasthenia gravis who underwent serologic autoantibody testing between 2012 and 2015.

Titers of AChR binding antibodies greater than 0.02 nmol/L were considered positive, as were AChR modulating antibodies more than 20%. The researchers used a greater than 10% decrement of the compound muscle action potential to repetitive nerve stimulation at 2 Hz or positive response on single-fiber EMG as electrophysiologic confirmation of myasthenia gravis.

In all, 123 of the 360 patients had a final clinical and electrophysiologic diagnosis of myasthenia gravis, including 23 with ocular myasthenia gravis and 100 with generalized myasthenia gravis.

The sensitivity of testing for AChR binding autoantibodies was 92%, and the sensitivity of testing for modulating autoantibodies was 90%. In comparison, the sensitivity of testing for either antibody subtype or both was 94%.

Among 45 patients with myasthenia gravis and coexisting neuromuscular disorders, including peripheral neuropathy, mononeuropathies, radiculopathy, and motor neuron disease, the sensitivities of testing for binding antibodies, modulating antibodies, and either or both were 96%, 91%, and 96%, respectively.

Of the 237 patients who did not have myasthenia gravis, 89 had electrophysiologic confirmation of alternative diagnoses. Among these 89 patients, AChR autoantibody testing yielded 11 false positives. Three patients tested positive for both binding and modulating antibodies, six for binding antibodies only, and two for modulating antibodies only. Those with false-positive results had diagnoses that were “diverse and clinically distinguishable from myasthenia gravis,” including myalgia, neuropathy, blurred vision, epilepsy, encephalopathy, and hemifacial spasm, the researchers said.

The researchers had no relevant disclosures.

jremaly@mdedge.com

SOURCE: Paul P et al. AANEM 2019, Abstract 236.

AUSTIN, TEX. – Patients with chronic inflammatory demyelinating polyneuropathy (CIDP) who receive intravenous immunoglobulin (IVIg) appear to have an increased risk of thromboembolic events if it is administered with a central venous access device (CVAD) when compared against those without a CVAD, according to a recent study.

Although CVADs can reliably deliver IVIg, they also represent an established risk factor for thromboembolic events, Ami Patel, PhD, a senior epidemiologist at CSL Behring, and colleagues noted on their poster at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine.

The results suggest a need for physicians to be vigilant about patients’ potential risk factors for thromboembolic events, Dr. Patel said in an interview. Further research is planned, however, because the current study did not control for other risk factors or explore other possible confounding, she said.

Dr. Patel and her associates analyzed U.S. claims data (IBM/Truven MarketScan) from 2006 to 2018 and included all patients with a CIDP diagnosis claim and a postdiagnosis code for IVIg. A code for CVAD up to 2 months before CIDP diagnosis without removal before IVIg treatment ended determined those with CVAD exposure, and thromboembolic events included any codes related to arterial, venous, or vascular prostheses.

The researchers then compared patients in a case-control fashion, matching each one with a CVAD to five patients of similar demographics without a CVAD. Characteristics used for matching included medical insurance type, prescription data availability, sex, age, geographic region, and years enrolled in the database.

Among 7,447 patients with at least one IVIg claim, 11.8% (n = 882) had CVAD exposure and 88.2% (n = 6,565) did not. Of those without a CVAD, 3,642 patients were matched to patients with CVAD. A quarter (25.4%) of patients with a CVAD had a thromboembolic event, compared with 11.2% of matched patients without CVADs (P less than .0001).

In the year leading up to IVIg therapy, 16.9% of those with a CVAD and 10.9% of matched patients without one had a previous thromboembolic event (P less than .0001). Patients with a CVAD also had significantly higher rates of hypertension (51.9% vs. 45.0% with placebo; P less than .001) and anticoagulation therapy (7.0% vs. 5.2% with placebo; P less than .05). Differences between the groups were not significant for diabetes (26.9% vs. 24.2%) and hyperlipidemia (19.1% vs. 17.8%).

Occlusion and stenosis of the carotid artery was the most common arterial thromboembolic outcome, occurring in 5.3% of those with a CVAD and in 2.8% of those without a CVAD. The most common venous thromboembolic event was acute venous embolism and thrombosis of lower-extremity deep vessels, which occurred in 7% of those with a CVAD and in 1.8% of those without.

The researchers also compared inpatient admissions and emergency department visits among those with and without a CVAD; both rates were higher in patients with a CVAD. Visits to the emergency department occurred at a rate of 0.14 events per month for those with a CVAD (2.01 distinct months with a claim) and 0.09 events per month for those without a CVAD (0.65 distinct months with a claim). Patients with a CVAD had 1.44 months with an inpatient admissions claim, in comparison with 0.41 months among matched patients without a CVAD. Inpatient admission frequency per month was 0.14 for those with a CVAD and 0.08 for those without.

The research was funded by CSL Behring. Dr. Patel and two of the other five authors are employees of CSL Behring.

SOURCE: Patel A et al. AANEM 2019, Abstract 94.

AUSTIN, TEX. – Patients with chronic inflammatory demyelinating polyneuropathy (CIDP) who receive intravenous immunoglobulin (IVIg) appear to have an increased risk of thromboembolic events if it is administered with a central venous access device (CVAD) when compared against those without a CVAD, according to a recent study.

Although CVADs can reliably deliver IVIg, they also represent an established risk factor for thromboembolic events, Ami Patel, PhD, a senior epidemiologist at CSL Behring, and colleagues noted on their poster at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine.

The results suggest a need for physicians to be vigilant about patients’ potential risk factors for thromboembolic events, Dr. Patel said in an interview. Further research is planned, however, because the current study did not control for other risk factors or explore other possible confounding, she said.

Dr. Patel and her associates analyzed U.S. claims data (IBM/Truven MarketScan) from 2006 to 2018 and included all patients with a CIDP diagnosis claim and a postdiagnosis code for IVIg. A code for CVAD up to 2 months before CIDP diagnosis without removal before IVIg treatment ended determined those with CVAD exposure, and thromboembolic events included any codes related to arterial, venous, or vascular prostheses.

The researchers then compared patients in a case-control fashion, matching each one with a CVAD to five patients of similar demographics without a CVAD. Characteristics used for matching included medical insurance type, prescription data availability, sex, age, geographic region, and years enrolled in the database.

Among 7,447 patients with at least one IVIg claim, 11.8% (n = 882) had CVAD exposure and 88.2% (n = 6,565) did not. Of those without a CVAD, 3,642 patients were matched to patients with CVAD. A quarter (25.4%) of patients with a CVAD had a thromboembolic event, compared with 11.2% of matched patients without CVADs (P less than .0001).

In the year leading up to IVIg therapy, 16.9% of those with a CVAD and 10.9% of matched patients without one had a previous thromboembolic event (P less than .0001). Patients with a CVAD also had significantly higher rates of hypertension (51.9% vs. 45.0% with placebo; P less than .001) and anticoagulation therapy (7.0% vs. 5.2% with placebo; P less than .05). Differences between the groups were not significant for diabetes (26.9% vs. 24.2%) and hyperlipidemia (19.1% vs. 17.8%).

Occlusion and stenosis of the carotid artery was the most common arterial thromboembolic outcome, occurring in 5.3% of those with a CVAD and in 2.8% of those without a CVAD. The most common venous thromboembolic event was acute venous embolism and thrombosis of lower-extremity deep vessels, which occurred in 7% of those with a CVAD and in 1.8% of those without.

The researchers also compared inpatient admissions and emergency department visits among those with and without a CVAD; both rates were higher in patients with a CVAD. Visits to the emergency department occurred at a rate of 0.14 events per month for those with a CVAD (2.01 distinct months with a claim) and 0.09 events per month for those without a CVAD (0.65 distinct months with a claim). Patients with a CVAD had 1.44 months with an inpatient admissions claim, in comparison with 0.41 months among matched patients without a CVAD. Inpatient admission frequency per month was 0.14 for those with a CVAD and 0.08 for those without.

The research was funded by CSL Behring. Dr. Patel and two of the other five authors are employees of CSL Behring.

SOURCE: Patel A et al. AANEM 2019, Abstract 94.

AUSTIN, TEX. – Patients with chronic inflammatory demyelinating polyneuropathy (CIDP) who receive intravenous immunoglobulin (IVIg) appear to have an increased risk of thromboembolic events if it is administered with a central venous access device (CVAD) when compared against those without a CVAD, according to a recent study.

Although CVADs can reliably deliver IVIg, they also represent an established risk factor for thromboembolic events, Ami Patel, PhD, a senior epidemiologist at CSL Behring, and colleagues noted on their poster at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine.

The results suggest a need for physicians to be vigilant about patients’ potential risk factors for thromboembolic events, Dr. Patel said in an interview. Further research is planned, however, because the current study did not control for other risk factors or explore other possible confounding, she said.

Dr. Patel and her associates analyzed U.S. claims data (IBM/Truven MarketScan) from 2006 to 2018 and included all patients with a CIDP diagnosis claim and a postdiagnosis code for IVIg. A code for CVAD up to 2 months before CIDP diagnosis without removal before IVIg treatment ended determined those with CVAD exposure, and thromboembolic events included any codes related to arterial, venous, or vascular prostheses.

The researchers then compared patients in a case-control fashion, matching each one with a CVAD to five patients of similar demographics without a CVAD. Characteristics used for matching included medical insurance type, prescription data availability, sex, age, geographic region, and years enrolled in the database.

Among 7,447 patients with at least one IVIg claim, 11.8% (n = 882) had CVAD exposure and 88.2% (n = 6,565) did not. Of those without a CVAD, 3,642 patients were matched to patients with CVAD. A quarter (25.4%) of patients with a CVAD had a thromboembolic event, compared with 11.2% of matched patients without CVADs (P less than .0001).

In the year leading up to IVIg therapy, 16.9% of those with a CVAD and 10.9% of matched patients without one had a previous thromboembolic event (P less than .0001). Patients with a CVAD also had significantly higher rates of hypertension (51.9% vs. 45.0% with placebo; P less than .001) and anticoagulation therapy (7.0% vs. 5.2% with placebo; P less than .05). Differences between the groups were not significant for diabetes (26.9% vs. 24.2%) and hyperlipidemia (19.1% vs. 17.8%).

Occlusion and stenosis of the carotid artery was the most common arterial thromboembolic outcome, occurring in 5.3% of those with a CVAD and in 2.8% of those without a CVAD. The most common venous thromboembolic event was acute venous embolism and thrombosis of lower-extremity deep vessels, which occurred in 7% of those with a CVAD and in 1.8% of those without.

The researchers also compared inpatient admissions and emergency department visits among those with and without a CVAD; both rates were higher in patients with a CVAD. Visits to the emergency department occurred at a rate of 0.14 events per month for those with a CVAD (2.01 distinct months with a claim) and 0.09 events per month for those without a CVAD (0.65 distinct months with a claim). Patients with a CVAD had 1.44 months with an inpatient admissions claim, in comparison with 0.41 months among matched patients without a CVAD. Inpatient admission frequency per month was 0.14 for those with a CVAD and 0.08 for those without.

The research was funded by CSL Behring. Dr. Patel and two of the other five authors are employees of CSL Behring.

SOURCE: Patel A et al. AANEM 2019, Abstract 94.

AUSTIN, TEX. – A three-drug combination agent called PXT3003 led to an improvement in symptoms for patients with Charcot-Marie-Tooth (CMT) disease type 1A, according to new research.

“The study has established for the first time that patients after up to 15 months of treatment had a statistically significant and clinically relevant disability improvement as illustrated by the change from baseline of their ONLS [Overall Neurology Limitations Scale] scale,” concluded Florian Thomas, MD, PhD, of Hackensack (N.J.) University Medical Center, and his associates at Pharnext. “PXT3003 with dose 4 has at least stabilized, even improved, the disease.”

The researchers presented their findings in a poster at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine.

The PLEO-CMT study was an international, multicenter, randomized, double-blind, placebo-controlled, phase 3 trial that evaluated the efficacy and safety of PXT3003, an oral 3-drug combination, for CMT1A. CMT1A neuropathy, occurring in an estimated 1 in 5,000 people, is characterized by distal muscle atrophy that affects walking and causes stocking-glove sensory loss and lower quality of life.

The trial enrolled 323 patients, aged 16-65, who had mild to moderate CMT1A that had been genetically confirmed. The modified full set analysis (n = 235), which represented the main study analysis for the primary endpoint, included a placebo group of 87 participants while two other groups received one of two doses of the fixed-dose drug combination twice daily: Ninety-three participants received 3 mg baclofen, 0.35 mg naltrexone, and 105 mg sorbitol (dose 1), and 55 participants received twice that dose (dose 2).

The primary endpoint was mean change from baseline to 12 and 15 months on the ONLS. At baseline, 90% of patients had an ONLS score of 2-4, and the researchers determined an average 0.3 points reduction to be a clinically meaningful effect.

Secondary endpoints included the 10-meter walk test, the 9-hole peg test, and a subscore of Charcot-Marie-Tooth neuropathy score version 2 (CMTNSv2).

Only those taking the higher dose (dose 2) showed a clinically significant drop in ONLS, –0.37 points, compared with those taking placebo (P = .0008). The in-group change from baseline to 15 months in ONLS score for patients taking dose 2 showed a trend of improvement that did not reach significance (–0.20; P = .098).

Participants receiving dose 2 of PXT3003 also walked 0.47 seconds faster on the 10-meter walk test, compared with those receiving placebo (P = .016). No significant differences occurred in the other secondary endpoints, although nonsignificant trends of improvement occurred.

Treatment-emergent adverse events were similar across all three groups and led to trial withdrawal at similar rates for dose 1 (5.5%), dose 2 (5.3%), and placebo (5.9%). One serious adverse event, benign thyroid adenoma, led to trial withdrawal, but no serious adverse events occurred related to the treatment.

Pharnext funded the research. Dr. Thomas is a researcher with Pharnext and Acceleron and has received speaking or advisory board fees from Novartis, Acceleron, Sanofi, and Genentech. The other seven authors are employees of Pharnext.

SOURCE: Thomas F et al. AANEM 2019, Abstract 92.

AUSTIN, TEX. – A three-drug combination agent called PXT3003 led to an improvement in symptoms for patients with Charcot-Marie-Tooth (CMT) disease type 1A, according to new research.

“The study has established for the first time that patients after up to 15 months of treatment had a statistically significant and clinically relevant disability improvement as illustrated by the change from baseline of their ONLS [Overall Neurology Limitations Scale] scale,” concluded Florian Thomas, MD, PhD, of Hackensack (N.J.) University Medical Center, and his associates at Pharnext. “PXT3003 with dose 4 has at least stabilized, even improved, the disease.”

The researchers presented their findings in a poster at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine.

The PLEO-CMT study was an international, multicenter, randomized, double-blind, placebo-controlled, phase 3 trial that evaluated the efficacy and safety of PXT3003, an oral 3-drug combination, for CMT1A. CMT1A neuropathy, occurring in an estimated 1 in 5,000 people, is characterized by distal muscle atrophy that affects walking and causes stocking-glove sensory loss and lower quality of life.

The trial enrolled 323 patients, aged 16-65, who had mild to moderate CMT1A that had been genetically confirmed. The modified full set analysis (n = 235), which represented the main study analysis for the primary endpoint, included a placebo group of 87 participants while two other groups received one of two doses of the fixed-dose drug combination twice daily: Ninety-three participants received 3 mg baclofen, 0.35 mg naltrexone, and 105 mg sorbitol (dose 1), and 55 participants received twice that dose (dose 2).

The primary endpoint was mean change from baseline to 12 and 15 months on the ONLS. At baseline, 90% of patients had an ONLS score of 2-4, and the researchers determined an average 0.3 points reduction to be a clinically meaningful effect.

Secondary endpoints included the 10-meter walk test, the 9-hole peg test, and a subscore of Charcot-Marie-Tooth neuropathy score version 2 (CMTNSv2).

Only those taking the higher dose (dose 2) showed a clinically significant drop in ONLS, –0.37 points, compared with those taking placebo (P = .0008). The in-group change from baseline to 15 months in ONLS score for patients taking dose 2 showed a trend of improvement that did not reach significance (–0.20; P = .098).

Participants receiving dose 2 of PXT3003 also walked 0.47 seconds faster on the 10-meter walk test, compared with those receiving placebo (P = .016). No significant differences occurred in the other secondary endpoints, although nonsignificant trends of improvement occurred.

Treatment-emergent adverse events were similar across all three groups and led to trial withdrawal at similar rates for dose 1 (5.5%), dose 2 (5.3%), and placebo (5.9%). One serious adverse event, benign thyroid adenoma, led to trial withdrawal, but no serious adverse events occurred related to the treatment.

Pharnext funded the research. Dr. Thomas is a researcher with Pharnext and Acceleron and has received speaking or advisory board fees from Novartis, Acceleron, Sanofi, and Genentech. The other seven authors are employees of Pharnext.

SOURCE: Thomas F et al. AANEM 2019, Abstract 92.

AUSTIN, TEX. – A three-drug combination agent called PXT3003 led to an improvement in symptoms for patients with Charcot-Marie-Tooth (CMT) disease type 1A, according to new research.

“The study has established for the first time that patients after up to 15 months of treatment had a statistically significant and clinically relevant disability improvement as illustrated by the change from baseline of their ONLS [Overall Neurology Limitations Scale] scale,” concluded Florian Thomas, MD, PhD, of Hackensack (N.J.) University Medical Center, and his associates at Pharnext. “PXT3003 with dose 4 has at least stabilized, even improved, the disease.”

The researchers presented their findings in a poster at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine.

The PLEO-CMT study was an international, multicenter, randomized, double-blind, placebo-controlled, phase 3 trial that evaluated the efficacy and safety of PXT3003, an oral 3-drug combination, for CMT1A. CMT1A neuropathy, occurring in an estimated 1 in 5,000 people, is characterized by distal muscle atrophy that affects walking and causes stocking-glove sensory loss and lower quality of life.

The trial enrolled 323 patients, aged 16-65, who had mild to moderate CMT1A that had been genetically confirmed. The modified full set analysis (n = 235), which represented the main study analysis for the primary endpoint, included a placebo group of 87 participants while two other groups received one of two doses of the fixed-dose drug combination twice daily: Ninety-three participants received 3 mg baclofen, 0.35 mg naltrexone, and 105 mg sorbitol (dose 1), and 55 participants received twice that dose (dose 2).

The primary endpoint was mean change from baseline to 12 and 15 months on the ONLS. At baseline, 90% of patients had an ONLS score of 2-4, and the researchers determined an average 0.3 points reduction to be a clinically meaningful effect.

Secondary endpoints included the 10-meter walk test, the 9-hole peg test, and a subscore of Charcot-Marie-Tooth neuropathy score version 2 (CMTNSv2).

Only those taking the higher dose (dose 2) showed a clinically significant drop in ONLS, –0.37 points, compared with those taking placebo (P = .0008). The in-group change from baseline to 15 months in ONLS score for patients taking dose 2 showed a trend of improvement that did not reach significance (–0.20; P = .098).

Participants receiving dose 2 of PXT3003 also walked 0.47 seconds faster on the 10-meter walk test, compared with those receiving placebo (P = .016). No significant differences occurred in the other secondary endpoints, although nonsignificant trends of improvement occurred.

Treatment-emergent adverse events were similar across all three groups and led to trial withdrawal at similar rates for dose 1 (5.5%), dose 2 (5.3%), and placebo (5.9%). One serious adverse event, benign thyroid adenoma, led to trial withdrawal, but no serious adverse events occurred related to the treatment.

Pharnext funded the research. Dr. Thomas is a researcher with Pharnext and Acceleron and has received speaking or advisory board fees from Novartis, Acceleron, Sanofi, and Genentech. The other seven authors are employees of Pharnext.

SOURCE: Thomas F et al. AANEM 2019, Abstract 92.

AUSTIN, TEX. – Patients with peripheral neuropathy may benefit from genetic testing to determine of the cause of their neuropathy even if they do not have a family history of the condition, according to new research.

The same research identified more than 80 genetic variants in patients with neuropathy who lacked any other known genetic mutations, potentially representing not-yet-identified pathogenic mutations.

Sasa Zivkovic, MD, PhD, of the University of Pittsburgh Medical Center (UPMC), and associates shared a poster of their findings at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine.

The researchers conducted next-generation sequencing (NGS) on 85 adult patients with peripheral neuropathy at the UPMC Neuromuscular Clinic during May 2017–Feb. 2019. The targeted NGS panel included 70 genes. The patients, aged 60 years on average, were primarily from Allegheny County, Pa., and had neuropathy either suspected to be hereditary or of unknown etiology.

Among the 19% of patients (n = 16) who tested positive for a known pathogenic mutation, half had Charcot-Marie-Tooth disease type 1A (CMT1A). Two patients – 13% of those with pathogenic variants – had hereditary neuropathy with liability to pressure palsies, and two had CMT1X. The remaining four patients had CMT1B, CMT2B1, CMT2E, and hereditary sensory and autonomic neuropathy mutations.

Another 4% of the overall patient sample (n = 3) had likely pathogenic mutations in genes associated with CMT2S, CMT4C and CMT4F. A third of the patients (32%) tested negative for the full NGS panel, and, comprising the largest proportion of patients, 46% had variants of unknown significance.

“The high occurrence of variants of unknown significance has uncertain significance but some variations may represent unrecognized pathogenic mutations,” the authors noted.

They identified 81 of these variants, with the DST, PLEKHG5, and SPG11 genes most commonly affected, each found in six patients. Four patients had a variant in the next most commonly affected gene, SBF2. The following variants occurred in three people each: BICD2, NEFL3, PRX, SCN11A, SCN9A, SLC52A2, and WNK1.

Among the 73 patients who underwent electrodiagnostic testing, 44 had sporadic axonal neuropathy, 17 had sporadic demyelinating neuropathy, and 11 had mixed neuropathies; the 1 remaining patient was not accounted for. Positive genetic testing occurred in a third (32%) of those with familial neuropathy (n = 28) and in 12% of those with sporadic neuropathy (n = 57).

No external funding was noted, and the authors had no disclosures.

SOURCE: Zivkovic S et al. AANEM 2019. Abstract 160. Targeted genetic testing in the evaluation of neuropathy .

AUSTIN, TEX. – Patients with peripheral neuropathy may benefit from genetic testing to determine of the cause of their neuropathy even if they do not have a family history of the condition, according to new research.

The same research identified more than 80 genetic variants in patients with neuropathy who lacked any other known genetic mutations, potentially representing not-yet-identified pathogenic mutations.

Sasa Zivkovic, MD, PhD, of the University of Pittsburgh Medical Center (UPMC), and associates shared a poster of their findings at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine.

The researchers conducted next-generation sequencing (NGS) on 85 adult patients with peripheral neuropathy at the UPMC Neuromuscular Clinic during May 2017–Feb. 2019. The targeted NGS panel included 70 genes. The patients, aged 60 years on average, were primarily from Allegheny County, Pa., and had neuropathy either suspected to be hereditary or of unknown etiology.

Among the 19% of patients (n = 16) who tested positive for a known pathogenic mutation, half had Charcot-Marie-Tooth disease type 1A (CMT1A). Two patients – 13% of those with pathogenic variants – had hereditary neuropathy with liability to pressure palsies, and two had CMT1X. The remaining four patients had CMT1B, CMT2B1, CMT2E, and hereditary sensory and autonomic neuropathy mutations.

Another 4% of the overall patient sample (n = 3) had likely pathogenic mutations in genes associated with CMT2S, CMT4C and CMT4F. A third of the patients (32%) tested negative for the full NGS panel, and, comprising the largest proportion of patients, 46% had variants of unknown significance.

“The high occurrence of variants of unknown significance has uncertain significance but some variations may represent unrecognized pathogenic mutations,” the authors noted.

They identified 81 of these variants, with the DST, PLEKHG5, and SPG11 genes most commonly affected, each found in six patients. Four patients had a variant in the next most commonly affected gene, SBF2. The following variants occurred in three people each: BICD2, NEFL3, PRX, SCN11A, SCN9A, SLC52A2, and WNK1.

Among the 73 patients who underwent electrodiagnostic testing, 44 had sporadic axonal neuropathy, 17 had sporadic demyelinating neuropathy, and 11 had mixed neuropathies; the 1 remaining patient was not accounted for. Positive genetic testing occurred in a third (32%) of those with familial neuropathy (n = 28) and in 12% of those with sporadic neuropathy (n = 57).

No external funding was noted, and the authors had no disclosures.

SOURCE: Zivkovic S et al. AANEM 2019. Abstract 160. Targeted genetic testing in the evaluation of neuropathy .

AUSTIN, TEX. – Patients with peripheral neuropathy may benefit from genetic testing to determine of the cause of their neuropathy even if they do not have a family history of the condition, according to new research.

The same research identified more than 80 genetic variants in patients with neuropathy who lacked any other known genetic mutations, potentially representing not-yet-identified pathogenic mutations.

Sasa Zivkovic, MD, PhD, of the University of Pittsburgh Medical Center (UPMC), and associates shared a poster of their findings at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine.

The researchers conducted next-generation sequencing (NGS) on 85 adult patients with peripheral neuropathy at the UPMC Neuromuscular Clinic during May 2017–Feb. 2019. The targeted NGS panel included 70 genes. The patients, aged 60 years on average, were primarily from Allegheny County, Pa., and had neuropathy either suspected to be hereditary or of unknown etiology.

Among the 19% of patients (n = 16) who tested positive for a known pathogenic mutation, half had Charcot-Marie-Tooth disease type 1A (CMT1A). Two patients – 13% of those with pathogenic variants – had hereditary neuropathy with liability to pressure palsies, and two had CMT1X. The remaining four patients had CMT1B, CMT2B1, CMT2E, and hereditary sensory and autonomic neuropathy mutations.

Another 4% of the overall patient sample (n = 3) had likely pathogenic mutations in genes associated with CMT2S, CMT4C and CMT4F. A third of the patients (32%) tested negative for the full NGS panel, and, comprising the largest proportion of patients, 46% had variants of unknown significance.

“The high occurrence of variants of unknown significance has uncertain significance but some variations may represent unrecognized pathogenic mutations,” the authors noted.

They identified 81 of these variants, with the DST, PLEKHG5, and SPG11 genes most commonly affected, each found in six patients. Four patients had a variant in the next most commonly affected gene, SBF2. The following variants occurred in three people each: BICD2, NEFL3, PRX, SCN11A, SCN9A, SLC52A2, and WNK1.

Among the 73 patients who underwent electrodiagnostic testing, 44 had sporadic axonal neuropathy, 17 had sporadic demyelinating neuropathy, and 11 had mixed neuropathies; the 1 remaining patient was not accounted for. Positive genetic testing occurred in a third (32%) of those with familial neuropathy (n = 28) and in 12% of those with sporadic neuropathy (n = 57).

No external funding was noted, and the authors had no disclosures.

SOURCE: Zivkovic S et al. AANEM 2019. Abstract 160. Targeted genetic testing in the evaluation of neuropathy .

AUSTIN, TEX. – Dichlorphenamide continues to reduce attacks from primary periodic paralysis (PPP) through 1 year with mild or moderate paresthesia and cognition-related adverse events, according to new research.

“These adverse events rarely resulted in discontinuation from the study and were sometimes managed by dichlorphenamide dose reductions,” concluded Nicholas E. Johnson, MD, of Virginia Commonwealth University, Richmond, and colleagues. “Reduction in dose was frequently associated with resolution of these events, suggesting a potential intervention to hasten resolution.” Dr. Johnson presented the findings in an abstract at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine.

Dichlorphenamide (Keveyis) was approved by the Food and Drug Administration in 2015 for treating primary hyperkalemic and hypokalemic periodic paralysis and similar variants. The original hyperkalemic/hypokalemic PPP trial was a phase 3 randomized, double-blind, placebo-controlled trial that lasted 9 weeks and assessed the efficacy of dichlorphenamide in reducing PPP attacks and its adverse events. In the dichlorphenamide group, 47% experienced paresthesia, compared with 14% in the placebo group, and 19% experienced cognitive disorder, compared with 7% in the placebo.

In a 52-week open-label extension, participants who had been receiving the placebo switched to receiving 50 mg of dichlorphenamide twice daily. The intervention group continued with the dose they had been receiving when the 9-week double-blind phase ended. (During the initial intervention, they took either 50 mg twice daily or the dose they had at baseline for those taking it before the study began.)

The researchers then tracked rates of attacks and their severity over the next year – through week 61 after baseline – to compare these endpoints both within the intervention groups and between them.

Among the 63 predominantly white (84.1%) male (61.9%) adults who began the trial, 36 received dichlorphenamide and 27 received placebo. Just over two-thirds (68.3%) had hypokalemic PPP. Among the 47 patients (74.6%) who completed the open-label extension phase, 26 had been in the original dichlorphenamide group and 21 had been in the placebo group.

The median weekly attack rate in the dichlorphenamide group dropped from 1.75 at baseline to 0.06 at week 61 (median decrease 1.00, 93.8%; P less than .0001). In the placebo group that switched over to dichlorphenamide at week 9, the median weekly attack rate dropped from 3.00 at baseline to 0.25 at week 61 (median decrease 0.63, 75%; P = .01).

The median attack rate weighted for severity in the dichlorphenamide group dropped from 2.25 at baseline to 0.06 at week 61 (median decrease 2.25, 97.1%; P less than .0001). In the placebo group, it dropped from 5.88 to 0.50 (median decrease 1.69, 80.8%; P = .01).

No significant difference in median weekly attack rates and severity-weighted attack rates was found between the intervention groups through week 61.

Across all patients during the extension, 39.7% patients experienced at least one paresthesia adverse event, none of which were determined to be severe and resulting in one discontinuation.

A quarter of the participants (25.4%) experienced at least one cognition-related adverse event, and four patients (6.3%) discontinued because of these side effects. Most (14.3%) were mild with 7.9% reporting moderate and 3.2% reporting severe effects.

Dr. Johnson has received research support from or consulted with a variety of pharmaceutical companies including Strongbridge Biopharma, the manufacturer of the drug. Other authors consulted for several pharmaceutical companies, and one author is an employee of Strongbridge Biopharma.
 

SOURCE: Johnson NE et al. AANEM 2019. Abstract 102. Long-term efficacy and adverse event characterization of dichlorphenamide for the treatment of primary periodic paralysis.

AUSTIN, TEX. – Dichlorphenamide continues to reduce attacks from primary periodic paralysis (PPP) through 1 year with mild or moderate paresthesia and cognition-related adverse events, according to new research.

“These adverse events rarely resulted in discontinuation from the study and were sometimes managed by dichlorphenamide dose reductions,” concluded Nicholas E. Johnson, MD, of Virginia Commonwealth University, Richmond, and colleagues. “Reduction in dose was frequently associated with resolution of these events, suggesting a potential intervention to hasten resolution.” Dr. Johnson presented the findings in an abstract at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine.

Dichlorphenamide (Keveyis) was approved by the Food and Drug Administration in 2015 for treating primary hyperkalemic and hypokalemic periodic paralysis and similar variants. The original hyperkalemic/hypokalemic PPP trial was a phase 3 randomized, double-blind, placebo-controlled trial that lasted 9 weeks and assessed the efficacy of dichlorphenamide in reducing PPP attacks and its adverse events. In the dichlorphenamide group, 47% experienced paresthesia, compared with 14% in the placebo group, and 19% experienced cognitive disorder, compared with 7% in the placebo.

In a 52-week open-label extension, participants who had been receiving the placebo switched to receiving 50 mg of dichlorphenamide twice daily. The intervention group continued with the dose they had been receiving when the 9-week double-blind phase ended. (During the initial intervention, they took either 50 mg twice daily or the dose they had at baseline for those taking it before the study began.)

The researchers then tracked rates of attacks and their severity over the next year – through week 61 after baseline – to compare these endpoints both within the intervention groups and between them.

Among the 63 predominantly white (84.1%) male (61.9%) adults who began the trial, 36 received dichlorphenamide and 27 received placebo. Just over two-thirds (68.3%) had hypokalemic PPP. Among the 47 patients (74.6%) who completed the open-label extension phase, 26 had been in the original dichlorphenamide group and 21 had been in the placebo group.

The median weekly attack rate in the dichlorphenamide group dropped from 1.75 at baseline to 0.06 at week 61 (median decrease 1.00, 93.8%; P less than .0001). In the placebo group that switched over to dichlorphenamide at week 9, the median weekly attack rate dropped from 3.00 at baseline to 0.25 at week 61 (median decrease 0.63, 75%; P = .01).

The median attack rate weighted for severity in the dichlorphenamide group dropped from 2.25 at baseline to 0.06 at week 61 (median decrease 2.25, 97.1%; P less than .0001). In the placebo group, it dropped from 5.88 to 0.50 (median decrease 1.69, 80.8%; P = .01).

No significant difference in median weekly attack rates and severity-weighted attack rates was found between the intervention groups through week 61.

Across all patients during the extension, 39.7% patients experienced at least one paresthesia adverse event, none of which were determined to be severe and resulting in one discontinuation.

A quarter of the participants (25.4%) experienced at least one cognition-related adverse event, and four patients (6.3%) discontinued because of these side effects. Most (14.3%) were mild with 7.9% reporting moderate and 3.2% reporting severe effects.

Dr. Johnson has received research support from or consulted with a variety of pharmaceutical companies including Strongbridge Biopharma, the manufacturer of the drug. Other authors consulted for several pharmaceutical companies, and one author is an employee of Strongbridge Biopharma.
 

SOURCE: Johnson NE et al. AANEM 2019. Abstract 102. Long-term efficacy and adverse event characterization of dichlorphenamide for the treatment of primary periodic paralysis.

AUSTIN, TEX. – Dichlorphenamide continues to reduce attacks from primary periodic paralysis (PPP) through 1 year with mild or moderate paresthesia and cognition-related adverse events, according to new research.

“These adverse events rarely resulted in discontinuation from the study and were sometimes managed by dichlorphenamide dose reductions,” concluded Nicholas E. Johnson, MD, of Virginia Commonwealth University, Richmond, and colleagues. “Reduction in dose was frequently associated with resolution of these events, suggesting a potential intervention to hasten resolution.” Dr. Johnson presented the findings in an abstract at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine.

Dichlorphenamide (Keveyis) was approved by the Food and Drug Administration in 2015 for treating primary hyperkalemic and hypokalemic periodic paralysis and similar variants. The original hyperkalemic/hypokalemic PPP trial was a phase 3 randomized, double-blind, placebo-controlled trial that lasted 9 weeks and assessed the efficacy of dichlorphenamide in reducing PPP attacks and its adverse events. In the dichlorphenamide group, 47% experienced paresthesia, compared with 14% in the placebo group, and 19% experienced cognitive disorder, compared with 7% in the placebo.

In a 52-week open-label extension, participants who had been receiving the placebo switched to receiving 50 mg of dichlorphenamide twice daily. The intervention group continued with the dose they had been receiving when the 9-week double-blind phase ended. (During the initial intervention, they took either 50 mg twice daily or the dose they had at baseline for those taking it before the study began.)

The researchers then tracked rates of attacks and their severity over the next year – through week 61 after baseline – to compare these endpoints both within the intervention groups and between them.

Among the 63 predominantly white (84.1%) male (61.9%) adults who began the trial, 36 received dichlorphenamide and 27 received placebo. Just over two-thirds (68.3%) had hypokalemic PPP. Among the 47 patients (74.6%) who completed the open-label extension phase, 26 had been in the original dichlorphenamide group and 21 had been in the placebo group.

The median weekly attack rate in the dichlorphenamide group dropped from 1.75 at baseline to 0.06 at week 61 (median decrease 1.00, 93.8%; P less than .0001). In the placebo group that switched over to dichlorphenamide at week 9, the median weekly attack rate dropped from 3.00 at baseline to 0.25 at week 61 (median decrease 0.63, 75%; P = .01).

The median attack rate weighted for severity in the dichlorphenamide group dropped from 2.25 at baseline to 0.06 at week 61 (median decrease 2.25, 97.1%; P less than .0001). In the placebo group, it dropped from 5.88 to 0.50 (median decrease 1.69, 80.8%; P = .01).

No significant difference in median weekly attack rates and severity-weighted attack rates was found between the intervention groups through week 61.

Across all patients during the extension, 39.7% patients experienced at least one paresthesia adverse event, none of which were determined to be severe and resulting in one discontinuation.

A quarter of the participants (25.4%) experienced at least one cognition-related adverse event, and four patients (6.3%) discontinued because of these side effects. Most (14.3%) were mild with 7.9% reporting moderate and 3.2% reporting severe effects.

Dr. Johnson has received research support from or consulted with a variety of pharmaceutical companies including Strongbridge Biopharma, the manufacturer of the drug. Other authors consulted for several pharmaceutical companies, and one author is an employee of Strongbridge Biopharma.
 

SOURCE: Johnson NE et al. AANEM 2019. Abstract 102. Long-term efficacy and adverse event characterization of dichlorphenamide for the treatment of primary periodic paralysis.

AUSTIN, TEX. – Patients with Charcot-Marie-Tooth disease (CMT) receive a range of supportive care that includes physical therapy, surgery, medications, orthoses, and walking aids, according to patient-reported data presented at the annual meeting of the American Association of Neuromuscular and Electrodiagnostic Medicine. Patients describe approaches to CMT management that are broadly consistent with guidelines, researchers said.

“The range of different CMT treatments was wide,” reported Tjalf Ziemssen, MD, PhD, a researcher at Technische Universität Dresden in Germany, and colleagues. “Of note, high proportions of respondents had received pain medication, and a relatively high number had also visited pain specialists. These results indicate that pain may have a substantial impact on people with CMT.”

The data also suggest that “lower-limb problems and mobility issues have a considerable impact on people with CMT,” they said.

CMT is a rare, progressive neuropathy that leads to distal muscle weakness, muscle atrophy, and sensory loss. There is no cure, and patients rely on supportive care. Until recently, few studies have assessed the impact of CMT on patients’ lives.

An ongoing, international, 2-year observational study is collecting data from adults with CMT. Patients report data via an app called CMT & Me.

To examine patient-reported treatment patterns and care standards for CMT in the United States and the United Kingdom, Dr. Ziemssen and colleagues analyzed data through Aug. 5, 2019, about 9.5 months into the study. Their interim analysis included data from 439 patients, including 222 patients in the United Kingdom and 217 in the United States.

More than 70% of participants visit a family doctor each year, and a similar proportion visit a neurologist. About 40% visit physical therapists, orthotists, or podiatrists. Other health care professionals seen by patients include occupational therapists (20%), orthopedic surgeons (nearly 20%), and pain specialists (about 15%).

About 70% of participants had received rehabilitation therapy such as physical therapy or occupational therapy, and about 70% had used medications, most frequently nonopioid analgesics (about 50%) and antidepressants (about 30%).

More than 80% used orthoses or walking aids, most commonly ankle or leg braces, insoles, or walking sticks.

In addition, about half of respondents had undergone a surgery for CMT. The most common procedures were osteotomy, hammertoe correction, and plantar fascia release.

Together, patients saw about a dozen types of health care professionals. “Small proportions of participants had visited each professional, which suggests that the care requirements of CMT patients are varied,” the researchers said.

The study was sponsored by Pharnext. Dr. Ziemssen and coauthors received compensation for participating in the study. Other coauthors are employees of Pharnext or Vitaccess, the company that developed the app used in the study.

jremaly@mdedge.com

SOURCE: Ziemssen T et al. AANEM 2019. Abstract 83. Treatment of Charcot-Marie-Tooth Disease in the United Kingdom and United States.

AUSTIN, TEX. – Patients with Charcot-Marie-Tooth disease (CMT) receive a range of supportive care that includes physical therapy, surgery, medications, orthoses, and walking aids, according to patient-reported data presented at the annual meeting of the American Association of Neuromuscular and Electrodiagnostic Medicine. Patients describe approaches to CMT management that are broadly consistent with guidelines, researchers said.

“The range of different CMT treatments was wide,” reported Tjalf Ziemssen, MD, PhD, a researcher at Technische Universität Dresden in Germany, and colleagues. “Of note, high proportions of respondents had received pain medication, and a relatively high number had also visited pain specialists. These results indicate that pain may have a substantial impact on people with CMT.”

The data also suggest that “lower-limb problems and mobility issues have a considerable impact on people with CMT,” they said.

CMT is a rare, progressive neuropathy that leads to distal muscle weakness, muscle atrophy, and sensory loss. There is no cure, and patients rely on supportive care. Until recently, few studies have assessed the impact of CMT on patients’ lives.

An ongoing, international, 2-year observational study is collecting data from adults with CMT. Patients report data via an app called CMT & Me.

To examine patient-reported treatment patterns and care standards for CMT in the United States and the United Kingdom, Dr. Ziemssen and colleagues analyzed data through Aug. 5, 2019, about 9.5 months into the study. Their interim analysis included data from 439 patients, including 222 patients in the United Kingdom and 217 in the United States.

More than 70% of participants visit a family doctor each year, and a similar proportion visit a neurologist. About 40% visit physical therapists, orthotists, or podiatrists. Other health care professionals seen by patients include occupational therapists (20%), orthopedic surgeons (nearly 20%), and pain specialists (about 15%).

About 70% of participants had received rehabilitation therapy such as physical therapy or occupational therapy, and about 70% had used medications, most frequently nonopioid analgesics (about 50%) and antidepressants (about 30%).

More than 80% used orthoses or walking aids, most commonly ankle or leg braces, insoles, or walking sticks.

In addition, about half of respondents had undergone a surgery for CMT. The most common procedures were osteotomy, hammertoe correction, and plantar fascia release.

Together, patients saw about a dozen types of health care professionals. “Small proportions of participants had visited each professional, which suggests that the care requirements of CMT patients are varied,” the researchers said.

The study was sponsored by Pharnext. Dr. Ziemssen and coauthors received compensation for participating in the study. Other coauthors are employees of Pharnext or Vitaccess, the company that developed the app used in the study.

jremaly@mdedge.com

SOURCE: Ziemssen T et al. AANEM 2019. Abstract 83. Treatment of Charcot-Marie-Tooth Disease in the United Kingdom and United States.

AUSTIN, TEX. – Patients with Charcot-Marie-Tooth disease (CMT) receive a range of supportive care that includes physical therapy, surgery, medications, orthoses, and walking aids, according to patient-reported data presented at the annual meeting of the American Association of Neuromuscular and Electrodiagnostic Medicine. Patients describe approaches to CMT management that are broadly consistent with guidelines, researchers said.

“The range of different CMT treatments was wide,” reported Tjalf Ziemssen, MD, PhD, a researcher at Technische Universität Dresden in Germany, and colleagues. “Of note, high proportions of respondents had received pain medication, and a relatively high number had also visited pain specialists. These results indicate that pain may have a substantial impact on people with CMT.”

The data also suggest that “lower-limb problems and mobility issues have a considerable impact on people with CMT,” they said.

CMT is a rare, progressive neuropathy that leads to distal muscle weakness, muscle atrophy, and sensory loss. There is no cure, and patients rely on supportive care. Until recently, few studies have assessed the impact of CMT on patients’ lives.

An ongoing, international, 2-year observational study is collecting data from adults with CMT. Patients report data via an app called CMT & Me.

To examine patient-reported treatment patterns and care standards for CMT in the United States and the United Kingdom, Dr. Ziemssen and colleagues analyzed data through Aug. 5, 2019, about 9.5 months into the study. Their interim analysis included data from 439 patients, including 222 patients in the United Kingdom and 217 in the United States.

More than 70% of participants visit a family doctor each year, and a similar proportion visit a neurologist. About 40% visit physical therapists, orthotists, or podiatrists. Other health care professionals seen by patients include occupational therapists (20%), orthopedic surgeons (nearly 20%), and pain specialists (about 15%).

About 70% of participants had received rehabilitation therapy such as physical therapy or occupational therapy, and about 70% had used medications, most frequently nonopioid analgesics (about 50%) and antidepressants (about 30%).

More than 80% used orthoses or walking aids, most commonly ankle or leg braces, insoles, or walking sticks.

In addition, about half of respondents had undergone a surgery for CMT. The most common procedures were osteotomy, hammertoe correction, and plantar fascia release.

Together, patients saw about a dozen types of health care professionals. “Small proportions of participants had visited each professional, which suggests that the care requirements of CMT patients are varied,” the researchers said.

The study was sponsored by Pharnext. Dr. Ziemssen and coauthors received compensation for participating in the study. Other coauthors are employees of Pharnext or Vitaccess, the company that developed the app used in the study.

jremaly@mdedge.com

SOURCE: Ziemssen T et al. AANEM 2019. Abstract 83. Treatment of Charcot-Marie-Tooth Disease in the United Kingdom and United States.

AUSTIN – Lack of upper motor neuron signs on examination, presence of sensory symptoms, and absence of tongue fasciculations are common causes of amyotrophic lateral sclerosis (ALS) misdiagnosis, according to an investigation presented at the annual meeting of the American Association of Neuromuscular and Electrodiagnostic Medicine.

designer491/Thinkstock

Because its initial presenting symptoms vary, ALS can be difficult for clinicians to diagnose. A diagnostic error may prompt clinicians and patients to pursue ineffective and potentially harmful medical or surgical interventions. Research suggests that surgery, for example, hastens the progression of ALS.

Catherine Rodriguez, a medical student at University of Missouri in Columbia, and colleagues conducted a study to identify the clinical factors and types of cognitive errors that can result in misdiagnosis of ALS. The researchers analyzed electronic medical records of 88 patients with a diagnosis of ALS who were receiving treatment at the University of Missouri Hospital during 2011-2017 with at least 1 year of follow-up. They collected demographic information and clinical characteristics (e.g., ALS Functional Rating Scale and site of symptom onset) for each patient. If a patient received an incorrect diagnosis, Ms. Rodriguez and colleagues recorded the number of physicians he or she had seen, the incorrect diagnosis, the treatment, the type of diagnostic error, the clinical factors contributing to the misdiagnosis, and the type of physician who gave the incorrect diagnosis.

The investigators classed diagnostic errors according to the four categories of cognitive bias of the Patient Safety Network. The categories are availability heuristic (i.e., the diagnosis of a current patient is biased by the clinician’s experience with previous cases), anchoring heuristic (i.e., relying on the initial impression despite the emergence of evidence that may contradict it), framing effects (i.e., subtle cues and collateral information bias the diagnosis), and blind obedience (i.e., undue reliance on test results or expert opinion). Ms. Rodriguez and colleagues used Fisher’s exact test to perform a statistical analysis of the data.

Thirty-four (39%) of the 88 patients were female, and the populations average age was about 60 years. Eighty patients (91%) were white, six (7%) were black, and two (2%) were Hispanic. Twenty patients (23%) received an incorrect diagnosis. Common incorrect diagnoses included spinal abnormality, Bell’s palsy, myasthenia gravis, ulnar neuropathy, autoimmune motor neuropathy, and stroke.

The investigators observed significant differences in the reasons for misdiagnosis, depending on patient characteristics. Veterans were misdiagnosed because of the availability heuristic, while nonveterans were misdiagnosed because of the anchoring heuristic. Lower-limb onset was most commonly misdiagnosed because of the anchoring heuristic. Bulbar onset was most commonly misdiagnosed because of the availability heuristic. Surgical intervention was the most common treatment for an incorrect diagnosis.

The data serve as a reminder of the prevalence of cognitive biases, said Ms. Rodriguez. “Common things are common, so we tend to stick with those [diagnoses]. Especially with ALS, nobody wants to give anyone that diagnosis.” Clinicians should “recognize that incorrect diagnoses have equally bad outcomes for those patients,” she concluded.

The study was supported by a University of Missouri School of Medicine Summer Research Fellowship Program.

egreb@mdedge.com

SOURCE: Rodriguez C et al. AANEM 2019. Abstract 10. Diagnostic errors and the implications for amyotrophic lateral sclerosis patients.

AUSTIN – Lack of upper motor neuron signs on examination, presence of sensory symptoms, and absence of tongue fasciculations are common causes of amyotrophic lateral sclerosis (ALS) misdiagnosis, according to an investigation presented at the annual meeting of the American Association of Neuromuscular and Electrodiagnostic Medicine.

designer491/Thinkstock

Because its initial presenting symptoms vary, ALS can be difficult for clinicians to diagnose. A diagnostic error may prompt clinicians and patients to pursue ineffective and potentially harmful medical or surgical interventions. Research suggests that surgery, for example, hastens the progression of ALS.

Catherine Rodriguez, a medical student at University of Missouri in Columbia, and colleagues conducted a study to identify the clinical factors and types of cognitive errors that can result in misdiagnosis of ALS. The researchers analyzed electronic medical records of 88 patients with a diagnosis of ALS who were receiving treatment at the University of Missouri Hospital during 2011-2017 with at least 1 year of follow-up. They collected demographic information and clinical characteristics (e.g., ALS Functional Rating Scale and site of symptom onset) for each patient. If a patient received an incorrect diagnosis, Ms. Rodriguez and colleagues recorded the number of physicians he or she had seen, the incorrect diagnosis, the treatment, the type of diagnostic error, the clinical factors contributing to the misdiagnosis, and the type of physician who gave the incorrect diagnosis.

The investigators classed diagnostic errors according to the four categories of cognitive bias of the Patient Safety Network. The categories are availability heuristic (i.e., the diagnosis of a current patient is biased by the clinician’s experience with previous cases), anchoring heuristic (i.e., relying on the initial impression despite the emergence of evidence that may contradict it), framing effects (i.e., subtle cues and collateral information bias the diagnosis), and blind obedience (i.e., undue reliance on test results or expert opinion). Ms. Rodriguez and colleagues used Fisher’s exact test to perform a statistical analysis of the data.

Thirty-four (39%) of the 88 patients were female, and the populations average age was about 60 years. Eighty patients (91%) were white, six (7%) were black, and two (2%) were Hispanic. Twenty patients (23%) received an incorrect diagnosis. Common incorrect diagnoses included spinal abnormality, Bell’s palsy, myasthenia gravis, ulnar neuropathy, autoimmune motor neuropathy, and stroke.

The investigators observed significant differences in the reasons for misdiagnosis, depending on patient characteristics. Veterans were misdiagnosed because of the availability heuristic, while nonveterans were misdiagnosed because of the anchoring heuristic. Lower-limb onset was most commonly misdiagnosed because of the anchoring heuristic. Bulbar onset was most commonly misdiagnosed because of the availability heuristic. Surgical intervention was the most common treatment for an incorrect diagnosis.

The data serve as a reminder of the prevalence of cognitive biases, said Ms. Rodriguez. “Common things are common, so we tend to stick with those [diagnoses]. Especially with ALS, nobody wants to give anyone that diagnosis.” Clinicians should “recognize that incorrect diagnoses have equally bad outcomes for those patients,” she concluded.

The study was supported by a University of Missouri School of Medicine Summer Research Fellowship Program.

egreb@mdedge.com

SOURCE: Rodriguez C et al. AANEM 2019. Abstract 10. Diagnostic errors and the implications for amyotrophic lateral sclerosis patients.

AUSTIN – Lack of upper motor neuron signs on examination, presence of sensory symptoms, and absence of tongue fasciculations are common causes of amyotrophic lateral sclerosis (ALS) misdiagnosis, according to an investigation presented at the annual meeting of the American Association of Neuromuscular and Electrodiagnostic Medicine.

designer491/Thinkstock

Because its initial presenting symptoms vary, ALS can be difficult for clinicians to diagnose. A diagnostic error may prompt clinicians and patients to pursue ineffective and potentially harmful medical or surgical interventions. Research suggests that surgery, for example, hastens the progression of ALS.

Catherine Rodriguez, a medical student at University of Missouri in Columbia, and colleagues conducted a study to identify the clinical factors and types of cognitive errors that can result in misdiagnosis of ALS. The researchers analyzed electronic medical records of 88 patients with a diagnosis of ALS who were receiving treatment at the University of Missouri Hospital during 2011-2017 with at least 1 year of follow-up. They collected demographic information and clinical characteristics (e.g., ALS Functional Rating Scale and site of symptom onset) for each patient. If a patient received an incorrect diagnosis, Ms. Rodriguez and colleagues recorded the number of physicians he or she had seen, the incorrect diagnosis, the treatment, the type of diagnostic error, the clinical factors contributing to the misdiagnosis, and the type of physician who gave the incorrect diagnosis.

The investigators classed diagnostic errors according to the four categories of cognitive bias of the Patient Safety Network. The categories are availability heuristic (i.e., the diagnosis of a current patient is biased by the clinician’s experience with previous cases), anchoring heuristic (i.e., relying on the initial impression despite the emergence of evidence that may contradict it), framing effects (i.e., subtle cues and collateral information bias the diagnosis), and blind obedience (i.e., undue reliance on test results or expert opinion). Ms. Rodriguez and colleagues used Fisher’s exact test to perform a statistical analysis of the data.

Thirty-four (39%) of the 88 patients were female, and the populations average age was about 60 years. Eighty patients (91%) were white, six (7%) were black, and two (2%) were Hispanic. Twenty patients (23%) received an incorrect diagnosis. Common incorrect diagnoses included spinal abnormality, Bell’s palsy, myasthenia gravis, ulnar neuropathy, autoimmune motor neuropathy, and stroke.

The investigators observed significant differences in the reasons for misdiagnosis, depending on patient characteristics. Veterans were misdiagnosed because of the availability heuristic, while nonveterans were misdiagnosed because of the anchoring heuristic. Lower-limb onset was most commonly misdiagnosed because of the anchoring heuristic. Bulbar onset was most commonly misdiagnosed because of the availability heuristic. Surgical intervention was the most common treatment for an incorrect diagnosis.

The data serve as a reminder of the prevalence of cognitive biases, said Ms. Rodriguez. “Common things are common, so we tend to stick with those [diagnoses]. Especially with ALS, nobody wants to give anyone that diagnosis.” Clinicians should “recognize that incorrect diagnoses have equally bad outcomes for those patients,” she concluded.

The study was supported by a University of Missouri School of Medicine Summer Research Fellowship Program.

egreb@mdedge.com

SOURCE: Rodriguez C et al. AANEM 2019. Abstract 10. Diagnostic errors and the implications for amyotrophic lateral sclerosis patients.