relevant disclosures “what’s new in neurology?”€¦ · meta-analysis of rcts suggested dapt...
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“What’s New in Neurology?”MEGAN RICHIE, MD
ASSISTANT PROFESSOR OF NEUROLOGY
Relevant DisclosuresNone
OutlineStroke
◦ Acute treatment◦ Prophylaxis◦ Intracranial hemorrhage
Epilepsy◦ First-line medications◦ Epilepsy surgery
Multiple sclerosis◦ New treatment options◦ Avoiding progression
Potpourri◦ Neuropathic pain◦ Parkinson’s disease◦ Cognitive decline◦ Lyme disease
Acute strokeDAWN Trial
Inclusion criteria◦ ICA or proximal MCA occlusion
◦ Last known well 6 – 24 hours earlier◦ Mismatch between clinical exam and infarct volume
Randomized Intervention◦ Thrombectomy + standard care◦ Standard care alone
Results◦ Terminated early due to efficacy
◦ Less disability and higher independence with thrombectomy
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Acute strokeDEFUSE-3 Trial
Inclusion criteria
◦ ICA or proximal MCA occlusion
◦ Last known well 6 – 16 hours earlier
◦ Perfusion: Small infarct size, high adjacent at-risk territory
Randomized Intervention
◦ Thrombectomy + standard care
◦ Standard care alone
Results
◦ Terminated early due to efficacy
◦ Lower mortality, less disability and higher independence with thrombectomy
Acute strokeWAKE-UP Trial
Inclusion criteria◦ Unknown time of onset◦ Particular MRI appearance
◦ Ischemic lesion on diffusion without T2 hyperintensity
Randomized intervention◦ Intravenous alteplase◦ Placebo
Results◦ Terminated early due to cessation of funding◦ More favorable outcomes and lower disability with alteplase◦ More hemorrhage with alteplase
Acute stroke: Take-homesØMore options available > 6 hours into symptoms
ØSend patients for emergent evaluation if < 24 hours
ØEducate patients & families regarding symptoms of acute stroke and importance of emergent care
After the Stroke: Prophylaxis
POINT trial
Inclusion criteria◦ Minor ischemic stroke or high-risk TIA
Randomized intervention◦ Clopidogrel + Aspirin◦ Aspirin alone
Results◦ Terminated early due to efficacy◦ Dual antiplatelet therapy (DAPT) with lower ischemic events and higher
hemorrhage◦ Meta-analysis of RCTs suggested DAPT within 24 hours reduced risk of recurrent stroke primarily
within the first 21 days
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After the Stroke: Risk factors
Post Hoc analysis of IRIS trial
Inclusion criteria◦ Prior stroke or TIA + insulin resistance (not diabetes)
◦ Prediabetes: Hgb A1c 5.7-6.4% or fasting BG 100-125 mg/dL
Randomized intervention◦ Pioglitazone ◦ Placebo
Results◦ Reduced risk of stroke, MI, progression to diabetes◦ Increase in bone fractures, weight, edema
After the Stroke: Take-homesØDual antiplatelet therapy after minor stroke/TIA for 21-30
days (POINT Trial)
ØTreat patients with prediabetes
ØHgb a1c 5.7 – 6.4 or Fasting BG 100-125
◦ Pioglitazone is one – but perhaps not the only – option
Hemorrhagic Stroke: Unruptured aneurysms
Risk of unruptured aneurysm repair: Meta-analysis of 74 studies
Endovascular therapy◦ 30-day complications 4.96%◦ Fatality 0.3%
Neurosurgical therapy◦ 30-day complications 8.34%◦ Fatality 0.1%
Decision model◦ Comparing management strategies
◦ Incidental ≤ 3mm aneurysms
Outcome◦ Quality-adjusted life years (QALYs)
Results◦ No follow-up was associated with highest
number of QALYs
◦ MRA every 5 years had second highest number of QALYs
Management strategies for tiny incidental aneurysms
Hemorrhagic Stroke: Unrupturedaneurysms
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Hemorrhagic Stroke: DOAC reversalInclusion criteria
◦ Acute major bleeding
◦ Factor Xa inhibitor within 18 hours
Intervention◦ Bolus à Infusion of Andexanet
Results◦ Intracranial (64%), gastrointestinal (26%) ◦ Reductions in median anti-factor Xa activity
◦ Modestly predictive of hemostatic efficacy in patients with ICH
◦ Excellent or good hemostasis at 12 hours: 82%◦ 30-day thrombotic events: 10%
Hemorrhagic Strokes: Take-homesØSmall aneurysms have very low risk of growing and rupturing◦ Repair is not benign◦ Preferred no follow-up, or at the most MRA every 5 years
ØDirect Oral Anticoagulants now have an FDA-approved reversal agent: Andexanet
Epilepsy: HistoryPrior to 2004, only 6 major antiepileptic drugs (AEDs) available for epilepsy treatment
◦ Carbamazepine◦ Phenytoin
◦ Valproic acid◦ Phenobarbital
◦ Primidone◦ Ethosuxamide (absence seizures)
Significant drawbacks associated with these AEDs◦ Enzyme-inducers
◦ Side-effect ridden
Epilepsy: History continuedIn 2004, AAN investigated 7 new AEDs for treatment of new-onset epilepsy, adding 4 options
◦ Lamotrigine◦ Gabapentin◦ Oxcarbazepine◦ Topiramate
Insufficient evidence to recommend◦ Levetiracetam◦ Tiagabine◦ Zonisamide
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Epilepsy: First-line update
New 2018 AAN guidelines◦ Lamotrigine Probably effective
◦ Including in patients aged > 60 years
◦ Levetiracetam Possibly effective
◦ Zonisamide Possibly effective
◦ Gabapentin Possibly effective age > 60 years
No change◦ Oxcarbazepine: Established as effective
Epilepsy: First-line take-homesEstablished optionsCarbamazepine prior to ‘04Phenytoin prior to ‘04Valproic acid prior to ‘04Oxcarbazepine in 2004Topiramate in 2004(Phenobarbital) (prior to ’04)
2018: New optionLamotrigine
Less certain options includeLevetiracetamZonisamideGabapentin
Epilepsy surgery: Works in children
Inclusion criteria◦ < 18 years◦ Drug-resistant epilepsy
Randomized Intervention◦ Epilepsy surgery◦ Medical therapy
Results◦ Seizure freedom higher in surgical group◦ Better scores in behavior and quality of life in surgical group
Epilepsy surgery: Works in adultsInclusion criteria
◦ Anterior temporal lobectomy
◦ 5 years of follow up
Intervention
◦ Antiepileptic drug (AED) withdrawal
Results
◦ 84.9% attempted to withdrew at least one AED
◦ 72.8% of these remained seizure free
◦ After recurrence, 86% of these later achieved seizure freedom
◦ AED-free, seizure-free in 54% of the entire population
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Epilepsy surgery: When to referØMedically refractory epilepsy: Traditional
◦ Therapeutic failure of 3 antiseizure drugs
ØMedically refractory epilepsy: Currently◦ Therapeutic failure of 2 antiseizure drugs◦ Seizures uncontrolled at 12 months
ØEncourage epilepsy center evaluation
Multiple Sclerosis: Quick reminder
Relapsing-remitting Secondary progressive
Primary progressive
Relapsing-Remitting Multiple Sclerosis: Disease-modifying therapy (DMTs)
Class of DMT Advantages Disadvantages RisksInjectable• Glatiramer
acetate• Interferons
EstablishedSafety profile
Less effectiveInjection route
Flu-like symptomsInjection site necrosisLeukopeniaTransaminitis
Oral• Dimethyl
fumarate• Teriflunomide*• Fingolimod*
Self-administered*Highly effective
*Safety Dimethyl fumarate: GI symptoms, lymphopenia, LFTsTeriflunomide : Teratogen, hair loss, GI symptoms, LFTsFingolimod: Arrhythmia, macular edema, skin cancer, LFTs, PML, other infections
**
*
Infusion• Natalizumab• Ocrelizumab• Alemtuzumab• Rituximab
*Highly effective SafetyNew
Natalizumab : PML, sx rebound Ocrelizumab : HBV activationAlemtuzumab : Infections, autoimmune diseaseRituximab: PML?
Primary progressive Multiple sclerosis
ORATORIO Trial
Inclusion criteria◦ Primary progressive multiple sclerosis patients
Randomized Intervention◦ Ocrelizumab◦ Placebo
Results◦ Reduced disability progression at 12 and 24 weeks◦ Reduced brain lesions and volume loss on MRI◦ More infusion reactions, URIs, oral herpes infections
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Secondary progressive Multiple sclerosisEXPAND Trial
Inclusion criteria◦ Secondary progressive multiple sclerosis patients
Randomized Intervention◦ Simponimod◦ Placebo
Results◦ Reduced risk of disability progression◦ More lymphopenia, transaminase elevation, bradycardia, bradyarrhythmia,
macular edema, hypertension, varicella zoster reactivation, convulsions
Avoiding Secondary Progression
Inclusion criteria◦ Relapsing-remitting MS patient◦ Beginning disease-modifying therapy◦ 4+ years of followup
Exposures◦ Interferon beta◦ Glatiramer acetate◦ Fingolimod◦ Natalizumab◦ Alemtuzumab
Results◦ Conversion to SPMS lower with early highly-effective therapy
Injectable
Highly-effective
New MS therapies: Stem Cell Transplant
Inclusion criteria◦ Relapsing remitting MS◦ At least 2 relapses on DMT◦ Disability score 2-6
Randomized Intervention◦ Stem cell transplant + cyclophosphamide + ATG◦ DMT of higher efficacy or different mechanism than prior
Results◦ Dramatically reduced disease progression in SCT◦ More short-term infections in SCT
Multiple Sclerosis: Take-homesØExpanding armamentarium for Relapsing-Remitting multiple sclerosis◦ B-cell therapies are promising
ØNew approved therapies exist for:◦ Primary progressive multiple sclerosis◦ Secondary progressive multiple sclerosis
ØUse (or escalate to) highly effective therapy early in disease to reduce progression to SPMS
ØStem cell transplant: emerging therapy but not ready for prime time
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OutlineStroke
◦ Acute treatment◦ Prophylaxis◦ Intracranial hemorrhage
Epilepsy◦ First-line medications◦ Epilepsy surgery
Multiple sclerosis◦ New treatment options◦ Avoiding progression
Potpourri◦ Neuropathic pain◦ Parkinson’s disease◦ Cognitive decline◦ Lyme disease
Neuropathic PainGabapentinoid use markedly increasing àReview of placebo-controlled RCTs
FDA approved indications◦ Gabapentin: postherpetic neuralgia
◦ Pregabalin: postherpetic neuralgia, diabetic neuropathy, spinal cord injury, fibromyalgia
Minimal or no evidence for◦ Low back pain◦ Sciatica
◦ Acute zoster pain◦ Traumatic nerve injury
◦ Complex regional pain syndrome◦ Burn injury◦ Sickle cell
Gabapentinoids: Take-homesØFew FDA-approved indications
◦ Modestly effective
ØSide effects◦ Dizziness, somnolence, gait disturbance◦ Use with opioids associated with increased odds of opioid-related death
ØAlternative therapies to opioids needed, but gabapentinoidslikely not the answer◦ Comprehensive pain management program
Parkinson’s diseaseInclusion criteria
◦ Early Parkinson’s disease
Randomized intervention◦ Levodopa + Carbidopa◦ Placebo à Levodopa + Carbidopa (delayed start)
Outcome◦ Score on Parkinson’s disease rating scale (UPDRS)
Results◦ No significant difference after 80 weeks
◦ But Levodopa was safe – motor complications not accelerated
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Deep brain stimulation indications
Movement-disorder approved indications◦ Essential tremor◦ Parkinson’s disease◦ Isolated dystonia
Off label indications◦ Tardive dystonia◦ Secondary dystonia◦ Tourette syndrome◦ Orthostatic tremor◦ Holmes tremor◦ Musician’s dystonia ( )Other approved
indications◦ Obsessive
compulsive disorder
◦ Epilepsy
CognitionInclusion criteria
◦ Cognitively normal adults ◦ Aged 20-67 years
Randomized Intervention◦ 4 x weekly aerobic exercise to target HR◦ 4 x weekly stretching / toning
Results◦ Aerobic exercise associated with increase in aerobic capacity, cortical thickness,
executive function (moderated by age)◦ Aerobic exercise associated with reduction in BMI
Lyme diseasePLEASE study secondary analysis
Inclusion criteria◦ B. burgdorferi antibodies OR linked to proven symptomatic Lyme
◦ Persistent symptoms (pain, sensory or cognitive symptoms)
Randomized Intervention ◦ Two weeks IV ceftriaxone and then …
◦ 12 weeks of doxycycline
◦ 12 weeks of clarithromycin/hydroxychloroquine
◦ 12 weeks of placebo
Results◦ No difference in cognitive performance at 14, 26, or 40 weeks
Potpourri: Take-homesØNo need for “Levodopa sparing” in Parkinson’s disease
ØIndications for deep brain stimulation slowly expanding
ØFurther evidence for benefit of aerobic exercise in cognitive functioning
ØProlonged antibiotics of no benefit in cognitive symptoms after Lyme disease
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Summary of Key PointsStroke
◦ Acute interventions within 24 hours◦ Treat prediabetes◦ Dual antiplatelet therapy x 21-30 days◦ Reversal agent for DOACs◦ Aneurysms ≤ 3mm are benign
Epilepsy◦ First-line medications (≠ Levetiracetam)◦ Epilepsy surgery works
Multiple sclerosis◦ Emerging B-cell therapies◦ New treatment options for PPMS, SPMS
Potpourri◦ Gabapentin isn’t a panacea◦ Levodopa is safe in Parkinson’s disease◦ Aerobic exercise benefits cognition◦ No prolonged antibiotics for Lyme
Questions?
References (1 of 2)Albers GW et al (DEFUSE 3 Investigators). Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. N Engl J Med. 2018 Feb 22;378(8):708-718
Algra AM et al. Procedural Clinical Complications, Case-Fatality Risks, and Risk Factors in Endovascular and Neurosurgical Treatment of Unruptured Intracranial Aneurysms: A Systematic Review and Meta-analysis. JAMA Neurol. 2018 Dec 28.
Brown JWL et al. (MSBase study group). Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis. JAMA. 2019 Jan 15;321(2):175-187.
Burk RK et al. Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial. JAMA. 2019 Jan 15;321(2):165-174.
Connolly SJ et al (ANNEXA-4 Investigators). Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2019 Apr 4;380(14):1326-1335.
Dwivedi R et al. Surgery for Drug-Resistant Epilepsy in Children. N Engl J Med. 2017 Oct 26;377(17):1639-1647
Goodman CW, Brett AS. A Clinical Overview of Off-label Use of Gabapentinoid Drugs. JAMA Intern Med. 2019 Mar 25.
Hao Q et al. Clopidogrel plus aspirin versus aspirin alone for acute minor ischaemic stroke or high risk transient ischaemic attack: systematic review and meta-analysis. BMJ. 2018 Dec 18;363.
Johnston SC et al. (POINT Investigators). Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. N Engl J Med. 2018 Jul 19;379(3):215-225.
References (2 of 2)Kappos L et al. (EXPAND Clinical Investigators). Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018 Mar 31;391(10127):1263-1273.
Malhotra A et al. Management of Tiny Unruptured Intracranial Aneurysms: A Comparative Effectiveness Analysis. JAMA Neurol. 2018 Jan 1;75(1):27-34.
Montalban X et al. (ORATORIO Clinical Investigators). Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017 Jan 19;376(3):209-220.
Nogueira RG et al. (DAWN Trial Investigators). Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. N Engl J Med. 2018 Jan 4;378(1):11-21
Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2018 Dec 11;91(24):1117
Rathore C et al. Outcome after seizure recurrence on antiepileptic drug withdrawal following temporal lobectomy. Neurology 2018 Jul 17;91(3).
Spense JD et al. (IRIS Investigators). Pioglitazone Therapy in Patients With Stroke and Prediabetes: A Post Hoc Analysis of the IRIS Randomized Clinical Trial. JAMA Neurol. 2019 Feb 7
Stern Y et al. Effect of aerobic exercise on cognition in younger adults: A randomized clinical trial. Neurology. 2019 Feb 26;92(9)
Thomalla G et al. (WAKE-UP Investigators). MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset. N Engl J Med. 2018 Aug 16;379(7):611-622.
Verschuur CVM et al. (LEAP Study Group). Randomized Delayed-Start Trial of Levodopa in Parkinson's Disease. N Engl J Med. 2019 Jan 24;380(4):315-324