Relevant Disclosures “What’s New in Neurology?”€¦ · Meta-analysis of RCTs suggested DAPT within 24 hours reduced risk of recurrent stroke primarily within the first 21 days

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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