UCSF: Advances in Internal Medicine · 2019 Advances in Internal Medicine: Updates in Neurology....

Megan Richie, MDAssistant Professor of Neurology

UCSF: Advances in Internal Medicine2020: “What’s New in Neurology?”

I have no relevant financial relationships with any companies related to the content of this course.

2019 Advances in Internal Medicine: Updates in NeurologySelect Take-homes: Multiple Sclerosis

Expanding armamentarium for Relapsing-Remitting multiple sclerosis: B-cell therapies

New approved therapies exist for:- Primary progressive multiple sclerosis- Secondary progressive multiple sclerosis

Use (or escalate to) highly effective therapy early in disease to reduce progression to SPMS

Stem cell transplant: emerging, but not ready for prime time

The list of first-line AEDs is shorter than you think- Before 2004: Carbamazepine, Phenytoin, Valproic acid, Phenobarbital,

Primidone, Ethosuxamide (absence seizures)- 2004: Oxcarbazepine, Topiramate- 2018: Lamotrigine- Levetiracetam, Zonisamide and Gabapentin are only “possibly effective”

Epilepsy surgery is effective in children and adults and should be considered in refractory epilepsy- Traditional definition: Therapeutic failure of 3 antiseizure drugs- Current definition: Therapeutic failure of 2 antiseizure drugs OR seizures

uncontrolled at 12 months- Encourage epilepsy center evaluation

2019 Advances in Internal Medicine: Updates in NeurologySelect Take-homes: Epilepsy

No need for “Levodopa sparing” in Parkinson’s disease

Indications for deep brain stimulation slowly expanding

Increasing evidence for benefit of aerobic exercise in cognitive functioning

Prolonged antibiotics of no benefit in cognitive symptoms after Lyme disease

Gabapentinoids have few FDA-approved indications, significant side effects, and are not a panacea alternative to opioids

2019 Advances in Internal Medicine: Updates in NeurologySelect Take-homes: Potpourri

2020 Updates In Neurology: Outline

Cognitive Decline- Microvascular disease

- Hypertension

- Agitation

Epilepsy and EEG- Dementia

- SUDEP

- Delirium

Multiple sclerosis- Vitamin D

- Smoking

- DMTs and malignancy

- Pediatric

Potpourri- Fibromyalgia

- Headache

- Suicide

- Guillain Barre Syndrome

- Checkpoint inhibitors

- Telehealth

Cognitive Decline and White Matter Lesions

Inclusion criteria- Age 35 – 69 years without cardiovascular disease

Outcomes- MRI brain scans

- INTERHEART risk score

- Cognitive assessments (Digit Symbol Substitution Test, Montreal Cognitive Assessment)

Results- 7547 adults age 35 – 69 years

- High INTERHEART risk score correlated with brain lesions (10.4% high-risk, 3.7% low-risk)

- Increasing age, INTERHEART risk score, brain lesions on MRI, > 2 brain infarctions, lack of post-secondary education each associated with reduced cognitive function Incidental brain lesions accounted for 10% of low cognitive test scores

Methods- 3 Prospective longitudinal cohort studies

Outcomes- MRI brain scans at baseline Small vessel disease (SVD) score

- Cognitive tests at follow up

- Progression to dementia

Results- In 1842 participants, SVD score improved prediction of dementia compared to clinical

risk factors alone (AUC 0.85) Performance better in patients with more severe SVD

Prediction slightly stronger with vascular dementia but was unchanged with addition of other vascular risk factors to the model

Cognitive Decline and White Matter Lesions

Hypertension & Microvascular ischemic disease

Inclusion criteria- Hypertensive, age 50+ without diabetes or stroke

Randomized intervention- Goal SBP < 120

- Goal SBP < 140

Results- 670 participants, of whom 449 had follow-up MRI scans

- Goal SBP < 120: Less of an increase in white matter microvascular disease burden on MRI after median of 3.97 years of follow up (0.53 cm3 difference)

Hypertension & Cognitive decline

Method- Cross-sectional pooled cohort study

- 20,000 patients from 5 major US cardiovascular risk studies, all without previous stroke or dementia

Outcomes- Mean SBP

- Change in global cognition, memory and executive function

Results- Cumulative mean SBP for Black patients was 4mm higher

- Cumulative SBP associated with cognitive decline in both groups Black patients with earlier onset of cognitive loss (2.4 – 4 years sooner) with steeper decline

Cognitive differences no longer statistically significant after adjusting for mean SBP

Hypertension & Cognitive decline

Method- Meta-analysis of observational studies (1980-2019) containing > 2000 participants and at

least 5 years’ of data

Outcomes- Blood pressure, use of antihypertensive medications, dementia events, mortality

Results- 6 prospective community-based studies, total N = 31,090 dementia-free adults > 55 yrs

- 3728 incident cases of dementia, including 1741 Alzheimer’s disease

- Those with HTN (15,537) treated with any antihypertensive medication had reduced risk of developing dementia (HR 0.88) and Alzheimer’s (HR 0.84) than those not on meds

- Patients with normal BP had no association with dementia & use of antihypertensives

Aggression & Agitation in Dementia

Method- Systematic review of RCTs comparing interventions for treating aggression and

agitation in adults with dementia

Results- 163 studies (N = 23,143 patients)

- Multidisciplinary care (SMD -0.5), massage and touch therapy (SMD -0.75) both more efficacious than usual care

- Recreational therapy statistically but not clinically more efficacious (SMD -0.29)- 46% of studies had missing outcome data

Cognitive Decline and Dementia: Take-homes

White matter disease on MRI is associated with cognitive decline

Hypertension is a modifiable risk factor for white matter disease and cognitive decline May partially account for observed racial disparity in cognitive decline

Nonpharmacologic interventions are more efficacious than usual care in management of aggression and agitation in dementia



- Hypertension

- Agitation


- SUDEP

- Delirium


- Smoking


- Pediatric


- Headache

- Suicide



- Telehealth

Dementia and Epilepsy

Method- Retrospective cohort study

- Random sample of 1 million veterans age 55+ from 2001 - 2015

Exposures & Outcomes- Exposure: Late-onset unprovoked seizure of unknown etiology

- Outcome: Incident dementia diagnosis

Results- 2166 veterans (0.7%) developed late-onset epilepsy- Veterans with late-onset epilepsy had greater risk of dementia (HR 1.89)

Epilepsy: Risk of Death

Inclusion criteria- North American SUDEP Registry Cases

from 10/2011 – 6/2018

Methods- Retrospective review of 237 SUDEP cases (38% female)

Results- All types of epilepsy: Generalized or localized, recent or longstanding, severe or mild

- High proportion (30%) were not on anti-seizure medications at time of death Only 37% had taken their last dose of anti-seizure medications

- 70% of cases occur in sleep, and of these, 69% were found prone

- High frequency of GTCs not strongly associated with SUDEP

EEG: Delirium

Methods- Prospective cohort - EEG for altered mental status

Outcomes- 3-minute Diagnostic Interview for Confusion Assessment Method (3D-CAM)- EEGs interpreted by neurophysiologists- Clinical outcomes: Length of stay, Glasgow outcome scales, mortality

Results- 200 patients evaluated, of whom 121 met delirium criteria (60.5%)- EEG finding most strongly associated with delirium: generalized slowing (sensitive) Correlated with severity of delirium and individual features on CAM

Correlated with longer hospitalizations, worse outcomes, increased mortality even after adjusting for delirium presence or severity

- Most specific EEG findings: periodic discharges, triphasic waves, lateralized rhythmic delta, low voltage/generalized attenunation (all insensitive)

Epilepsy and EEG: Take-homes

New-onset epilepsy in older patients may herald incipient dementia

Sudden unexplained death in epilepsy (SUDEP) can occur in any patient, and the biggest risk factors are poor adherence to epileptics and poor seizure control

EEG is helpful in the evaluation and prognostication of delirium



- Hypertension

- Agitation


- SUDEP

- Delirium


- Smoking


- Pediatric


- Headache

- Suicide



- Telehealth

Multiple Sclerosis: Smoking and Vitamin D

Inclusion criteria- Adults with clinically isolated syndrome

Outcomes- Neurofilament levels, cognitive function (PASAT), vitamin D levels, EBV IBNA-1 IgG,

cotinine (nicotine metabolite) all measured at 6, 12, 24 months

- Follow up data obtained at year 11

Results- 278 participants with 11 year follow-up data (of original 468)

- Higher vitamin D levels predicted better cognitive performance

- Smoking predicted worse cognitive performance

- Anti-EBNA-1 did not predict cognitive performance

- NFL levels corroborated results

Multiple Sclerosis: Cancer Risk

Method- Cohort study of first DMT initiation

Outcomes- Cancer incidence in MS patients and age/sex/location matched controls

Results- 4187 rituximab initiations, 1620 fingolimod, 1670 natalizumab

- 78 total invasive cancers 33 Rituximab (HR 0,85, 95% CI 0.57 – 1.77)

28 fingolimod (HR 1.01, 95% CI 0.57 – 1.77)

17 natalizumab (HR 1.53, 95% CI 0.98 – 2.38)

- No specific cancer type with significantly increased risks, though fingolimod with numerically highest incidence of basal cell carcinoma and cervical intraepithelial neoplasia

Multiple Sclerosis: Vaccinations

Method- Working group practice guideline recommendations (update from 2002)

Recommendations - No definite evidence suggesting vaccines contribute to risk of MS

- Vaccinations should be offered prior to starting immune suppression when able

- Latent/chronic infections should be screened for prior to immune suppression

- Routine vaccinations are recommendable with exception of live attenuated vaccines Annual influenza vaccination is recommended

- BCG vaccine may be considered where TB prevalence is high

- Vaccinations should be held during an exacerbation

Multiple Sclerosis: Pediatrics

Method- Cohort study of MS/ICS children < 18 years

- On DMTs: Newer therapy or older injectables

Outcomes- Relapse rate

Results- 741 children of whom 197 were on newer DMTs, 544 on injectables Newer DMT: Older, less likely to have monofocal presentation

- Newer DMT: lower relapse rate (rate ratio 0.45, rate difference 0.27), lower rate of new/enlarging T2 lesions and enhancing lesions NNT: need 3.7 person-years of newer DMT over injectables to prevent 1 relapse

Multiple Sclerosis: Breast feeding

Method- Prospective observational study - Pregnant patients with multiple sclerosis

Outcome: Relapse rate

Results- 466 pregnancies in 375 women in Kaiser system (2008 – 2016)- Disease-modifying therapy (DMT) discontinued for 1+ year prior to pregnancy in 48% 26% conceived on DMT; only 3% on highly-effective DMT

- Relapses declined during pregnancy and returned to baseline 4-6 months postpartum- Patients who used exclusive breast-feeding for at least 2 months had fewer relapses

(9%) than non-exclusive (17%) or no breastfeeding at all (25%) Exclusive breastfeeding adjusted HR 0.37 Resuming modestly effective DMTs had no effect on relapse

Multiple sclerosis: Take-homes

Low Vitamin D and smoking are both associated with worsened cognitive scores

If DMTs increase cancer risk, the degree is modest Fingolimod: Epithelial cancers

Generally safe to vaccinate patients with MS; prefer before DMTs

Evidence for use of newer, more highly active DMTs in children

Breastfeeding associated with reduced relapse rate postpartum



- Hypertension

- Agitation


- SUDEP

- Delirium


- Smoking


- Pediatric


- Headache

- Suicide



- Telehealth

Fibromyalgia

Inclusion criteria- 117 Adult women with fibromyalgia syndrome (FMS)

- Controls: Women with major depression, chronic pain, or healthy

Assessments- Neurologic examination, questionnaires, neurophysiology assessment

- Skin-punch biopsy, corneal confocal microscopy, microneurography, quantitative sensory testing, pain-related evoked potentials

Results- Intraepidermal nerve fiber density lower in FMS compared to controls

- Corneal innervation reduced in FMS

- Higher 1B nociceptor conduction velocities in FMS

- Generalized skin denervation seen in more severe FMS

Headache

Purpose- To establish guidelines on imaging for headache

Recommendations- HCT without contrast for thunderclap headache (+/- CTA)

- MRI or HCT for headache + papilledema (+/- contrast or venous imaging)

- MRI or HCT for progressive headache or other “red flags” Subacute trauma, exertional, neurologic deficit, cancer, immune compromise, pregnancy, age 50+

- MRI +contrast for headache of trigeminal autonomic origin

- MRI +/- contrast for chronic headache with new features or progression

No imaging for new diagnosis migraine or tension-type headache with normal exam, or for chronic stable headache without deficit

Suicide in Neurological Disorders

Design- Retrospective cohort study

- Persons age 15+ in Denmark from 1980-2016 (N = 7,300,395)

- Outcome: Death by suicide

Results- 35,483 of 7.3 million individuals died by suicide 77.4% males

14.7% diagnosed with neurological disorder; adjusted IRR 1.8

Highest risk: ALS > Huntington disease > multiple sclerosis > head injury = epilepsy > stroke

Highest risk in those with shorter time to diagnosis (IRR 3.1 if only 1-3 months since dx)

Second course IVIG in Guillain Barre Syndrome (GBS)

Inclusion criteria- Patients with GBS with poor prognosis

Method- Observational study of patients treated for GBS with IVIG, either: Once

Twice, the second course occurring within 2 weeks of first dose

Twice, the second course occurring 3-4 weeks after first course

Results- Scores on GBS disability scale at 4 weeks did not differ between those who

received a second course and those who did not

Neurotoxicity of Immune Checkpoint Inhibitors

Method- 6-year institutional experience of 1834 patients who received immune checkpoint

inhibitors (ICIs)

Results- 28 patients (1.5%) with Grade III or IV neurologic adverse events (AEs)

- Risk factors: combination ICIs > CTLA-4 therapy > anti-PD therapy

- 39% CNS, 43% PNS, 18% both- Glucocorticoids associated with favorable clinical outcome (76% vs 24%) Recommendation: IV methylprednisolone 1g/day x 3-5 days 4-6 week prednisone taper

If relapse or not responsive, add another agent (mycophenolate, rituximab, IVIG, PLEX)

- Relapse in 7 patients (25%), including 60% of those re-challenged with ICI

Telehealth in Dementia Care

Inclusion criteria- Diagnosis of dementia living in the community- Caregiver reported difficulty managing ADLs and/or behavioral symptoms

Intervention- Telehealth or home visit delivery of same intervention program

Outcomes- Caregiving Mastery Index- Caregiver perception of change, ADL function, type/frequency of behavioral symptoms

Results- 63 dyads recruited and randomized- Both groups showed improvements for primary outcome- No significant differences between groups for primary or secondary outcomes at 4 months

Potpourri: Take-homes

Fibromyalgia has increasing evidence for a physiologic basis

Headache without red flags does not require neuroimaging: Chronic + unremarkable exam

Neurologic disorders carry increased risk of suicideParticularly untreatable conditions, relapsing-remitting/episodic conditions

Checkpoint inhibitors have rare but serious and heterogeneous neurologic adverse eventsGlucocorticoids are mainstay of therapyMost patients re-challenged with checkpoint inhibitors relapse

Mounting evidence for utility of telehealth in neurologic patients

Take-homes: Summary

Cognitive Decline- Hypertension is a modifiable risk factor for

white matter disease on MRI and cognitive decline

- Nonpharmacologic interventions are efficacious for aggression & agitation in dementia

Epilepsy and EEG- Epilepsy may herald dementia in older

patients

- Patients should take AEDs to avoid SUDEP

- EEG is helpful in delirium

Multiple sclerosis- Low vitamin D and smoking associated

with worsened cognition

- Vaccines + routine cancer screening

- Highly active DMTs indicated in children

- Encourage breastfeeding

Potpourri- Fibromyalgia has physiologic bases

- Red-flag approach to headache imaging

- Increased suicide risk in neurologic disorders

- Treat neurologic adverse events from checkpoint inhibitors with steroids

- Telehealth is appropriate in neurology

Questions?

References (1 of 2) Al Olama, AA et al. Simple MRI Score Aids Prediction of Dementia in Cerebral Small Vessel Disease. Neurology

2020 Mar 24;94(12):e1294-1302. Alping et al. Cancer Risk for Fingolimod, Natalizumab, and Rituximab in Multiple Sclerosis Patients. Ann Neurol

2020 May;87(5):688-699. Anand et al. Reduced Cognitive Assessment Scores Among Individuals With Magnetic Resonance Imaging-

Detected Vascular Brain Injury. Stroke 2020 Apr;51(4):1158-1165. 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.

Cortese et al. Vitamin D, smoking, EBV, and long-term cognitive performance in MS. Neurology 2020;94:e1950-e1960.

Ding et al. Antihypertensive Medications and Risk for Incident Dementia and Alzheimer's Disease: A Meta-Analysis of Individual Participant Data From Prospective Cohort Studies. Lancet Neurol 2020 Jan;19(1):61-70.

Dubey D et al. Severe Neurological Toxicity of Immune Checkpoint Inhibitors: Growing Spectrum. Ann Neurol 2020 May;87(5):659-669.

Dwivedi R et al. Surgery for Drug-Resistant Epilepsy in Children. N Engl J Med. 2017 Oct 26;377(17):1639-1647 Erlangsen et al. Association Between Neurological Disorders and Death by Suicide in Denmark. JAMA 2020 Feb

4;323(5):444-454. Evdokimov et al. Reduction of Skin Innervation is Associated With a Severe Fibromyalgia Phenotype. Ann

Neurol. 2019 Oct;86(4):504-516. Farez et al. Practice Guideline Update Summary: Vaccine-preventable Infections and Immunization in Multiple

Sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology 2019 Sep 24;93(13):584-594.

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.

Keret et al. Association of Late-Onset Unprovoked Seizures of Unknown Etiology With the Risk of Developing Dementia in Older Veterans. Jama Neurol 2020 Mar 9;e200187.

Kimchi EY et al. Clinical EEG Slowing Correlates With Delirium Severity and Predicts Poor Clinical Outcomes. Neurology 2019 Sep 24;93(13):e1260-e1271.

Krysto et al. Real-World Effectiveness of Initial Disease-Modifying Therapies in Pediatric Multiple Sclerosis. Ann Neurol 2020 Apr 8.

Langer-Gould A et al. Pregnancy-related Relapses and Breastfeeding in a Contemporary Multiple Sclerosis Cohort. Neurology 2020 May 5;94(18):e1939-e1949.

Laver et al. Does Telehealth Delivery of a Dyadic Dementia Care Program Provide a Noninferior Alternative to Face-To-Face Delivery of the Same Program? A Randomized, Controlled Trial. Am J Geriatr Psychiatry 2020 Jun;28(6):673-682.

Levine et al. Association of Blood Pressure and Cognition After Stroke. J Stroke Cerebrovasc Dis 2020 May 1;104754.

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.

Nasrallah et al (SPRINT MIND Investigators). Association of Intensive vs Standard Blood Pressure Control with Cerebral White Matter Lesions. JAMA 2019 Aug 13;322(6):524-534.

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).

Stern Y et al. Effect of aerobic exercise on cognition in younger adults: A randomized clinical trial. Neurology. 2019 Feb 26;92(9)

Verboon et al. Original Research: Second IVIg Course in Guillain-Barré Syndrome With Poor Prognosis: The Non-Randomised ISID Study. J Neurol Neurosurg Psychiatry. 2020 Feb;91(2):113-121.

Verducci et al. SUDEP in the North American SUDEP Registry. Neurology 2019; 93:e227-e236.

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

Watt JA et all. Comparative Efficacy of Interventions for Aggressive and Agitated Behaviors in Dementia: A Systematic Review and Network Meta-analysis. Ann Intern Med 2019 Nov 5;171(9):633-642.

Whitehead MT et al (Expert Panel on Neurologic Imaging). ACR Appropriateness Criteria: Headache. J Am Coll Radiol 2019 Nov;16(11S):S364-S377.

References (2 of 2)

UCSF: Advances in Internal Medicine · 2019 Advances in Internal Medicine: Updates in Neurology....

Documents

Transcript of UCSF: Advances in Internal Medicine · 2019 Advances in Internal Medicine: Updates in Neurology....