UCSF: Advances in Internal Medicine 2020: Whats New in Neurology? - - PowerPoint PPT Presentation

Megan Richie, MD Assistant Professor of Neurology

UCSF: Advances in Internal Medicine

2020: “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 Neurology

Select 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 Neurology

Select 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

• pioids

2019 Advances in Internal Medicine: Updates in Neurology

Select 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
• n 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
• r 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
• f 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

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

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

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

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

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

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 suicide
• Particularly untreatable conditions, relapsing-remitting/episodic conditions
• Checkpoint inhibitors have rare but serious and heterogeneous

neurologic adverse events

• Glucocorticoids are mainstay of therapy
• Most 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?

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References (2 of 2)