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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
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 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?
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References (2 of 2)