Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South...
-
Upload
allan-singleton -
Category
Documents
-
view
213 -
download
0
Transcript of Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South...
![Page 1: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/1.jpg)
Two common Neurodegenerative diseases encountered in primary care practicesLaurie Weisensee MDAssociate Professor, Sanford School of Medicine of the University of South Dakota
![Page 2: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/2.jpg)
Multiple Sclerosis
![Page 3: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/3.jpg)
Demographics of Multiple sclerosis
Age at onset 15 to 45 years Gender 70% women US incidence 8,500 to 10,000
yr US prevalence 350,000 North South gradient
high prevalence 30+/100,000Northern US and Canada,
most of Europe, Southern Australia, New Zealand, Northern Russia
![Page 4: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/4.jpg)
Economic burden of multiple sclerosis
Total Annual Cost world wide 6.8 to 13.6 billlion
Lifetime cost of 2million per patient in the
US
![Page 5: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/5.jpg)
Pathology of Multiple Sclerosis
Immune-mediated disease in genetically susceptible individuals (HLA-DR1501 and HLA-DQ0601)
Axonal injury and destruction, It affects myelin of both white and gray matter. Damage to axons occurs early in MS. Persists at all times during course of disease, even in quiescence
Lesions, in periventricluar white matter, cerebral cortex, optic nerves, brain stem, cerebellum and spinal cord
![Page 6: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/6.jpg)
Cause of demyelination and axonal loss in Multiple Sclerosis?
Activation of autoreactive CD4+ cells in the peripheral
immune system
Migration of cross-reactive T cells into CNS
Insitu reactivation by
myelin autoantigens
Inflammation, demyelination,
axonal transection,
degeneration
Sectretion of proinflammatory
cytokines, antibodies
Activation of macrophages by Th1 cells, B cell
by Th2 cells (CD4+ T cells
subtypes)
![Page 7: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/7.jpg)
Prognostic factors in MS
Better Worse
![Page 8: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/8.jpg)
Better Prognosis
FemaleOnset: relapsing-remitting, optic neuritis, sensory involvement
Age at onset < 30 yearsLow MRI T2 lesions burdenFrequent Attack
![Page 9: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/9.jpg)
Worse Prognosis
MaleOnset: progressive course, pyramidal and or cerebellar involvement
Age at onset > 40 yearsHigh MRI T2 lesion burdenInfrequent attacks
![Page 10: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/10.jpg)
Diagnosis of Multiple Sclerosis
Presenting symptomsSensory symptoms arms/legs 33%Unilateral vision loss 16%Multiple symptoms at onset 14%Diplopia 7%Acute Motor deficit 5%Other, e.g. bladder, heat intoler, fatigue, pain, movement disorder, dementia <5%
•Ultimately a clinical diagnosis, no definite laboratory test•Fits clinical profile•Laboratory evaluation•Evidence of lesions in Space and time•Exclusion of other diagnoses
![Page 11: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/11.jpg)
McDonald Criteria
CLINICAL PRESENTATION
>2 attack, evidence of > 2 lesions or clinical evidence of 1 lesion with historical evidence of prior attack.
>2 attacks, clinical evidence of 1 lesion.
1 attack, clinical evidence of > 2 lesions
1 attack, clinical evidence of 1 lesion (CIS) clinically isolated syndrome. Clinical event > 24 hrs
ADDITIONAL CRITERIA FOR DIAGNSOSIS
None
Dissemination in space, > 1 T2 lesion in at least 2 or 4 MS regions, periventircular, juxtacortical, infratentorial, spinal cord.
Disseminated in Time, gadolinium enhancing lesions, and non-enhancing lesions.
Disseminated space and time
![Page 12: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/12.jpg)
![Page 13: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/13.jpg)
Disease modifying therapies
![Page 14: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/14.jpg)
In the absence of curative therapy, treatment is limited to reducing CNS inflammation.
![Page 15: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/15.jpg)
1. Reduce the frequency, severity and duration of relapses.
2. Reduce MRI enhancing lesions, brain atrophy and promote repair.
3. Delay disability due to disease.4. Manage clinical symptoms of the
disease.
![Page 16: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/16.jpg)
DMT Usual Dose Primary Indication
Adverse affects
IFN beta-1aAvonex
30 mcg IM q week
CISRRMS
Flu-like symptoms, liver and bone marrow abnormalities, neutralizing AB
IFN beta-1aRebif
22 Or 44 mcg SQ
tiw
CIS,RRMS,SPMS
Same as above
IFN beta-1bBetaseron
0.0625MG to0.25mg qod SQ
CIS,RRMS,SPMS
Same as above
FinfolimodGilyena
0.5m PO daily RRMS bradycardia
Glatiramer acetate Copaxone
20mg SC daily CIS, RRMS
Local injection site, flushing
NatalizumabTysabri
300mg IV q 4 weeks
RRMS PML
MitoxantroneNovantrone
12mg/m2 IV q 3 months
Worsening RRMS, SPMS
cardiotoxicity
![Page 17: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/17.jpg)
MS subtypes
RRMS relapsing remitting MSPPMS primary progressive MS
SPMS secondary progressive MS
?? Neuromyelitis optica (serum IgG autoantibody
![Page 18: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/18.jpg)
Progression to Disability ( EDSS)0 Normal Neurological Exam
1.0-1.5 No Disabiltiy
2.0-2.5 Minimal Disability
3.0-3.5 Mild to Moderate Disability
4.0-4.5 Moderate Disability
5.0-5.5 Increasing limitations in ability to walk
6.0-6.5 Walking assistance is needed
7.0-7.5 Confined to a wheelchair
8.0-8.5 Confined to a bed/chair, self-care with assistance
9.0-9.5 Completely dependent
10 Death due to MS
![Page 19: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/19.jpg)
Differential Diagnosis
Lyme diseaseNeurosyphilisPML, HIV, HTLV-1HHV-6SLESjogren’sOther CNS vasculitisSarcoidosisBechet’s disease
![Page 20: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/20.jpg)
DDX continued
Metabolic: Vitamin B12 and E deficiencies
CADASILMELASCNS LymphomaSpinal Stenosis/HNPALSMyasthenia Gravis
![Page 21: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/21.jpg)
Acute exacerbation RX
Most Importantly, look for underlying infection.
![Page 22: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/22.jpg)
Indications for treatment of an acute exacerbation include:
Objective evidence of neurological impairment.
Examples: loss of vision, motor and or cerebellar symptoms, mild sensory attacks are often not treated, although sometimes necessary due to discomfort.
![Page 23: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/23.jpg)
Glucocorticoids RX for acute
Most often 3-7 days of IV methylprednisolone 500mg-1000mg daily, with or without prednisone taper, that is most commonly done.
Large doses of orals in one study shows some similar outcomes, bioavailability of prednisone (1250 mg equal to 1000 mg IV methylprednisolone. More side affects w/oral
![Page 24: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/24.jpg)
Parkinson Disease
![Page 25: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/25.jpg)
Diagnosis Parkinson Disease
Rest TremorRigidityBradykinesiaPostual instability
![Page 26: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/26.jpg)
Dopamine depletion from the basal ganglia results in major disruptions in the connections to the thalamus and motor cortex
Pathology
![Page 27: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/27.jpg)
Insidious onset
About 60 % of the neurons in the Substantia nigra pars compact have been lost by the time a patient presents with PD concerns to their doctor.
![Page 28: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/28.jpg)
Protein misfolding, aggregation and toxicity
Mutations in the gene that codes for alpha-synuclein have emerged as one of the most important elements of cell death in various neurodegenerative disorders, together knowns as SYNUCLEINOPATHIES.
Including Parkinsons, dementia with Lewie bodies, Multple system atrophy
![Page 29: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/29.jpg)
Epidemiology of Parkinson Prevalence of PD is about 0.3 percent of
general population. Approx 1 percent of persons >60 years old Most studies show Male preponderance Greater age and greater risk Parkinson low prevalence of most cancer Inverse relationship to cigarette smoking
![Page 30: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/30.jpg)
Coffee and caffeine intake, lower incidence PD.
High iron intake, especially combined with manganese associated with increase in PD
Excessive body weight, increase risk PD
Greater in industrial countries, esp copper and manganese.
Associated with Pesticide and Herbicides
Veterans (Agent Orange)
![Page 31: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/31.jpg)
Genetics
Majority of PD appear to be Sporadic.
Observation 20-25% of patient with sporadic PD have at least one first degree relative
![Page 32: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/32.jpg)
Clinical Subtypes of Parkison
Tremor dominantAkinetic-rigidPostural instability and gait difficulty
Tremor dominant associated with slower progression
![Page 33: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/33.jpg)
Other Motor Features
Craniofacial Visual Musculosketal Gait
Hypomimia Blurred vision micrographia Shuffling
Decrease blink Impaired contrast
dystonia Short steps
Speech impairment
Hypometric saccades
myoclonus Freezing
Dysphagia Impaired vestibuoccular relfex
Stooped posture
Festination
Sialorrhea Impair upgaze Flexion thoracolumbar
Eyelid apraxia kyphosis
scoliosis
Difficult roll in bed
![Page 34: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/34.jpg)
Non motor symptoms Parkinson
Cognitive dysfunction Psychosis and hallucinations Mood disorders including depression,
anxiety, apathy Sleep disorders Fatigue Autonomic dysfunction Olfactory dysfunction Pain Sensory disturbances Dermatologic findings (seborrhea)
![Page 35: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/35.jpg)
Differential Diagnosis Parkinson Progressive Supranuclear Palsy (PSP) Lewie Body dementia Multiple System Atrophy (akinetic rigid
syndrome) prominent cerebellar, autonomic
Corticobasal degenerative, lower limb onset
Vascular Parkinsonism Normal Pressure hydrocephalus Other neurodegenerative disorders…list
long
![Page 36: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/36.jpg)
Treatment
SYMPTOMATIC NEUROPROTECTIVE
????????
![Page 37: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/37.jpg)
When to begin symptomatic RX
Effect of disease on dominant hand Degree disease interferes with
ADL’s,Work Significant bradykinesia Personal philosophy
![Page 38: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/38.jpg)
Neuroprotective??
MAO B inhibitors
Selegiline (Eldepryl)Rasagiline
Appear to be modestly effective with early symptomatic treatment for PD. Inconclusive regarding neuroprotective. Numerous drug interactions
![Page 39: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/39.jpg)
Symptomatic Treatment
Levodopa MAO B inhibitors Dopamine agonists COMT inhibitors Anticholinergic agents Amantadine
![Page 40: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/40.jpg)
Levodopa—still Gold Standard
No evidence of in-vivo neuo –toxicity of Levo-dopa.
No substantial evidence that one should wait to initiate Levodopa
![Page 41: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/41.jpg)
Formulations of Levodopa
Levodopa is combined with peripheral decarboxylase inhibitor to block conversvion to dopamaine in systemic circulation.
The Combination Cabidopa-Levodopa is available in
10/100, 25/100, 25,100 numerator= carbidoopa and denominator=Levodopa
![Page 42: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/42.jpg)
Agonist
Bromocriptine Pramipexole, (Mirapex) Ropinirole, (Requip) Rotigotine, in Europe Injectable apomorphine
![Page 43: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/43.jpg)
Complications of treatment
DyskinesiasConfusion, hallucinationsDopaminergic dysregulation syndromeImpulse control disorders
![Page 44: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/44.jpg)
Adjunct Rx
COMT Inhibitors, tolcapone(Tasmar) and entacapone (Comtan)
For motor fluctuation and end- of dose wearing off.
It is the buddy pill for Sinemet
Anticholinergics--- Tremor dominant, younger age
Trihexyphenidyl, Benztropine
![Page 45: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/45.jpg)
Surgical Treatment for Parkinson
Current therapy is DBS (Deep Brain Stimulation)
Subthalamic nucleus Globus Pallidus
This consideration when Motor fluctuations and dyskinesia become prominent about 5 yrs typically
![Page 46: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/46.jpg)
Good Candidates
Healthy patients, younger age who previously responded well to Levodopa
?? How long do you wait. Some insurance companies will not pay after 70, any signs of dementia which is part of progression of PD
![Page 47: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/47.jpg)
DBS
Typically do not get off PD meds, but reduce amount and have more on time
DBS expensive, pre-authorization work up is extensive
Works for at least 3-5 years Surgical complications are
infrequent, but do occur, infection, stroke, lack of response, memory decline, behavior change, depression, suicide.
![Page 48: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/48.jpg)
Future treatments
Stem cells, little set back but research continues
Duodenal levodopa infusion Gene therapy Possible portal of delivery of
Levodopa directly to the brain, via same route as DBS electrode placement, under investigation
![Page 49: Laurie Weisensee MD Associate Professor, Sanford School of Medicine of the University of South Dakota.](https://reader030.fdocuments.in/reader030/viewer/2022032605/56649e6a5503460f94b674c3/html5/thumbnails/49.jpg)
THANK YOU