Two common Neurodegenerative diseases encountered in primary care practicesLaurie Weisensee MDAssociate Professor, Sanford School of Medicine of the University of South Dakota

Multiple Sclerosis

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

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

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

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)

Prognostic factors in MS

Better Worse

Better Prognosis

FemaleOnset: relapsing-remitting, optic neuritis, sensory involvement

Age at onset < 30 yearsLow MRI T2 lesions burdenFrequent Attack

Worse Prognosis

MaleOnset: progressive course, pyramidal and or cerebellar involvement

Age at onset > 40 yearsHigh MRI T2 lesion burdenInfrequent attacks

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

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

Disease modifying therapies

In the absence of curative therapy, treatment is limited to reducing CNS inflammation.

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.

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

MS subtypes

RRMS relapsing remitting MSPPMS primary progressive MS

SPMS secondary progressive MS

?? Neuromyelitis optica (serum IgG autoantibody

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

Differential Diagnosis

Lyme diseaseNeurosyphilisPML, HIV, HTLV-1HHV-6SLESjogren’sOther CNS vasculitisSarcoidosisBechet’s disease

DDX continued

Metabolic: Vitamin B12 and E deficiencies

CADASILMELASCNS LymphomaSpinal Stenosis/HNPALSMyasthenia Gravis

Acute exacerbation RX

Most Importantly, look for underlying infection.

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.

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

Parkinson Disease

Diagnosis Parkinson Disease

Rest TremorRigidityBradykinesiaPostual instability

Dopamine depletion from the basal ganglia results in major disruptions in the connections to the thalamus and motor cortex

Pathology

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.

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

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

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)

Genetics

Majority of PD appear to be Sporadic.

Observation 20-25% of patient with sporadic PD have at least one first degree relative

Clinical Subtypes of Parkison

Tremor dominantAkinetic-rigidPostural instability and gait difficulty

Tremor dominant associated with slower progression

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

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)

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

Treatment

SYMPTOMATIC NEUROPROTECTIVE

????????

When to begin symptomatic RX

Effect of disease on dominant hand Degree disease interferes with

ADL’s,Work Significant bradykinesia Personal philosophy

Neuroprotective??

MAO B inhibitors

Selegiline (Eldepryl)Rasagiline

Appear to be modestly effective with early symptomatic treatment for PD. Inconclusive regarding neuroprotective. Numerous drug interactions

Symptomatic Treatment

Levodopa MAO B inhibitors Dopamine agonists COMT inhibitors Anticholinergic agents Amantadine

Levodopa—still Gold Standard

No evidence of in-vivo neuo –toxicity of Levo-dopa.

No substantial evidence that one should wait to initiate Levodopa

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

Agonist

Bromocriptine Pramipexole, (Mirapex) Ropinirole, (Requip) Rotigotine, in Europe Injectable apomorphine

Complications of treatment

DyskinesiasConfusion, hallucinationsDopaminergic dysregulation syndromeImpulse control disorders

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

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

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

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.

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

THANK YOU