Multiple Sclerosis

Dr. Richard Braun

VP & Chief Medical Officer,

SCOR Global Life Americas

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Introduction: Richard Braun, MD

1. Joined SCOR in 2013 as VP & Chief Medical Officer

2. 30 years industry experience

3. Frequent lecturer on wide range of underwriting & medical topics

4. Past President of the American Academy of Insurance Medicine (2002), currently VP of ACLI Medical Section

5. Certified by the Board of Insurance Medicine and the American Board of Internal Medicine in Internal Medicine & Insurance Medicine

Multiple Sclerosis

A 32 year-old female, mother of 2 applies for life insurance.

Six months prior she noted an episode of double vision and

consulted with her OB/gyn physician. She ordered an MRI

of the brain with enhancement, and referred her to a

Neurologist. Other than routine childhood illnesses she had

always been in good health. Her FH was positive for MS

in her mother, who was living at age 60. Her only other

symptom was fatigue, which she thought was normal with

2 small children. The MRI report showed 2 hyperintense T2

lesions measuring .8 and 1 cm. The smaller lesion is in the

Pons, the larger lesion in the corpus callosum. Both lesions

showed moderate enhancement with gadolinium. There

were no records from the neurologist.

Multiple Sclerosis

Review Brain Anatomy & Function

Multiple Sclerosis

Epidemiology

Etiology

Diagnosis

Natural History

Treatment

Risk of Progressive Multifocal Leukoencephalopathy

(PML)

Prognosis

5

Human Brain

Consists of neurons, glial cells, and blood vessels

Consists of 86 billion neurons and 86 billion non-

neuronal cells

Weighs about 1.35 kg (3 lbs), roughly 2% of ideal

body weight

Volume is ~ 1200 cm3

About 19% of brain neurons are located in the

cerebral cortex (includes subcortical white matter)

About 80% of all brain neurons are in the cerebellum

Consumes 15% of cardiac output, 20% of total

oxygen consumption, and 25% of glucose utilization

6

Human Brain

The parietal lobe contains areas involved in

somatosensation, hearing, language, attention, and

spatial cognition.

The frontal lobe functions to control attention, abstract

thinking, behavior, problem solving tasks, complex

physical reactions and personality.

The occipital lobe is the smallest lobe; its main functions

are visual reception, visual-spatial processing, and color

recognition.

The temporal lobe controls auditory and visual memories,

language, and some hearing and speech.

7

Human Brain

8

Human Brain

9

Multiple Sclerosis

The frequency of MS varies geographically

In the US the estimated prevalence is 100 per 100,000 or 0.1%

Based on pooled prevalence analysis, the number of people with MS

in the world in 2013 was 2.0 million, compared to 1.8 million in 2008.

10

Multiple Sclerosis

Female:Male affected ratio estimates range

from 1.4:1 to 3:1.

There is suggestive evidence that the

incidence of MS is increasing in females

Some studies indicate that the increase may

correspond to a shift from rural to urban

living

Sun exposure

Reduced exposure to pathogens

11

Multiple Sclerosis

The mean age of onset for MS is from 28-31

with the range of 15 to 45 years.

Relapsing remitting averages 25-29 years

Secondary progressive at age 40-49 years

Primary progressive mean age of onset is 39-41

years

From the Nurses’ Health Study II, women

taking 400+ IU/day of vitamin D had relative

risk of .59 of developing MS

12

Multiple Sclerosis

The cause of underlying MS is unknown

The most widely-held belief is an autoimmune reaction

Begins with auto-reactive lymphocytes causing inflammation

Later it is dominated by microglial activation and nerve cell

death

Other theories

Immune reaction to a chronic viral infection (none identified)

A genetically determined neuroglial degenerative process

Chronic cerebrospinal venous insufficiency (CCSVI)

13

Multiple Sclerosis

MS is often associated with other autoimmune disorders

Psoriasis 7.7%

Thyroiditis 6.4%

Inflammatory Bowel Disease

Uveitis

Phemphigoid

Type 1 Diabetes

Familial MS frequency varies from 3% to 23%

Dizygotic twins (fraternal) or siblings risk is 3-5%

Monozygotic twins (identical) risk ranges from 20-39%

Environmental factors associated with MS

Latitude

Place of birth

Sunlight exposure & Vitamin D levels

Urbanization

14

Multiple Sclerosis-Diagnosis

Typically presents as a young adult

Common Presenting Symptoms

15

Symptom Percent affected

Sensory issues in

limbs

31%

Almost all affected

at some time

Visual Loss 16%

Multiple Symptoms

at onset

14%

Subacute motor

issues

9%

Double Vision 7%

Gait disturbance 5%

Balance issues &

vertigo

5%

Motor issues acutely 4%

Multiple Sclerosis - Diagnosis

16

Lhermitte sign – sensation of electric shock down the back

or arms with flexion of the neck (9%)

Uhthoff phenomena – increase in body heat worsen signs

and symptoms

Multiple Sclerosis

More symptoms

Fatigue (in 86%, most distressful

symptom in 65%)

Depression (occurs in up to 2/3)

Cognitive Impairment (significant %

affected on neuropsych testing), it

correlates with the severity of MRI

cerebral lesions and cortical atrophy

17

Multiple Sclerosis – List of demyelinating disorders

18

Other conditions that can cause

Plaques on MRI

Ischemia

Systemic Lupus

Bechet’s syndrome

Vasculitis

HTLV-1 infection

Sarcoidosis

Ischemia especially makes MRI

Less reliable for MS diagnosis

After age 50.

Multiple Sclerosis

Clinically Isolated syndromes (CIS)

Single attack, typically with at least partial resolution

Optic neuritis, or a brainstem, cerebellar or spinal cord

syndrome

25% will have multifocal abnormalities

Sensory symptoms (numbness, tingling, radicular pain,

intense unilateral itching, etc.)

Weakness more often in the legs, abnormal reflexes

Diplopia

Vertigo

Problems with coordination

19

Multiple Sclerosis

Radiologically Isolated Syndromes (RIS)

Typical T2 hyperintensities found incidentally

Ovoid, homogeneous, well-circumscribed lesions

with or without cerebellar involvement, > 3 mm

CNS white matter lesions do not follow a vascular

pattern

No history of clinical symptoms or neurological

dysfunction

No other cause of

demyelination apparent

20

Multiple Sclerosis

21

Demyelinated

Plaques

Multiple Sclerosis

Progression to MS – an active area of

research

Long-term (10-20 years)

CIS plus a lesion on MRI – 60-80% progress to

MS

CIS and normal MRI – 20% progression

RIS – 59% progressed, higher when enhanced

with gadolinium

RIS in the cervical spine 84% progressed in

median 3.3 years

22

Multiple Sclerosis

Progression to MS

Isolated Optical neuritis

5 years – 30%

12 years – 40%

15 years – 50%

Isolated Optical Neuritis with 1 or more lesions on MRI

10 years – 56%

Acute transverse Myelitis (partial)

With brain MRI lesions 60-90% develop MS in 3-5 years

Without brain MRI lesions 10-30% develop MS

Treatment with interferon beta-1a (Avonex), glatiramer acetate,

or intravenous immune globulin (IVIG) has been shown to

reduce the progression of CIS to MS

23

Multiple Sclerosis - Diagnosis

McDonald diagnostic criteria: requires

dissemination in both space and time

Dissemination in time

2 or more clinical attacks

Multiple MRI lesions, some of which enhance

with gladolinium, some do not enhance

Dissemination in space

Typical MRI hyperintense T2 lesions in 2 or

more typical areas (periventricular, juxtacortical,

infratentorial, or spinal cord)

24

Multiple Sclerosis - Diagnosis

The McDonald Criteria – Dissemination in Space or time

One or more T2 (MRI) lesions in typical regions: periventricular;

juxtacortical; infratentorial; or spinal cord

Or MRI showing gadolinium enhancing and non-enhancing lesions

or new T2 lesions on sequential MRIs

May also be demonstrated with 2 or more clinical attacks over time

with the confirmation by MRI or cerebrospinal fluid findings

Plaques on MRI appear hyperintense on T2 weighted images

May be underestimated

Discrete region of demyelination

Newer lesions enhance with gadolinium

Oligoclonal bands in cerebrospinal fluid,

specificity ~ 92%

25

Multiple Sclerosis

26Neurology 1983; 33:1444

Multiple Sclerosis

27

50% at 9 years, ultimately

80%

May represent 15-17%

The longer without

progression and low EDSS,

the less likely

to progress

Malignant course (6-12%) – EDSS > 6 w/in 5 years of onset

Multiple Sclerosis

Treatment

Immune Stimulation (e.g. IFN)

Immune modulators (e.g. glucocorticoids, IVIG,

Natalizumab, Rituximab)

Immune Suppression (e.g. methotrexate,

Mitoxantrone, cyclophosphamide, azathioprine,

cladribine)

Hematopoetic Stem Cell Transplant

28

Multiple Sclerosis

Disease Modifying Therapy – Goals

Reduce number & severity of relapses and extend

time period between relapses

Extend the time to disability (slow progression)

Prevent new MRI lesions and/or reduce the current

lesions

29

Multiple Sclerosis

Natalizumab and risk of Progressive Multifocal

Leukoencephalopathy (PML)

Natalizumib – recombinant monoclonal antibody

against integrin receptors on the surface of

lymphocytes and monocytes that play a role in

adhering to vascular endothelium

Thought to be one of the best disease modifying

therapies

In 2005 Natalizumab was withdrawn from the

market when 2 MS patients developed PML

Reintroduced in 2006 and by 2013, 398 cases of

PML associated with drug reported world wide

30

Multiple Sclerosis

PML is a severe demyelinating disease of the central

nervous system

It almost always occurs in immunosuppressed individuals

(HIV, organ transplant, myeloproliferative diseases, etc.)

PML is caused by reactivation of the Polyomavirus JC (JC

virus)

JC virus infection is typically asymptomatic in childhood

JC virus antibodies found in ~ 86% of adults

PML may mimic MS relapse or exacerbation

Symptoms – altered mental status; weakness (mono or

hemi); ataxia; diploplia or visual field cuts

Imaging – PML lesions often unifocal, in the frontal lobes;

occur at the gray-white matter junction; may be large; may be

hyperintense on diffusion-weighted MRI sequences

31

Multiple Sclerosis

PML diagnosis

JC virus DNA in the cerebrospinal fluid

Brain biopsy & immunochemistry

Prognosis of Natalizumab-associated

PML

> 80% survival at one year

Most survivors are moderately to severely

disabled

32

Multiple Sclerosis

Risk of PML with Natalizumab treatment

The risk is increased by:

Previous JC virus infection

Prior immunosuppression

The length of time on Natalizumab

Lack of JCV antibodies a theoretic risk of <0.09 per

1000 (test has a 3% false negative rate)

Positive for JCV

33

Time No immunosuppression With immunosuppression

1-24 months 0.56 per 1000 1.6 per 1000

25-48 months 4.6 per 1000 11.1 per 1000

Multiple Sclerosis

Stopping natalizumab quickly results in

immune reconstitution inflammatory

syndrome (IRIS)

Often has a reactivation of MS with

symptoms and enlarging lesions on MRI

(54% in one study)

Disease activity peaks at 4-7 months after

stopping

Rx for IRIS is IV corticosteroids

34

Multiple Sclerosis

Worsening of disability in MS is variable

Bimodal distribution with EDSS score peaks at 1 and 6

One large study in British Columbia

Median time from MS onset to EDSS 6 (cane for walking) was 27.9 years

Median time from birth to EDSS 6 was 59 years (men 58.8, women 60.1)

35

Multiple Sclerosis

Frequency of relapses

Average .4-.6 per year, highly variable

Higher frequency relapses may correlate to earlier

disability

Questionable relation between stressful life events

and relapses

Corticosteroids may relieve symptoms in the short

term, but do not affect the frequency of relapses

Disease Modifying Drugs (DMD) can reduce the

frequency of relapses, however there is no long

term data on progression to disability

36

Multiple Sclerosis

37

Neurology. 2013 Jul 9; 81(2): 184–192.

Multiple Sclerosis

38

PLOS ONE | DOI:10.1371/journal.pone.0132033 July 6, 2015

Factors increasing risk of death

- Male sex

- Older age at onset

- Primary Progressive

- Onset in an earlier year

Multiple Sclerosis

39PLOS ONE | DOI:10.1371/journal.pone.0132033 July 6, 2015

Multiple Sclerosis

40J Neurol (2014) 261:1508–1517

Index date < 50 years-old

Index date > 50 years-old

41

J Neurol Neurosurg Psychiatry

2014;85:1091–1095.

doi:10.1136/jnnp-2013-307187

Multiple Sclerosis

42

Neurology® 2012;78:1315–1322

Multiple Sclerosis

43

Neurology. 2013 Jul 9; 81(2): 184–192.

Multiple Sclerosis

A 32 year-old female, mother of 2 applies for life insurance.

six months prior she noted an episode of double vision and

consulted with her OB/gyn physician. She ordered an MRI

of the brain with enhancement, and referred her to a

Neurologist. Other than routine childhood illnesses she had

always been in good health. Her FH was positive for MS

in her mother, who was living at age 60. Her only other

symptom was fatigue, which she thought was normal with

2 small children. The MRI report showed 2 hyperintense T2

lesions measuring .8 and 1 cm. The smaller lesion is in the

Pons, the larger lesion in the corpus callosum. Both lesions

showed moderate enhancement with gadolinium. There

were no records from the neurologist.

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