jeffry d. gerson, o.d., faao
TRANSCRIPT
Jeffry D. Gerson, O.D., FAAO
37 year old female
Vision 20/40 OS
No pain or pain with
movements
No APD
Normal Anterior
segment exam
Recent ER visit for
LOV
Then went to
Ophthal.
Either MS, Diabetes or
nothing…wait and see
Further History:
Previous episodes of vision “Graying”
Unable to take hot showers
Electric like impulses through arms/back
Numbness in fingers
Clumsy walking
Decreased contrast/color OS
What is the normal visual outcome?
Will this recur?
What is risk of MS?
What is eye treatment?
What is Systemic Treatment?
What tests are needed?
Autoimmune Disease of the CNS
Demyelination of white matter
Brain Spinal cord
Can often lead to
disability
Not limited to one
“system”
Sx may worsen over
time: relapse/progress
Likely triggers:
Stress, viral illness,
pregnancy (less w
time), early post-
partum
Dymyelination results in Paresthesia (numbness & weakness) Loss of skeletal muscle coordination Loss of autonomic function
Multiple sites of CNS involvement Multiple attacks over time Recognized since late 1300’s
Early recognized cases in Iceland,
Holland and England
Became distinctly recognized
disease in 1868
Thought to be caused by “Viking
Gene”
Although even some “northern” people
have lower genetic risk
Approx 350,000 people in US have MS
Wide varience in prevelance: 2-150/100,000
Higher incidence if family member
If general incidence up to 1:1000, then if 1st or 2nd degree family member w MS: risk is 3-5%
Female Geographic risk varies with equatorial latitude during
puberty Gender inequality less at later ages
25-40 years old at initial event Primary progressive more common in older Dx
Vitamin D deficiency As result of lack of sunlight: recognized since 1960
Inheritance 3-4% chance in offspring or siblings 30% chance in identical twins
Most Relevant Signs and Symptoms
of MS in the Primary Care Setting
Pain
Vertigo Depression
Fatigue Numbness
Diplopia
Bladder Dysfunction
Gait impairments Cognitive Dysfunction
Sexual Dysfunction Bowel Dysfunction
Paresis
Progressive Relapsing 10-15%
Secondary Progressive (galloping MS) 65% of RRMS become this,
mean onset 19yrs
Primary Progressive
Relapsing/Remitting MS (RRMS)
Mixed Forms
The initial demyelinating event is referred to as “Clinically Isolated Syndrome” (CIS)
Common presentations include:
Optic neuritis
Transverse myelitis
Brainstem syndromes (INO, cranial neuropathy, nystagmus)
Ascending numbness from the feet up through the torso or hands to the arms
Balance problems
Partial or complete motor paralysis
L’Hermitte’s Sign
Bladder & sexual dysfunction
are common
Diagnostic Work-Up for Patients With
Suspected CIS and/or MS
CSF: cerebrospinal fluid.
Garcia Merino A, Blasco MR. Int MS J. 2007;14:58-63.
MRI imaging studies • Brain w/ contrast
• Cervical spine w/ contrast
• Thoracic spine w/ contrast
• Areas where symptoms manifest
should guide imaging
CSF/lumbar puncture • Assess degree of immune
cell infiltration of CNS
Blood tests • Rule out MS mimetics, other
autoimmune diseases
Additional tests • Evoked potential testing
– Visual
– Auditory
– Somatosensory
• Helpful in detecting
multifocal disease
+
Requires multiple sites of CNS involvement over time
MRI of brain and spinal cord T2 weighted FLAIR
T1 weighted with gadolinium contrast To show active vs chronic lesions
Number of MRI lesions is the single most important predictor of conversion to clinically definite MS (CDMS) and disability progression
T2-Weighted/FLAIR Brain MRI1-3
1. Image obtained from http://www.mslivingwell.org/new/understanding-your-mri. Accessed March 31, 2010.
2. Filippi M. Mult Scler. 2000;6:320-326. 3. Inglese M. Psychiatr Times. 2007;3(7). http://www.psychiatrictimes.com/display/
article/10168/56481?pageNumber=2. Accessed March 31, 2010.
• Reveals hyperintense lesions
• Shows total number of lesions
• Indicative of disease burden
• Lesions may sometimes mimic
brain tumors
• Available scanning protocols
– Sagittal Fluid Attenuated
Inversion Recovery
(FLAIR)
– Axial FLAIR
Old lesions
New lesions
Baseline MRI Correlates With Risk of
Conversion to MS
1. Tintore M et al. Neurology. 2006;67:968-972. 2. Brex PA et al. N Engl J Med. 2002;346:158-164.
3. Fisniku LK et al. Brain. 2008;131:808-817.
0
20
40
60
80
100
0 1 to 3 4 to 9 ≥10
Number of Lesions
Patients
Convert
ing t
o M
S,
%
7 yearsa,1
14 yearsb,c,2
20 yearsb,c,3
a McDonald criteria. b Poser criteria. c Same patient cohort.
Baseline MRI Correlates With Disability
Progression
EDSS: Expanded Disability Status Scale.
Tintore M et al. Neurology. 2006;67:968-972.
# of Lesions on Baseline MRI Patients With EDSS 3
at 5 years
0 5.8%
1-3 8.7%
4-9 11.1%
10 25.4%
Lab tests to R/O mimetics
Serum B12, ESR, Lyme titer, ANA, RF, anticardiolipin, TSH, NMO-IgG
Lumbar puncture with CSF analysis
Oligoclonal banding: B-lymphocyte infiltration of CNS
Elevated IgG Index
• 80-95% of patients with MS have CSF Obs w electrophoresis
• IgG index is rarely elevated in CSF OB-negative patients
Oligoclonal Bands (OBs) in CSF1,2
1. Link H, Huang YM. J Neuroimmunol. 2006;180:17-28. 2. Image adapted from:
http://library.med.utah.edu/kw/ms/mml/ms_oligoclonal.html. Accessed February 25, 2010.
Normal Abnormal
CSF CSF Plasma Plasma
OBs absent
OBs present { {
Evoked Potentials
Visual
Auditory
Somatosensory
OCT: meta-analysis shows RNFL thinning in pts with MS (with & w/o previous optic neuritis)
Arch Neurol. 2009 Nov;66(11):1366-72.
Select Journal or Resource
RNFL thickness may be able to be predictive as to MS or level of vision loss
RNFL thickness signif. reduced in MS eyes
Disease free thickness>MS = fellow of ON > MS w ON
Lower visual function with less RNFL
Avg. RNFL declined w increased neuro impair & disability
Fisher et al. RNFL in MS. Ophthal 2/06
NMO is a fairly uncommon distinctly different disease that affects ON and spinal cord
Peaks of incidence in childhood and 40’s
Prime Sx are loss of vision (more likely to be bilateral) and spinal cord fxn Depending on level: weakness, sensation, bowel &
bladder control may be affected
Sx usually more severe than in MS at presentation
Different markers than MS: newest is marker for antibodies to aquaporin-4 (NMO-IgG) that detects about 70% of cases
Responds to Tx differently than MS: Does not respond to typical disease modifying drugs of MS
NMO (Devic’s Disease) • Optic neuritis and/or myelitis
• Brain MRI shows less involvement than
MS
• Often more severe presentation &
disability
Myeltis extending over
3+ disk segments
Extended Disability Status Score (EDSS)
Scoring for each of 8 functional systems
Pyramidal (ability to walk)
Cerebellar (coordination)
Brain stem (speech and swallowing)
Sensory (touch and pain)
Bowel and bladder functions
Visual
Mental
Other (includes any other neurological findings due to MS)
•90% of pts ambulatory at 10 years
•75% ambulatory at 15 years
•Ampyra may be Rx’d to help walking
but limited data and approx 12k/yr
•Mean decrease in life expectancy: 5-10
years
•40% reach 7th decade
•Mean time to death after Dx is 30yrs
•Up to 2/3 die from MS related
complications
Optic Neuritis
Sudden loss/change of vision in one or both eyes w/ MS, most likely monocular (NMO more likely binoc)
Pain on eye movement possible Color desaturation: may remain decreased after
resolution Contrast sensitivity: may remain decreased after
resolution Visual field defects
Recovery of acuity over days to weeks
15-20% of MS present with ON
38-50% of MS will develop ON
Most predictive factor in who will develop MS is
presence of white matter abnormalities
(demyelinating lesions) on brain MRI
*Overall 10-year risk of MS 38%
no baseline MRI lesions 22%
> 1 baseline MRI lesions 56%*
All 3 agree, and confirm likelyhood of
progression to further demyelinization
Recurrence of Optic Neuritis:
28% at 5 yrs
35% at 10 yrs
Recurrence more frequent in those that eventually
developed MS
Single occurrence not associated with poor vision
Multiple occurrence associated with worse vision, approx.
25% were 20/400 at 5 years
Oral steroids alone not effective
At 3 years, MS risk for IV vs PO vs Placebo 17% vs 21% vs 25%
IV methylprednisilone x 3 days followed by 11 days of oral pred.
Treatment with IMA? 12,000/yr with wkly/daily
injections and side effects
Interferon Retinopathy1
Retinopathy of MS on Interferon. Saito.et al. MS: April 07
• Internuclear Ophthalmoplegia (INO)
– Brainstem demyelination (MLF)
– Loss of adduction with intact convergence
• + Horizontal Nystagmus of abducting eye
– Diplopia on lateral gaze
– Bilateral INO is pathognomonic
for MS, especially in young pts
Bull Soc Belge Ophtalmol. 2009;65-8.
• Nystagmus with oscillopsia
• Cranial nerve palsies (typically CN VI)
• RNFL Thinning and perimetric defects
• Phosphenes
• Ocular Inflammation
– Pars planitis
– Retinal periphlebitis
Curr Opin Ophthalmol. 2005 Oct;16(5):315-20
Ocul Immunol Inflamm. 2004 Jun;12(2):137-42
• Disease Modifying Drugs (DMDs)
– Interferon B (1a and 1b)
• B 1a IM (AvonexTM)
• B 1a SC (RebifTM)
• B 1b IM (BetaseronTM)
– Glatiramer acetate (CopaxoneTM)
– These 4 primary DMDs demonstrate fairly equivalent
reduction in event relapse rates and EDSS
progression
Key Principles for Early Treatment With
Disease-Modifying Therapies
Goodin DS, Bates D. Mult Scler. 2009;15:1175-1182.
Patients who present with CIS are at high risk of developing clinically definite MS
This risk is increased if their baseline MRI suggests the presence of multi-focal disease
Treatment with DMDs at the initial episode of demyelination may:
Postpone progression of CIS to clinically definite MS
Reduce risk of disability progression
Depression (IFB)
Injection site reactions (Both)
Flu-like symptoms (fever, chills, nausea) (IFB)
Elevated liver function tests (IFB)
Chest Pain & Shortness of breath (glatiramer)
50% of pts D/C initial DMD due to AEs
Management: pt education; prophylax anti-depressants with IFNs; rotate injection sites & warm meds; dose reduction
lipoatrophy
Natalizumab (TysabriTM): humanized monoclonal antibody against a4-integrin CAM Prevents T cell egress thru BBB
IV infusion Q28 days
Small risk of progressive multifocal leukoencephalopathy (PML) – 31 total cases
Mitoxantrone (NovantroneTM): anti-cancer drug (topoisomerase inhibitor) used in 2° progressive MS Cumulative cardiac toxicity
1 in 133 pts develop leukemia
Current AAN Recommendations for DMDs
in Patients With MS1
AAN: American Academy of Neurology.
1. Goodin DS et al. Neurology. 2002;58:169-178. 2. Goodin DS et al. Neurology. 2008;71:766-773.
First-Line Therapies
IFN -1a
IFN -1b
GA
Second-Line Therapies
Natalizumab2
Mitoxantrone
Therapeutic Goals
Prevent future relapses
Slow disease progression
Prevent long-term disability
The AAN does not currently recommend one first-line therapy over another; the choice of IFN betas or GA is made at the discretion of the clinician and patient
Natalizumab may be considered for first-line therapy for patients with an “aggressive” disease course (ie, ≥9 lesions on baseline MRI)
Goal: equivalent or superior efficacy to
injectable agents & convenience
Currently Available: Fingolimod (GilenyaTM)
Prevents egress of T cells from lymph nodes
Diminishes auto-aggressive lymphocytic infiltration of CNS
Superior reduction of relapses when compared head-to-head with Interferon B-1a
Increased risk of infection, HTN and bradycardia
0.5-1.5% incidence of CME
Cohen JA et al. New Engl J Med. 2010;362:402-415. Kappos L et al. N Engl J Med. 2010;362:387-401.
Fingolimod Improves ARR, MRI Outcomes
vs IFN β
• MRI outcomes significantly favored fingolimod
– Fewer new/enlarged lesions, Gd-enhancing lesions vs IFN β group
– Lower 12-mo reduction in brain volume vs IFN β
– Disability progression infrequent across all 3 groups
Cohen JA et al. New Engl J Med. 2010;362:402-415.
Fingolimod at 2 dosing levels
improves ARR vs IFN β
Oral Cladribine in MS : Not FDA approved
1. Beutler E. Lancet. 1992;340:952-956. 2. Guarnaccia JB et al. World Congress on Treatment and
Research in Multiple Sclerosis (WCTRMS 2008). Poster. 3. Rice GP et al. Neurology 2000;54:1145-1155.
4. Leist T, Weissert R. Presented at the 23rd CMSC (2009). 5. Romine JS et al. Proc. Assoc. Am.
Physicians. 1999;111:35-44.
• Oral formulation of purine nucleoside analog
– Effects include rapid and sustained reductions in CD4+
and CD8+ cells1-4
– Rapid, more transient effects on CD19+ B cells, with
relative sparing of other immune cells
– Reduction in levels of proinflammatory cytokines, serum
and cerebrospinal fluid chemokines
• Cladribine in MS: oral formulation tested after parenteral
cladribine effective in small RRMS trial5
– Improvement in MRI outcomes only in chronic
progressive setting
Other Oral Therapies in Development
for MS
BG12
(oral fumarate
derivative)1
• Anti-inflammatory and neuroprotective effects; decreases
circulating T cells
• Associated with reduction in MRI-measured lesions in phase 2
trial1
Laquinimod
(ABR-215062)2
• Immunomodulatory, anti-inflammatory actions; inhibits
infiltration of CD4+ T cells, macrophages into CNS
• At 0.6 mg/day has induced statistically significant decrease in
cumulative number of Gd-enhancing lesions vs PBO
Teriflunomide3
• Inhibits pyrimidine synthesis; immunomodulatory and
anti-inflammatory activity
• Teriflunomide-treated patients in phase 2 trial showed
statistically significant decrease in active MRI lesions vs PBO
• Trend towards a lower ARR and fewer relapsing patients with
teriflunomide 14 mg/day vs placebo
• Significantly fewer patients receiving 14 mg/day dose
demonstrated disability increase vs placebo
1. Kappos L et al. Lancet. 2008;372:1463-1467. 2. Comi G et al. Lancet. 2008;371:2085-2092.
3. O'Connor PW et al. Neurology. 2006;66:894-900.
Dietary
Swank Diet: low fat (< 20 g/d) showed 84% reduction in MS mortality over 34 years
Best Bet Diet: low saturated fat, correction of leaky gut, elimination of food allergens using ELISA
Both diets recommend elimination of eggs, legumes, dairy
Low Dose Naltrexone (LDN)
Very popular amongst MS bloggers
Lots of anecdotal evidence of benefit
Limited scientific evidence for improved QoL
Estrogen & Testosterone Therapies
Reduced MRI lesions and relapses during pregnancy (estriol effect) and lower AI Dz in men
UCLA pilot studies showed dramatic improvement in RRMS MRI lesions with supplemental estriol in women and cognitive scores/brain atrophy in men
.J Immunol. 2003 Dec 1;171(11):6267-74. Arch Neurol. 2007 May;64(5):683-8.
Ann Neurol. 2010 Aug;68(2):145-50
Impact of Vitamin D on MS
• Should you add vitamin D to your MS treatment
regimen?
– Vitamin D deficiency is a risk factor for MS;
multivitamin is recommended (1,000-2,000
IU/day vitamin D3)
– There are no data that show vitamin D
supplementation improves outcomes in patients
with MS
BUT……. Higher serum 25-OH vitamin D levels are
associated with up to a 54% decrease in MS Dx
Legend:
All percentages reference a common baseline of 25 ng/ml as shown on the chart. %’s reflect the disease prevention % at the beginning and ending of
available data. Example: Breast cancer incidence is reduced by 30% when the serum level is 34 ng/ml vs the baseline of 25 ng/ml. There is an 83% reduction
in incidence when the serum level is 50 ng/ml vs the baseline of 25 ng/ml. The x’s in the bars indicate ‘reasonable extrapolations’ from the data but are
beyond existing data.
References:
All Cancers: Lappe JM, et al. Am J Clin Nutr. 2007;85:1586-91. Breast: Garland CF, Gorham ED, Mohr SB, Grant WB, Garland FC. Breast cancer risk according
to serum 25-Hydroxyvitamin D: Meta-analysis of Dose-Response (abstract).American Association for Cancer Research Annual Meeting, 2008. Reference
serum 25(OH)D was 5 ng/ml. Garland, CF, et al. Amer Assoc Cancer Research Annual Mtg, April 2008,. Colon: Gorham ED, et al. Am J Prev Med.
2007;32:210-6. Diabetes: Hyppönen E, et al. Lancet 2001;358:1500-3. Endometrium: Mohr SB, et al. Prev Med. 2007;45:323-4. Falls: Broe KE, et al. J Am
Geriatr Soc. 2007;55:234-9. Fractures: Bischoff-Ferrari HA, et al. JAMA. 2005;293:2257-64. Heart Attack: Giovannucci et al. Arch Intern Med/Vol 168 (No 11)
June 9, 2008. Multiple Sclerosis: Munger KL, et al. JAMA. 2006;296:2832-8. Non-Hodgkin’s Lymphoma: Purdue MP, et al. Cancer Causes Control.
2007;18:989-99. Ovary: Tworoger SS, et al. Cancer Epidemiol Biomarkers Prev. 2007;16:783-8. Renal: Mohr SB, et al. Int J Cancer. 2006;119:2705-9. Rickets:
Arnaud SB, Copyright GrassrootsHealth, 10/16/08 www.grassrootshealth.org.
Benefits to increased levels of Vitamin D
Ocular findings are common in MS
Optometrists should be aware of the pharmacologic and non-pharmacologic management of MS
Encouraging patients to continue with DMD may help reduce disability
