Multiple Sclerosis -Diagnostic Issues

Multiple Sclerosis -Diagnostic Issues
By:Christopher Bourque

* Manifestations due to CNS
o Slowing or failure of transmission
+ Inflammatory demyelination
+ Axonal damage
o Mostly damage of white matter tracts
+ Optic neuritis, weakness, sensory loss, ataxia nystagmus, bladder dysfunction, cognitive impairment
* Diagnosis based on clinical and laboratory evidence of
+ Dissemination in time
+ Dissemination in space
Patterns of MS
* Relapsing - remitting
o Attacks with complete/incomplete recovery
o Stable between attacks
* Secondary - progressive
o Initially relapsing-remitting
o Then progression +/- attacks
* Progressive - relapsing
o Initial gradual detioriation
o Subsequent episodes
* Primary progressive
o Gradual decline
o No attacks


Schumacher Clinical Criteria MS Diagnosis 1965
* Age (onset 10-50 years)
* CNS white matter disease
* Lesions disseminated in time and space
* Objective abnormalities on exam
* Consistent time course
o Attacks lasting > 24 hrs., spaced at least 1 month apart
o Slow or stepwise progression for > 6 months
* No better explanation
* Diagnosis by experienced clinician

Poser Criteria for the Diagnosis of MS 1983
* Widely used for last 20 years
* Definite or probable
* Laboratory supported MS
* Replaced by McDonald criteria 2001
o Technical advances enable quicker dx.
o Controversial
Additional Requirements to Make Diagnosis
Objective Lesions
Clinical (attacks)
McDonald Criteria
Positive CSFand
Dissemination in space by MRI evidence of 9 or more T2 brain lesions or 2 or more cord lesions or 4-8 brain and 1 cord lesion or positive VEP with 4-8 MRI lesions or positive VEP with less than 4 brain lesions plus 1 cord lesion and Dissemination in time by MRI or continued progression for 1 year

Clinical Manifestations
* Demographic
o Female
+ Women make up to 70%-75% MS patients
o Young age
+ Onset before age 16: 5% of cases
+ Peak onset post puberty, early 20’s
# Relapsing MS 28-30 years
* Symptoms
o Recent onset
o Frequently progressive
+ Coming on over 1-several days
+ Very acute symptoms possible
The MS Event
* Attack/relapse/exacerbation
o Acute episode of CNS dysfunction
o Lasting at least 24 hours
o In absence of fever or metabolic derangement
o All events within 30 days are unitary

MS Symptoms
* Motor
o Weakness, spasticity, ataxia
o Rarely radicular
+ lesion ant. horn, root entry zone
+ painful
+ atrophy
* Somatosensory
o 1st sx. in 43% patients
+ Includes visual
o Any anatomic distribution
o Any combination
+ Loss pain, temp, light touch, vbn, position
o Positive sx. common
+ Paresthesiae, hyperpathia, allodynia, dysesthesias
Nonspecific Associated Features That Suggest MS
* Excessive unexplained fatigue
* Temperature sensitivity
o Hot, humid weather
* Relatively recent symptoms
* History of Lhermitte’s sign
* History of bandlike sensation around the waist
* Uhthoff’s phenomenon
o eg, blurry vision with exercise or heat exposure * Fatigue
o One of the most important causes of disability
o Several sources
+ Handicap fatigue
# Increased effort to perform routine tasks
+ Secondary fatigue
# Depression, sleep disturbances, medication side-effects, other conditions
+ Systemic fatigue
# Chronic lack of energy, tirdness, malaise
# Etiology unknown

* Cognitive Disturbances
o Common, frequently overlooked
+ Estimated 50-75%
o Most common
+ Impaired attention, slow info processing, short term memory loss, reduced visuospatial skills, impaired executive function
o Impaired driving skills
o Important impact QoL, ADL
o Can occur independent
+ of disease course
+ other manifestations
MRI in MS
* Brain lesions
o Character
o Location
Evoked Potentials
* Visual evoked potentials
Principal Differential Diagnosis of Multiple Sclerosis

* Infection
* Inflammatory
* Metabolic
* Neoplastic
* Spine disease
Cerebrospinal Fluid
* Useful, not diagnostic
o Other conditions
+ Chronic CNS infections, viral syndromes, neuropathies
* Immunoglobulin abnormalities
o Production of immunoglobulin
# By plasma or B cells in CNS
+ Oligoclonal bands of immunoglobulin (IgG) (OCB)
# In CSF, not serum
# Isoelectric focusing technique
+ Elevated IgG index
# Ratio of IgG/protein in serum and CSF
# index = (csf IgG/csf albumin)
(serum IgG/serum albumin)

* First event - chance of progression to MS
o In 3 years
+ OCB +ve: 25%
+ OCB -ve: 9%
* CIS:clinically isolated syndrome
o 62.5% cases +ve OCB
* Clinically definite MS
o 90% +OCB
MRI in MS

* Spinal cord lesions
o Character
+ Asymptomatic lesions
+ Focal T2/proton density hyperintense lesions
+ Diffuse proton density abnormalities
+ Atrophy
+ Asymmetric involvement
# Multiple scattered lesions
+ Edema with acute plaques
# Often enhancing
o Location
+ Cervical and thoracic
# Especially midcervical
+ Peripheral
+ Less than 2 vertebral segments
+ Less than 50% cross-sectional area
+ Lateral, dorsal cord
Paroxysmal Symptoms in MS
* Trigeminal neuralgia (and others)
* Tonic “seizures”
* Paroxysmal dysarthria
* Hemifacial spasm
* Paroxysmal itching
* Abrupt loss of muscle tone
* Paroxysmal aphasia
* Paroxysmal kinesogenic choreoathetosis
* Lhermitte’s sign
* Visual symptoms, afferent
o Almost any pattern, related to location
o Optic neuritis
+ Central scotoma
# Mild: color desaturation
# Severe: blindness
* Vast majority have excellent return by 6 months
+ Frequent pain
# Worse on eye movement
Optic Neuritis Risk of Subsequent MS
* Other Brain Stem Structures
o Facial weakness
o Vertigo
o Loss of hearing, taste
o Dysarthria, dysphagia
+ Bulbar muscles
# Weakness, ataxia, spasticity
* Psychiatric Disturbances
o Depression
o Emotional incontinence
* Bladder dysfunction; the importance of urodynamic studies
o Failure to store: detruser hyperactivity
+ Urgency, frequency, nocturia
o Failure to empty
+ Detruser-sphincter dyssynergia
+ Poor detruser contraction
# Hesitancy, increased residual vol., retention
o Both
+ Combined
# detruser hyperactivity
# detruser-sphincter dyssynergia
o Incontinence
+ Detruser hyperactivity or
+ Overflow
+ Symptoms may not be accurate indicator of urodynamic pathology
* Bowel dysfunction
* Sexual dysfunction
o Erectile dysfunction
o Women: loss of libido, anorgasmia
o Both sexes
+ Loss of perineal sensation
+ Neuropathic pain
+ Spasticity
+ Incontinence
+ Depression, fatigue

Pain Syndromes in MS
* Primary pain
o Neuralgic
+ Trigeminal neuralgia
+ Other neuralgias
o Dysesthetic pain
+ Most often burning (legs)
+ Other dysesthesias
o Radicular pain
o Tonic seizures
o Spasticity
+ Flexor spasms
+ Extensor spasms
* Secondary pain
o Low back pain
o Osteoporosis with fractures
Neurologic Syndromes Likely for MS
* Optic neuritis
+ Unilateral eye involvement
+ Retrobulbar rather than papillitis
+ Eye pain
+ Partial vision loss, with at least some recovery
+ No retinal exudates, disc hemorrhages, macular star
o 10 years follow-up: 38% develop MS
+ MRI other lesions: risk 56%
+ MRI normal: risk 22%
o 20 years follow-up: 70% develop MS
* Transverse Myelitis
+ Incomplete
+ Sensory > motor
+ Associated
# Lhermitte’s sign
# Bandlike abdominal or chest pressure
* Internuclear Ophthalmoplegia
* Trigeminal Neuralgia
* Hemifacial Spasm
* Paroxysmal symptoms
+ Last seconds to minutes
+ Occur multiple times daily
o Tonic spasms
o Dysarthria, ataxia
o Hemiparesis, hypesthesia
Clues to a Misdiagnosis; MS
o Examination
+ Prominent
# fever, headache, uveitis, pain
+ Abrupt
# hemiparesis, hearing loss
+ No
# optic nerve/ocular involvement
# bowel/bladder involvement
+ Progressive myelopathy
# Without bowel/bladder involvement
+ Impaired level of consciousness
+ Nonscotomatous visual field defects
+ Grey matter features
# Early dementia, aphasia
# Fasciculations
# Extrapyramidal features
o MRI
+ Brain
# Normal
# Small lesions < 3 mm.
# Subcortical location (internal capsule)
# Prominent infratentorial involvement
# Prominent grey matter involvement (basal ganglia)
# Symmetric, confluent hemispheric white matter involvement
# Hydrocephalus
# Severe cerebellar/brain stem atrophy
# No callosal/periventricular lesions
* Manifestations due to CNS
o Slowing or failure of transmission
o Mostly damage of white matter tracts
o Recent appreciation of axonal/grey matter involvement
* Diagnosis based on clinical and laboratory evidence of
o Dissemination in time
o Dissemination in space
o Recent appreciation of role of MRI in assisting diagnosis
* In-office pattern recognition
o Appropriate demographic
o Appropriate clinical event

Multiple Sclerosis Diagnostic Issues.ppt

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Clinical outcome Measures, Trials

Clinical outcome Measures, Trials
By:Professor and Acting Chair of Neurology
Director, MS Comprehensive Care Center
SUNY at Stony Brook, New York


MS: Diagnostic Issues
* Diagnostic principles
* Misdiagnosis clues
* Differential diagnosis
* Case presentations

Diagnosis Of MS
Diagnosis Based On Schumacher Criteria
* Appropriate age (10-50 years)
* CNS white matter disease
* Lesions disseminated in time and space
* Objective abnormalities
* Consistent time course
* No better explanation
* Diagnosis by a competent clinician
(preferably neurologist)

MRI Dissemination In Space
MRI Dissemination In Time
Diagnostic Criteria
Diagnostic Criteria For Primary Progressive MS
Diagnosis Of MS: MRI
MRI Features Suggestive of MS
Diagnosis Of MS: CSF
Diagnosis Of MS: Blood And Ancillary Tests
Diagnosis Of MS: Evoked Potentials
Misdiagnosis of MS
* Clinical
* Neuroimaging
* Cerebrospinal fluid (CSF)

Clinical Clues
* Normal examination
* No dissemination over time and
space
* Onset before age 10 or after age 55
* Genetic "red flag”
+ positive family history
+ early age onset
+ unexplained non CNS disease
* Progressive course starting before age 35
* Localized disease
* Atypical features
+ prominent fever
+ prominent headache
+ abrupt hemiparesis
+ abrupt hearing loss
+ prominent pain (except trigeminal
neuralgia)
+ no optic nerve or ocular motility
disturbance
+ normal sensory and bladder function
+ progressive myelopathy without
bladder /bowel involvement
+ impaired level of consciousness
+ prominent uveitis
+ peripheral neuropathy
+ nonscotomatous field defects
+ gray matter features (prominent
early dementia, seizures, aphasia,
fasciculations, extrapyramidal
features)

Neuroimaging Clues
Brain
* Normal brain MRI
* Small lesions (< 3mm)
* Subcortical lesions (internal
capsule)
* Predominant infratentorial
involvement
* Prominent GM involvement (basal
ganglia)
Neuroimaging Clues
Brain
* Symmetric, confluent hemispheric
WM involvement
* Significant mass effect
* Hydrocephalus
* Severe cerebellar/ brainstem atrophy
* Absence of callosal or periventricular
lesions

Neuroimaging Clues
Spinal cord
* Lesion > 2 vertebral segments
* Severe swelling
* Full thickness lesions
CSF Clues
* Normal CSF
* Disappearance of oligoclonal bands;
normalization of intrathecal IgG production
* Cell count > 50 WBC /mm3
* Protein > 100 mg/dl

Differential Diagnosis of MS
* Genetic
* Infectious
* Inflammatory
* Metabolic
* Miscellaneous
* Neoplastic
* Psychiatric
* Structural
* Toxic
* Vascular
* Variants

Acute Leukoencephalopathy
Feature Disorders
Cranial neuropathies - Lyme disease, Sarcoidosis
Cortical blindness - multiple infarcts, PML,
Hearing loss - Cogan’s, Susac
Intracranial - hemorrhagic infarction, tumor,
hemorrhage venous infarction
Acute Leukoencephalopathy
Feature Disorders
Lockedin syndrome - CPM, infarction
Migraine - antiphospholipid syndrome,CADASIL, mitochondrial encephalopathy
Muscular rigidity - paraneoplastic brainstem encephalitis
Myoclonus - antiamphiphysin paraneoplastic syndrome, hashimoto’s
Papilledema - Gliomatosis, venous sinus thrombosis
Differential Diagnosis:
Variants
* Balo's concentric sclerosis
* Disseminated subpial demyelination
* Neuromyelitis optica (Devic's disease)
* Marburg variant
* Tumefactive MS
* Myelinoclastic diffuse sclerosis
(Schilder disease)
* Postinfectious encephalomyelitis
* Clinically isolated syndromes

CIS Issues
CIS Controversies
* What features define first attack MS
* What features predict subsequent course
* Who should be offered MS DMT

CIS Considerations
* Appropriate age
o excludes too young and too old
* Characteristic syndrome
* Other causes excluded
* Abnormal brain MRI
o with suggestive features
MS CIS Syndromes
* typically unilateral
* retrobulbar
* typically painful
* some recovery expected
* no retinal exudates or

Optic neuritis
MS CIS Syndromes
Myelitis
MS CIS Syndromes
MRI Dissemination in Space*
MRI Dissemination In Time
Diagnostic Criteria
CIS and MRI Predictors*
Role Of MRI In Suspected MS*
MS Differential Diagnosis
* Migraine
* Sarcoid
* Sjögren syndrome
* Stroke and ischemic
* Unidentified bright objects on MRI
* Vascular malformations
* Vasculitis (primary CNS or other)
* Vitamin deficiency (B12, E)
* Number and volume of brain MRI
CIS and Therapy
CIS: Conclusions
Cognitive Impairment In Minimal Disability MS*
Diagnostic Criteria For Primary Progressive MS
Neuromyelitis Optica (NMO)
NMO Differential
NMO: Clinical Features
Recent Pediatric Series ..........

Clinical outcome Measures, Trials.ppt

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Clinical Trial Design Considerations

SMA Type I Clinical Trial Design Considerations
Outcome measure for non ambulant patients
by: Eugenio Mercuri
Catholic University, Rome

Comments on the non ambulant phenotype
o Patients with type II SMA or type III who are not able to walk 10 M independently
o Wide variability
o Standards of care available
o Relatively stable condition within 12-18 months
o No consistent endpoint or life altering event
o Need for defining clinically meaningful changes over time in possible trials

Which outcome measures?
* most measures (timed items, 6 minute walk) not applicable to non ambulant patients with neuromuscular disorders
* muscle strength measurements have been used but are not adequate for very weak children
* Recent studies (after 2005) mainly used functional scales
Why functional scales?
* measures of function more sensitive than strength measurements in weak patients
* More clinically meaningful: patients, families and doctor do have difficulties in identifying generic increase in muscle strength if disjointed from measurements of daily life activity that “mean” something.

* Unlike other measures such as myometry or pulmonary function, functional scales can be reliably used in young children from 30 months

Which functional scales?

* There are a number of functional scales available for non ambulant patients with SMA
* In the last few years TREAT NMD and ICC have promoted a series of workshops in Europe and in the US to find a consensus on outcome measures among all the experts on outcome measures and on trials in SMA

Combined TREAT NMD/ICC
* TREAT NMD consensus further discussed with ICC representatives for outcome measures
* In a recent combined meeting in Boston (June 2008) involving both TREAT NMD and ICC representatives a more general consensus was reached for all three forms of SMA, identifying the Hammersmith Motor Functional scale as the most appropriate and specific scale for type II and more generally, for non ambulant patients

Why the Hammersmith scale?
* Disease specific (developed for and validated in non ambulant SMA children)
* Easy, little equipment,
* Short
* Not stressful for children
* Easily used in routine practice

Evidence from literature: ICC review of the literature
AMBULATORY PROBABILITIES
HAMMERSMITH FUNCTIONAL MOTOR SCALE
UPPER EXTREMITY GRADE
SMA FUNCTION RATING SCALE (SMAFRS)
SCOTT SCALE
JEBSEN TEST OF HAND FUNCTION
STANDARDIZED PROTOCOL
FUNCTIONAL MOTOR SCALE
GROSS MOTOR FUNCTION MEASURE (GMFM)
MOTOR FUNCTION MEASURE SCALE (MFM)
EXPANDED HAMMERSMITH FUNCTIONAL MOTOR SCALE
EK SCALE
Method Studies* (Cross-Sectional)
Natural History (Cross-Sectional)
Natural History (Longitudinal)
Clinical Trials
Outcome Measures
Validation studies available
Validation in
* UK (Main et al, 2003)
* Italy (Mercuri et al, 2007)
* US (PNCR data, PC SMA)
* Excellent interobserver reliability
* Very simple instructions, manual available, ideal for multicentric studies

Widely used across the world
* ICC survey on outcome measures (2008)
* ICC Survey Parameters
* Sent to International SMA Community (ICC and TREAT-NMD lists) in February, 2008
* 35 Sites responded
* 22 Countries were represented
* 858 patient exposures (estimated)
* 27 sites
o Ljubljana, Slovenia
o Ankara, TR
o Messina, IT
o Birmingham, UK
o Oswestry, UK
o Rome, Italy
o Bristol, UK
o Warsaw, Poland
o Freiburg, Germany
o Kharkiv, Ukraine
o Rio de Janeiro, Brazil
o Philadelphia, PA USA
o Boston, MA USA
o New York, NY USA
o Chicago, IL USA
o Salt Lake City, Utah USA
o Philadelphia, PA USA
o Salt Lake City, Utah USA
o Chicago, IL USA
o Sydney, Australia

Natural history data available
* 3 and 6-month data available in 110 non ambulant Italian children age 30 months 12 years
* 6, 12 and 18 month data available in 17 patients (Pediatric Neuromuscular Clinical Research Network (PNCR) .
* Similar data collected by the Project Cure SMA network
* No significant changes between baseline and any of the 6,12, 18 months assessment
* According to these data the diseases is relatively stable over 3, 6, 12 and 18 months periods with minimal changes
* Non ambulant patients generally do not have obvious increases in their scores
* Less than 10% has an increase > 2 points

Already used in trials
* Salbutamol (published)
* Phenylbutyrate (double blind) (published)
* Valproate (just completed)

Is this clinically meaningful?
* Difficult to define what is clinically meaningful
* No clear life altering events that could be predicted
* Relatively stable condition
* Quite wide variability in functional abilities and in possible improvements
What is clinically meaningful for families
* Questionnaire developed by ICC
* 91 families of children with non ambulant SMA
* Families were asked if they were happy to participate to clinical trials and what would be the reason for participating into a trial
* THE CURE!
* Stabilization of the disease over long periods of time
* Any improvement of functional activities

(short term studies)

* While in the long run stabilization would be acceptable by families, in a short trial (1 year) any improvement would be considered beneficial
Primary endpoint: Hammersmith scale
* Evidence from literature
* Validation studies
* Widely used across Europe and US
* Natural history data available
* Already used in trials on non ambulant SMA patients
Secondary measures
* Electrophysiology measure: CMAP
* QOL measure
* Caregiver assessment questionnaire
* Growth parameters
* Pulmonary Function: excellent outcome measure

Reliable, already used in clinical trials but can only be reliably performed in children above the age of 5
* Strength reliable in most patients but can only be reliably performed in children above the age of 5
Summary

Clinical Trial Design Considerations.ppt

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