Clinical outcome Measures, Trials,

1
MS Diagnostic Issues
Professor and Acting Chair of Neurology
Director, MS Comprehensive Care Center SUNY at
Stony Brook, New York
2
MS Diagnostic Issues

• Diagnostic principles
• Misdiagnosis clues
• Differential diagnosis
• Case presentations

3
Diagnosis Of MS

• Prototypic patient young caucasian
• female with episodic acute/
• subacute neurologic deficits that
• spontaneously improve

4
Diagnosis Of MS

• Many variations on this theme
• male
• pediatric or older individuals
• slow worsening
• Hispanic, Asian, Middle Eastern,
• African, African-American
• populations
• This is likely a heterogeneous
• disease

5
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
• attacks lasting gt 24 hours spaced one
• month apart
• slow/stepwise progression gt 6 months
• No better explanation
• Diagnosis by a competent clinician
• (preferably neurologist)

6
MRI Dissemination In Space

• 3 of 4 criteria
• 1Gd lesion, or 9 T2W hyperintense lesions
• ? 1 infratentorial lesion
• ? 1 juxtacortical lesion
• ? 3 periventricular lesions
• lesions ordinarily gt 3mm
• Spinal cord lesion may substitute
• for brain lesion

7
MRI Dissemination In Time

• First scan ? 3 mos after clinical event
• Gd lesion (at independent site)
• demonstrates dissemination
• in time
• Gd scan follow up MRI ? 3 mos
• new T2W or Gd lesion
• demonstrates dissemination
• in time

8
MRI Dissemination In Time

• First scan lt 3 mos after clinical event on 2nd
  scan ? 3 mos after event
• Gd lesion demonstrates
• dissemination in time
• Gd scan follow up 3rd MRI ? 3 mos
• after 1st new T2W or Gd lesion
• demonstrates dissemination in time

9
Diagnostic Criteria

• Clinical presentation Space Time
• ? 2 attacks objective no no
• clinical evidence of
• ? 2 lesions
• ? 2 attacks objective abn MRI no
• clinical evidence or
• of 1 lesion ? 2 MRI lesions
• abn CSF
• or
• new attack
• at new site

10
Diagnostic Criteria

• Clinical presentation Space Time
• 1 attack objective no MRI
• clinical evidence criteria or
• of ? 2 lesions 2nd attack
• 1 attack objective MRI criteria MRI
• clinical or criteria
• evidence of ? 2 MRI or
• 1 lesion lesions 2nd
• (CIS) abnormal attack
• CSF

11
Diagnostic Criteria For Primary Progressive MS

• Abnormal CSF
• Either
• ? 9 T2W brain MRI lesions
• ? 2 spinal cord lesions
• 4-8 brain plus 1 cord lesion(s)
• 4-8 brain lesions plus abn VEP
• lt4 brain plus 1 cord lesion abn VEP
• Dissemination in time by MRI, or
• continued progression for 1 yr

12
Diagnosis Of MS MRI

• Brain MRI with contrast endorsed
• for all patients
• Spinal MRI more selective
• abnormal in most patients
• in a minority, MRI lesions confined
• to spinal cord
• Number, size, location, and features
• of the lesions are important

13
MRI Features Suggestive of MS

• Multiple white matter lesions
• Large lesions (? 3mm)
• Ovoid, perpendicular to ventricle

14
MRI Features Suggestive of MS

• Brainstem/ infratentorial lesions
• Juxtacortical lesions
• Corpus callosum lesions
• (sagittal T2W, pointing away,
• moth eaten changes, atrophy)
• Open ring enhancement
• Enhancing lesions

15
Diagnosis Of MS CSF

• OCB (by IEF/ immunoblot) and IgG
• index are key tests
• MBP not useful
• OCB most specific (but must be
• interpreted with paired serum)
• Low positive IgG index may be
• false positive (high or low protein)

16
Diagnosis Of MS Blood And Ancillary Tests

• No suggestive blood tests to support
• diagnosis (? Anti-MOG, MBP IgM)
• Blood tests used to exclude
• alternative or co-diagnoses
• Basic panel
• CBC, chemistries, ESR, ANA,
• Vit B12, TSH, anticardiolipin
• antibodies
• Lyme serology (endemic areas),
• RPR

17
Diagnosis Of MS Blood And Ancillary Tests

• Additional panel
• ACE, antineuronal antibodies,
• SS-A/ SS-B
• Vit E, VLCFA, lactate
• Ancillary tests
• CXR, U/A, EKG
• bladder ultrasound,
• cystometrogram

18
Diagnosis Of MS Evoked Potentials

• Used to detect silent lesion or
• confirm suspected lesion
• VEP most useful (esp in PP MS),
• followed by SSEP (lower
• extremities)

19
Clues To A Misdiagnosis of MS

• Clinical
• Neuroimaging
• Cerebrospinal fluid (CSF)

20
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

21
Clinical Clues (cont.)

• Progressive course starting
• before age 35
• Localized disease

22
Clinical Clues (cont.)

• Atypical features
• prominent fever
• prominent headache
• abrupt hemiparesis
• abrupt hearing loss
• prominent pain (except trigeminal neuralgia)

23
Clinical Clues (cont.)

• Atypical features (cont.)
• no optic nerve or ocular motility disturbance
  
• normal sensory and bladder function
• progressive myelopathy without bladder
  /bowel involvement
• impaired level of consciousness
• prominent uveitis

24
Clinical Clues (cont.)

• Atypical features (cont.)
• peripheral neuropathy
• nonscotomatous field defects
• gray matter features (prominent early
  dementia, seizures, aphasia, fasciculations,
  extrapyramidal features)

25
Neuroimaging Clues

• Brain
• Normal brain MRI
• Small lesions (lt 3mm)
• Subcortical lesions (internal capsule)
• Predominant infratentorial involvement
• Prominent GM involvement (basal ganglia)

26
Neuroimaging Clues

• Brain
• Symmetric, confluent hemispheric WM
  involvement
• Significant mass effect
• Hydrocephalus
• Severe cerebellar/ brainstem atrophy
• Absence of callosal or periventricular
  lesions

27
Neuroimaging Clues

• Spinal cord
• Lesion gt 2 vertebral segments
• Severe swelling
• Full thickness lesions

28
CSF Clues

• Normal CSF
• Disappearance of oligoclonal bands
• normalization of intrathecal IgG production
• Cell count gt 50 WBC /mm3
• Protein gt 100 mg/dl

29
Differential Diagnosis of MS

• Genetic
• Infectious
• Inflammatory
• Metabolic
• Miscellaneous
• Neoplastic

• Psychiatric
• Structural
• Toxic
• Vascular
• Variants

30
Acute Leukoencephalopathy

• Feature Disorders
• Cranial neuropathies - Lyme disease,
  Sarcoidosis
• Cortical blindness - multiple infarcts, PML,
• posterior
• leukoencephacopathy of
• Caplan
• Hearing loss - Cogans, Susac
• Intracranial - hemorrhagic infarction,
  tumor,
• hemorrhage venous infarction

31
Acute Leukoencephalopathy

• Feature Disorders
• Lockedin syndrome - CPM, infarction
• Migraine - antiphospholipid syndrome,
• CADASIL, mitochondrial
• encephalopathy
• Muscular rigidity - paraneoplastic brainstem
• encephalitis
• Myoclonus - antiamphiphysin paraneoplastic
• syndrome, hashimotos
• Papilledema - Gliomatosis, venous sinus
• thrombosis

32
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

33

• CIS Issues

34
CIS Controversies

• What features define first attack MS
• What features predict subsequent
• course
• Who should be offered MS DMT

35
CIS Considerations

• Appropriate age
• excludes too young and too old
• Characteristic syndrome
• Other causes excluded
• Abnormal brain MRI
• with suggestive features

36
MS CIS Syndromes
Optic neuritis

• typically unilateral
• retrobulbar
• typically painful
• some recovery expected
• no retinal exudates or
• macular star
• disc hemorrhages
• infrequent

37
MS CIS Syndromes
Myelitis

• partial sensory or motor
• sensory more common
• lhermitte sign
• bowel and bladder
• dysfunction common
• band-like" abdominal or
• chest pressure
• acute dystonias

38
MS CIS Syndromes

• ocular motor syndromes
• (INO, nystagmus)
• hemisensory, crossed
• sensory syndromes
• hemiparesis
• trigeminal neuralgia
• hemifacial spasm

Brainstem/ Cerebrum
39
MS CIS Syndromes

• cerebellar outflow
• tremor
• acute ataxic syndrome
• tonic spasms
• paroxysmal
• dysarthria/ataxia
• other paroxysmal
• attacks

Cerebellum
Paroxysmal symptoms
40
MRI Dissemination in Space

• Three of four of the following
• One gadolinium-enhancing lesion
• or 9 T2 lesions if there is no
• Gd-enhancing lesion
• At least 1infratentorial lesion
• At least 1juxtacortical lesion
• At least 3 peri-ventricular lesions
• (spinal cord lesion can substitute
• for brain lesion)
• McDonald Ann Neurol 2001

41
MRI Dissemination In Time

• First scan ? 3 mos after clinical event
• Gd lesion (at independent site)
• demonstrates dissemination
• in time
• Gd scan follow up MRI ? 3 mos
• new T2W or Gd lesion
• demonstrates dissemination
• in time

42
MRI Dissemination In Time

• First scan lt 3 mos after clinical event on 2nd
  scan ? 3 mos after event
• Gd lesion demonstrates
• dissemination in time
• Gd scan follow up 3rd MRI ? 3 mos
• after 1st new T2W or Gd lesion
• demonstrates dissemination in time

43
Diagnostic Criteria

• Clinical presentation Space Time
• 1 attack objective no MRI
• clinical evidence criteria or
• of ? 2 lesions 2nd attack
• 1 attack objective MRI criteria MRI
• clinical or criteria
• evidence of ? 2 MRI or
• 1 lesion lesions 2nd
• (CIS) abnormal attack
• CSF

44
CIS and MRI Predictors

• CHAMPS placebo group analysis (n190)
• 27 developed CD MS by 18 mos
• Best MRI predictor for CD MS was ?
• 2 Gd brain lesions (52 vs 24)
• Barkhof criteria less predictive
• (32 vs 16)
• these findings followed high dose
• steroid treatment
• CD MS and / or ? 1 T2 lesions occurred
• in 84 Neurology 2002 59 998

45
ETOMS-Baseline Prognostic Factors for Conversion
to CDMS at 2 Years

• Polysymptomatic OR2.2 P0.009
• T2 lesions (gt8) OR3.6 P0.011
• T2 lesions (gt8) OR6.1 P0.017
• Gd lesion
• Gd lesions OR1.5 P0.88
• Comi G, et al. Lancet 2001 357 1576-1582.
• Barkhor F, et al. Ann Neurol 2003 53718-724

46
MRI in CIS

• N42 CIS patients, followed 8.7 yrs
• (median)
• ? 2 infratentorial lesions was best
• predictor of disability (EDSS ?3)
• lesser predictors were ? 9,
• ?3 periventricular, ? 2 callosal,
• ? 4 frontal, ? 2 temporal, ? 2 more
• than 6 mm lesions
• Arch Neurol 2004 61 217, 222 Neurology
  1999 53 1184

47
MRI in CIS

• N51 CI brainstem (CIBS) lesion,
• 102 other CIS patients, followed
• 34 to 40 mos (median)
• infratentorial lesion criteria for
• dissemination in space had
• ? diagnostic specificity in CIBS
• vs. CIS (61 vs. 73)
• Arch Neurol 2004 61 217, 222 Neurology
  1999 53 1184

48
MRI in CIS

• CIS patients with T1 hypointense
• lesions show ? rates of new lesion
• formation
• Arch Neurol 2004 61 217, 222 Neurology
  1999 53 1184

49
Role Of MRI In Suspected MS

• CIS patients
• ? 3 T2 WM lesions sensitive predictor of
• CDMS within 7-10 yrs (type A
• recommendation)
• possible that 1-3 WM lesions may be equally
• predictive
• ? 2 Gd lesions highly predictive for CDMS
• (type B)
• new T2 or Gd lesions on followup MRI
• (? 3 mos) highly predictive for CDMS in
• the near term (type A) Neurology 2003 61602

50
Role Of MRI In Suspected MS

• once alternative diagnoses are
• excluded, CIS with any of above
• MRI findings is not likely to have
• a non-MS Dx established
• (type A)
• MRI features helpful for Dx of PP MS
• are not yet clear (type U)
• Neurology 2003 61602

51
MS Differential Diagnosis

• Age-related MRI WM changes
• ADEM
• Behcet disease
• Bacterial infections (syphilis, Lyme
• disease)
• CADASIL

52
MS Differential Diagnosis

• Cervical spondylosis or stenosis
• Viral infections (HIV, HTLV-I/II)
• Ischemic optic neuropathy (arteritic
• and nonarteritic)
• Leukodystrophies (ALD, MLD)
• Neoplasms (lymphoma, glioma,
• meningioma)

53
MS Differential Diagnosis

• Migraine
• Sarcoid
• Sjögren syndrome
• Stroke and ischemic
• cerebrovascular disease
• SLE, antiphospholipid antibody
• syndromes, and related collagen
• vascular disorders

54
MS Differential Diagnosis

• Unidentified bright objects on MRI
• Vascular malformations
• Vasculitis (primary CNS or other)
• Vitamin deficiency (B12, E)

55
CIS

• Number and volume of brain MRI
• lesions predict at 10 yrs
• development of MS
• subtype of MS
• impairment/disability
• Most later lesions in the first 5 yrs
• Disease modifying therapy delays
• diagnosis of MS (at least for
• several years)

56
CIS 14yr Followup

• Clinically definite MS 48/71 (68),
  probable 5 (7)
• Initial MRI abnormal
• CD MS 44/50 (88)
• 49 (98) clinical or MRI disease
• Initial MRI normal
• CD MS 4/21 (19)
• 8/21 (38) clinical or MRI disease
• NEJM 2002346158.

57
CIS 14yr Followup

• Disability correlates
• initial lesion number, volume
• lesion burden change (esp first 5 yrs)
• Major conclusions
• virtually all CIS patients (ages 10-50)
• with abnormal MRI have MS
• baseline MRI predicts disability
• early lesion development predicts
• disability
• NEJM 2002346158.

58
CIS CNS Atrophy Over 3 yrs

• MS GM WM
• activity -3.3 1.3
• - activity -1.1 0.2

59
CIS Prognosis

• N103, with abnormal brain MRI
• and CSF (OCB)
• anti-MOG, anti-MBP Abs measured in
• serum (blot)
• Mean f/u 50.9 (12-96) mos
• Seronegative
• 9/39 (23) had relapse
• mean 45.1 13.7 mos
• mean T2 lesions 4.5 2.4
• mean Gd lesions 0.8 0.8
• IgG index 0.4 0.4 NEJM 2003 349 139

60
CIS Prognosis

• Dual seropositive
• 21/22 (95) had relapse (plt 0.001)
• mean 7.5 4.4 mos
• mean T2 lesions 6.0 2.6
• mean Gd lesions 1.5 1.3 (p 0.008)
• IgG index 1.0 0.6
• NEJM 2003 349 139

61
CIS Prognosis

• Anti-MOG Ab
• 35/42 (83) had relapsed (plt 0.001)
• 14.6 9.6 mos
• mean T2 lesions 5.6 2.4
• mean Gd lesions 1.3 1.2
• IgG index 1.1 0.6
• Conclusion Anti-MOG, MBP Abs in
• CIS predict early MS conversion
• NEJM 2003 349 139

62
CIS and Therapy

• Appropriate features can define CIS
• with close to 100 probability of
• MS
• Two phase III trials document MS
• treatment benefit for CIS
• (over several years)

63
CIS and Therapy

• Data suggests MS is best treated
• and most easily treated early
• Any DMT which treats relapsing MS
• treats CIS (first attack MS)
• Treatment is prudent choice

64
CIS Conclusions

• CIS can be identified as first attack
• MS using demography, clinical,
• MRI, laboratory data
• Prognostic factors can be applied
• to CIS analysis
• CIS benefits from MS DMT
• There is a strong rationale for
• treating CIS with effective,
• strong therapy

65
Cognitive Impairment In Minimal Disability MS

• 50 MS (EDSS ? 3.5) vs. 50 matched
• controls
• Cognitive deficits noted in MS
• patients
• memory, abstract reasoning,
• problem solving
• Cognitive deficits correlated with
• disease duration, not EDSS
• Acta Neurol Scand 2003 108 323

66

• This young female presents with diplopia.
• Exam shows left INO. Brain MRI
• has 3 lesions 1 periventricular, 1 in
• the pons, and 1 enhancing lesion in
• the corpus callosum. CSF is OCB
• positive, with 13 WBCs.
• Does this patient meet formal
• criteria for MRI dissemination in
• space? For definite MS?

67

• You elicit history two years earlier of tingling
  from the waist down, lasting 10 days.
• Does she meet formal criteria for
• MS?

68

• This 40 year old man gives a 10 month history of
  slowly worsening gait. Exam shows a spastic
  paraparesis with vibration loss to the knee.

69

• What is your differential Dx?
• What workup would you order?

70

• Brain MRI shows 4 T2/ PD lesions, 3-6 mm in size
  one involves corpus callosum. CSF is OCB.
  Cervical MRI shows a nonenhancing posterior
  lesion at C4
• What is the patients Dx?

71

• Does the patient meet formal criteria for a Dx
  of PP MS?

72
Diagnostic Criteria For Primary Progressive MS

• Abnormal CSF
• Either
• ? 9 T2W brain MRI lesions
• ? 2 spinal cord lesions
• 4-8 brain plus 1 cord lesion(s)
• 4-8 brain lesions plus abn VEP
• lt4 brain plus 1 cord lesion abn VEP
• Dissemination in time by MRI, or
• continued progression for 1 yr

73

• This 35 year old African American presents with
  left sided tingling
• from the waist down, eye pain. Exam shows left
  C4-T10 sensory deficit, and a right afferent
  pupil with
• red color desaturation.
• What tests would you order?
• What is the differential Dx?

74
Neuromyelitis Optica (NMO)

• Idiopathic inflammatory
• demyelinating CNS disease
• Involves attacks of optic neuritis,
• myelitis
• Majority distinct from MS on clinical,
• pathologic, laboratory features
• only 10 have MS

75
NMO Differential

• Subset of MS
• more common in certain areas
• Asia, India, Brazil, Nigeria
• Associated with collagen vascular
• disease
• SLE
• Sjogrens
• P ANCA
• MCTD
• anticardiolipin antibodies

76
NMO Differential

• Associated with infection
• TB
• HIV
• VZV
• EBV
• Associated endocrinopathies
• familial cases

77
NMO Clinical Features

• Relapsing attacks in 80
• 41, FM ratio
• Monophasic in 20
• 11, FM ratio
• Outcome often poor
• can see respiratory failure, ventilator
• dependency

78
NMO Clinical Features

• Racial predilection for non
• Caucasians
• Therapeutic responses reported for
• glucocorticoids, azathioprine,
• plasma exchange, IVIG,
• mitoxantrone

79
NMO MRI

• Normal brain MRI
• optic nerve (chiasmal) signal changes
• Abnormal spinal cord MRI
• extensive longitudinal signal
• abnormality during acute attacks
• (? 3 vertebral segments)
• acute swelling

80
NMO CSF

• Pleocytosis
• may be prominent (gt100 WBC/mm3)
• neutrophil predominance
• ? Protein
• gt 100 mg/dl (40)
• ? CSF serum albumin quotient
• Oligoclonal bands, ?IgG index
• unusual
• MMP-9 (gelatinase b) not ? (vs MS)

81
NMO Laboratory

• ? ESR (33)
• B cell autoimmunity
• ? ANA in up to 50
• ? Anti-MOG Abs
• ? HLA-DR2

82
NMO Pathology

• Demyelination with necrosis
• Vascular changes
• fibrosis, hyalinization
• Inflammation
• M?, eosinophils, granulocytes
• Complement activation
• White and gray matter involved
• Central cord involved (? edema
• induced ischemia)

83
NMO

• ? Complement activation,
• eosinophilic/ granulocytic
• infiltration, vascular
• fibrosis/ hyalinization vs. MS
• role for humoral immunity in NMO
• ? perivascular space 1 injury site (vascular
  Ag)
• ? IC mediated injury
• acute relapses may respond to plasma
  exchange
• Brain 2002 1251450

84
NMO Restricted Topography

• ? Restricted CNS/ vascular antigen
• ? Vulnerable to Ab-mediated injury
• because of BBB leakiness

85
NMO Future Therapies

• ? Complement activation
• ? Eosinophil degranulation
• ? Neutrophli/ M?/ microglia
• activation

86
NMO Diagnostic Criteria

• Required, plus 1 major or
• 2 minor criteria
• Required
• Optic neuritis
• Acute myelitis
• Spinal cord MRI lesion ? 3
• segments 90
• No clinical disease other than optic
• nerve, spinal cord
• Neurology 1999 53 1107

87
NMO Diagnostic Criteria

• Major criteria
• Brain MRI negative (at onset) 90
• CSF pleocytosis gt 50 WBC/mm3,
• or gt5 neutrophils/mm3 37

88
NMO Diagnostic Criteria

• Minor criteria
• Bilateral optic neuritis 83
• Severe optic neuritis, fixed VA
• lt20/200 in at least 1 eye 45
• Severe fixed weakness (? 2/5) in
• ? 1 limb 45
• Neurology 1999 53 1107

89

• This 36 year old man presents with a
• 30 minute episode of left hemiparesis.
• He has a prior history 6 months ago
• of numbness of the right face and
• arm lasting 5 minutes. Family history
• is positive for strokes. Brain MRI shows
  multiple white matter lesions.
• What is the differential diagnosis?
• What further workup would you order?

90
CADASIL

• Cerebral AD arteriopathy
• subcortical infarcts and
  leukoencephalopathy
• Notch 3 gene mutation (19p13.1)

91
CADASIL

• Suggestive clinical picture
• recurrent ischemic episodes (TIA, CVA) in 71
  (gait disturbance 90,
• urinary incontinence 86,
• pseudobulbar palsy 52)
• cognitive deficits 48 (dementia 28)
• migraines (? 38)
• psychiatric disturbances in 30
• seizures in 10
• cognitive, gait problems can slowly worsen

92
CADASIL

• Suggestive clues
• FH of strokes without risk factors,
• FH of dementia
• MRI often abnormal in presymptomatic
• patients symmetric WM, basal
• ganglia involvement with dramatic
• worsening over time
• CSF normal
• Diagnosis gene testing, skin biopsy
• (osmiophilic deposition in vessel wall)

93

• This 43 year old male business executive presents
  with monocular vision loss VA 20/40, with red
  color deficit. There is no prior neurologic
  history. Brain MRI is negative.
• What are the diagnostic possibilities?
• What further tests would you do?

94
Central Serous Choroidopathy

• Male to female ratio 6-101
• Typical onset 20-55yrs, type A personality
• Acute monocular vision loss
• Serous retinal detachment, abnormal
  fluorescein/indocyanine green angiography

95

• This 48 year old female complains of numbness of
  the right face and burning eyes. Exam shows mild
  blunting of pin sensation on the right face, with
  swelling around the temporomandibular joint.
• What are the diagnostic possibilities?
• What workup would you do?

96
 Sjogren Syndrome

• Immune-mediated disorder of exocrine glands
• Most common features are dry eyes
  (keratoconjunctivitis sicca), dry mouth
  (xerostomia)

97
 Sjogren Syndrome

• Two forms of the disease
• 1 (no associated autoimmune disorder)
• 2 (associated connective tissue disease
  RA, SLE, scleroderma, polymyositis, 1 bilary
  cirrhosis)
• 1 Sjogren syndrome shows female sex
  preference (91)
• most common in 4th, 5th decades

98
 Sjogren Syndrome and MS

• Sjogren syndrome can cause MRI and CSF
  abnormalities
• Inconsistent reports of patients misdiagnosed
  as relapsing MS
• Recent study reported Sjogren syndrome in 10
  (16.6) of 60 consecutive patients meeting
  criteria for PPMS
• Neurology 2001 571359

99

• This 25 year old female has a 6 month history of
  progressive myelopathy. Brain MRI shows
  significant occipital white matter disease. CSF
  is normal.
• What are the diagnostic possibilities?
• What further workup would you do?

100
Adrenoleukodystrophy

• Mutations in gene encoding ALD protein
  (Xq28)
• Male phenotypes
• childhood cerebral (48), adolescent
  cerebral (5), adult cerebral (3)
• adrenomyeloneuropathy (25)
• Addison only (asymptomatic
  presymptomatic) (8)

101
Adrenoleukodystrophy

• Female phenotype
• 10 to 15 of heterozygous women develop
  adrenomyeloneuropathy symptoms (3rd 5th
  decades)
• Children show 1 visual, cerebral features
  adults show slowly progressive spinal cord
  syndrome

102
Adrenoleukodystrophy

• MRI predilection for parieto- occipital WM
  CSF normal
• Diagnosis based on VLCFA in plasma

103

• This 30 year old woman has 5 years history of
  progressive gait difficulty, history significant
  for chronic diarrhea , cataracts. Brain MRI shows
  WM changes with dentate nuclei also involved.
• What is the diagnosis?

104
MS Differential Diagnosis

• Cerebrotendinous xanthomatosis
• (CTX)
• AR lipid storage disorder
• deficient enzyme sterol
• 27-hydroxylase (CYP27)
• CYP27 mutations impair 1º bile
• acids synthesis
• cholesterol, cholestanol accumulate
• in CNS, PNS, eye lens, tendons
• J Neurol 2004 251 105

105
MS Differential Diagnosis

• CTX phenotype
• juvenile onset cataracts
• chronic intractable diarrhea
• tendon xanthomas (esp ankles)
• progressive neurologic disease
• Disease onset from early infancy to
• middle adulthood
• J Neurol 2004 251 105

106
MS Differential Diagnosis

• Phenotypic expression can vary
• widely in same family
• Neurologic involvement
• cognitive decline
• psychiatric disorders
• seizures
• corticospinal tract dysfunction
• cerebellar signs
• sensorimotor neuropathy
• J Neurol 2004 251 105

107
MS Differential Diagnosis

• MRI
• cerebral, cerebellar WM
• hyperintensities
• distinct alterations in cerebellar
• dentate nuclei
• J Neurol 2004 251 105

108
MS Differential Diagnosis

• Can mimic PP MS (in young person)
• Diagnosis
• ? serum cholestanol levels,
• ? urine bile alcohol excretion
• sequence analysis of CYP 27 gene
• Treatment involves
• chenodeoxycholic acid
• Should consider in young onset
• PP MS
• J Neurol 2004 251 105

109

• This 14 year old boy presents with headache,
  bilateral decreased vision, upgoing toes, and
  mild left hemiparesis.
• What is the diagnosis?

110
Postinfectious Encephalitis/Encephalomyelitis

• CNS inflammatory and demyelinating
• disorder
• Reflects indirect immune-mediated
• syndrome
• Not a sequela of direct organ
• infection
• May account for 20 of acute
• encephalitis cases
• Prototypic syndrome a diffuse
• encephalopathy, with
• superimposed multifocal
• involvement

111
Postinfectious Encephalomyelitis Spectrum

• Monophasic course
• acute disseminated encephalomyelitis
• (ADEM)
• acute hemorrhagic leukoencephalitis
• (Hurst syndrome) more severe form
• Relapsing course
• biphasic disseminated
• encephalomyelitis
• multiphasic disseminated
• encephalomyelitis (up to 4
• relapses within 32 months)

112
Clinical Features

• Age preference
• predominantly children, young adults
• rare in very young (ages 2-3 yrs) and
• in elderly
• No strong sex preference (? slight
• male predominance)
• Onset over days (occasionally
• weeks)

113
Clinical Features

• Antecedent prodromal event in ? 70
• (occasionally follows or occurs
• during neurologic illness)
• infection
• occasionally immunization
• rarely other events
• Multifocal CNS involvement
• Abnormal mental status/ level of
• consciousness
• Monophasic process
• Good outcome

114
Recent Pediatric Series

• N168 (97 males, 71 females) in four
• series
• 3 showed male predominance
• Ages 4.5 months to 24 years
• average 5-7 years
• Seasonal predominance (winter gt
• spring) in 2 studies, temporal
• (by year) in one

115
Recent Pediatric Series

• Prodromal event in 70
• (immunization in up to 6)
• Average time to onset of neurologic
• problems 10 days
• maximum deficits over 4-7 (range 1-42)
• days
• Clinical features corticospinal/ long
• tract signs (71-85), altered mental
• status (69), cerebellar deficits
• (39-65), seizures (lt20)

116
Recent Pediatric Series

• Mortality 0, morbidity 11-43
• motor (9-17)
• visual (? 11)
• cognitive (? 11)
• seizures (? 9)
• paresthesias (? 6)
• Relapses in 10-20
• MRI abnormal in 100
• CT abnormal in 11 - 78
• CSF abnormal in 28-76
• EEG abnormal in 71-95

117
Adult Postinfectious Encephalitis

• N40 (28 f, 12 m)
• Ages 15-68 years (mean 33.5 years)
• N14 (35) 2nd attack (indicating MS)
• within 1 yr
• Of the 26 without MS
• 65 female, ages 19 61(median 33)
• 46 prior infection , (0 immunization)
• clinical syndrome of motor deficits (77),
• sensory deficits (65), brainstem
• abnormalities (62), loss of consciousness,
• (19), fever/ stiff neck/ myelitis (15),
• seizures 4

118
Postinfectious Encephalitis Modern Series

• Multiregional abnormalities with
• ? level of consciousness
• Fever, meningismus, headache
• generally not prominent
• Visual disturbances generally 2º optic
• neuritis
• often bilateral
• Prognosis is relatively good, death
• virtually unheard of
• locked in syndrome has made full
• recovery
• significant morbidity rare

119

• This 18 year old female presents with tingling
  from the chest down. Exam shows a subtle T4
  sensory level with mild paraparesis.

120
Acute Transverse Myelitis

• 1-4 per million per year
• All ages
• bimodal peaks 10-19 yrs, 30-39 yrs
• Maximum deficit
• 50 have paraplegia
• almost 100 have bladder
• dysfunction
• 80 to 94 numbness,
• paresthesias, band dysesthesias

121
Acute Transverse Myelitis

• Variable prognosis
• 1/3 recover, 1/3 modest deficit,
• 1/3 severe disability
• poorer prognosis with rapid onset
• back pain, spinal shock, absent
• EP central conduction,
• ? CSF 14-3-3 protein

122
Acute Transverse Myelitis

• ? MS risk
• asymmetric findings
• predominant sensory/ relative
• motor sparing
• MR lesions lt 2 spinal segments
• abnormal brain MRI
• CSF OCB

123
Acute Noncompressive Myelopathies

• MS
• Systemic disease
• systemic lupus erythematosus
• anti-phospholipid syndrome
• Sjogren disease
• Parainfectious
• Delayed radiation myelopathy
• Spinal cord infarct
• Idiopathic myelopathy

124
Diagnosis Of Idiopathic ATM

• Sensory, motor, or autonomic
• dysfunction attributable to spinal
• cord
• Bilateral signs/ symptoms (not
• necessary symmetric)
• Sensory level
• Extra-axial compressive etiology
• excluded by Gd MRI or
• myelography (not CT)

125
Diagnosis Of Idiopathic ATM

• Spinal cord inflammation (? CSF
• cells/ IgG index or Gd MRI)
• if negative repeat CSF / MRI
• between days 2 to 7
• Maximum deficits at 4 hrs to
• 21 days (lt 4 hrs vascular)
• Specific exclusions

126
Specific Exclusions

• No spine radiation within prior 10 yrs
• Anterior spinal artery syndrome
• Spinal AVM
• Disease associated (Sarcoid, Behcet, Sjogren,
  SLE, MCTD)

127
Specific Exclusions

• Infections (Syphilis, Lyme, HIV, HTLV-1,
  Mycoplasma, EBV, CMV, HHV-6, HSV-1, HSV-2,
  VZV, enteroviruses)
• Brain MRI suggestive of MS
• H/O optic neuritis

128
ATM Evaluation

• Gd spinal cord MRI or CT- myelography
• no structural cause
• LP
• Gd brain MRI
• VEP

129
ATM Evaluation

• Selective tests
• CSF infection studies (culture, stain,
  serology, PCR)
• chest X-ray/ CT
• serum ACE, complement, autoantibodies
• urinalysis
• Schirmer test
• lip/ salivary gland biopsy
• EMG/ NCT

130
ATM Evaluation

• Autoantibodies
• ANA
• anti DS DNA
• SS-A, SS-B
• Anticardiolipin Abs
• Lupus anticoagulant
• ?2 glycoprotein I

131

• This 32 year old female presents with
• an incomplete T8 transverse myelitis.
• There is no prior infection/
• vaccination. MRI shows an
• enhancing thoracic lesion. Brain MRI
• shows a few small peripheral T2
• hyperintense lesions. CSF shows 26
• WBCs (all mononuclear), protein of
• 48 mg/dl. Platelet count is 90,000
• ESR is 35, blood ANA is positive at
• 11280.
• What are the diagnostic possibilities?
• What further workup would you do?

132
SLE

• Gender preference (female)
• autoimmune disease
• Neurologic involvement in 50-60
• risk factors include cutaneous
• vasculitic lesions, arterial
• thromboses
• associated with ? morbidity,
• mortality

133
SLE

• Pathogenetic mechanisms include
• vasculopathy, anti-neuronal
• antibodies
• anticardiolipin antibodies
• (thrombosis)
• antiribosomal p antibodies
• (psychosis)

134
SLE

• CSF abnormal in diffuse syndromes,
• often normal in focal syndromes
• MRI may be abnormal in major focal
• syndromes

135
SLE CNS Neurologic Involvement

• Aseptic meningitis
• Cerebrovascular disease
• Demyelinating syndrome
• Headache (vascular, intracranial
• hypertension)
• Chorea
• Myelopathy (1-2)

136
SLE CNS Neurologic Involvement

• Seizure disorder
• Acute confusional state
• Anxiety disorder
• Cognitive dysfunction
• Mood disturbance
• Psychosis

137
SLE PNS Neurologic Involvement

• Guillain Barre syndrome
• Atutonomic disorder
• Mononeuropathy (single, multiplex)
• Myasthenia gravis
• Cranial neuropathy
• Plexopathy
• Polyneuropathy

138
Antiphospholipid Syndrome

• Recurrent pregnancy loss
• Vascular thrombosis
• Hemolytic anemia
• Thrombocytopenia
• Livedo reticularis
• Neuropsychiatric manifestations

139
Antiphospholipid Syndrome

• Laboratory
• anticardiolipin antibodies
• MRI (putamenal lesions vs white
• matter, posterior fossa)
• Therapy
• anticoagulation response

140

• This 34 year old African American female
• presents with a subacute onset over
• several weeks of left optic neuritis. The
• only additional exam abnormality is subtle
• right face weakness. Brain MRI shows
• several nonenhancing scattered T2
• hyperintense WM lesions. CSF shows
• ? protein (60mg/dl). OCB are present in
• CSF, but are also found in serum.
• What are the diagnostic possibilities?
• What further w/u would you do?

141
Sarcoidosis

• Multisystem granulomatous disease
• Involves lungs and rarely nervous
• system (5 10 based on
• pathologic studies)

142
Sarcoidosis

• Neurologic involvement includes
• optic nerve (38) other cranial
• nerve palsies especially VIII (34)
• spinal cord (28) brainstem/
• cerebellum (21) meningitis (12)
• cognitive loss (9) hydrocephalus
• (6) and pituitary/ hypothalamic
• dysfunction (3)
• diabetes insipidus

143
Sarcoidosis

• Abnormal CXR, whole body
• gallium scan, ?serum IgG, Kveim
• test
• CSF abnormal in gt 80, esp
• ? protein (73), mononuclear
• pleocytosis (55), OCB (37),
• ? ACE (33)

144
Sarcoidosis

• ? CSF ACE most meaningful when
• out of proportion to ? protein,
• when cell count is low, when serum
• ACE not ? (? ACE index,
• CSF/serum ACE, most meaningful)

145
Sarcoidosis

• MRI abnormalities include WM
• lesions, hydrocephalus, mass
• lesions, meningeal enhancement,
• spinal cord lesions, optic nerve
• sheath enhancement
• vs MS, meningeal and lesion
• enhancement may persistent

146

• This 30 year old man presents with
• left hemiparesis, diffuse hyperreflexia,
• bilateral plantar extensors, and low
• grade fever. Brain MRI shows T2
• hyperintense lesions in the brainstem
• and basal ganglia, as well as a few
• subcortical lesions. CSF shows 25
• WBCs (60mononuclear),
• protein 50 mg/dl, IgGI 1.3.
• What are the diagnostic possibilities?
• What further history and workup would you
• obtain?

147
Behcet Disease Diagnosis

• Recurrent oral ulcerations
• Two of the following
• recurrent genital ulcerations
• eye lesions (anterior or posterior
• uveitis, retinal vasculitis)
• skin lesions (E. nodosum,
• pseudofolliculitis, papulopustular
• eruption, acneiform nodules)
• positive pathergy test

148
Behcet Disease Diagnosis

• Often associated with constitutional
• symptoms, oligoarthropathy
• Rare involvement of lung, GI tract,
• kidneys

149
Behcet Disease

• Young adult, male gender preference
• Most common in Mediterranean,
• Middle East, Eastern Asia (Japan)
• Extraneural involvement
• Neurologic involvement in 3-25
• generally 5 to 6 yrs into disease

150
Behcet Disease

• Common clinical features are motor
• involvement, fever, headache,
• behavioral changes
• MRI lesions involve upper brainstem,
• basal ganglia, internal capsule,
• peduncles

151
Behcet Disease

• CSF shows pleocytosis (neutrophil
• component), ? protein, intrathecal
• IgG production (abnormal CSF,
• pleocytosis indicate worse
• prognosis)
• Pathology chronic mononuclear
• meningoencephalitis, multifocal
• necrotic foci

152
Summary

• The goal is accurate diagnosis and
  classification
• Atypical history, examination, and/or
  laboratory features suggest MS masqueraders
• Appropriate laboratory evaluation
  facilitates diagnosis, prognosis,
• and identification of other disorders