MS

MS

Definition

Pathogenesis

Epidemiology

Clinical features

Optic Neuritis

Cognitive impairment

Depression

Fatigue

Diagnosis

MacDonald Criteria

Poser Criteria

DDx:

Investigations

Treatment – see MS treatment

Prognosis

Exam

For CIS see: Clinically Isolated Syndromes

Definition

· Disorder of the CNS, manifesting pathologically as acute focal inflammatory demyelination and axonal loss with limited remyelination, culminating in chronic multifocal sclerotic plaques.

Pathogenesis

· Perinuclear cuffing with inflammatory mononuclear cells

· Predominately T cells and macrophages

· Destruction of myelin sheath with relative sparing of axons

o However in some instances significant axonal degeneration can occur (and can occur early).

· Variable levels of oligodendrocyte regeneration occur

o Regeneration block occurring in some. - ?primary pathology

· BBB is disrupted – however unlike vasculitis vessel wall is intact

· Myelin specific autoantibodies

· As lesions evolve – prominent astrocytic proliferation (gliosis)

· There are differences between patients in terms of nature of the inflammatory response – prominence of antibodies etc.

· 4 histological subtypes – may reflect different immunopathogenesis

o Pattern I – T cell/macrophage mediated demyelination

o Pattern II – Antibody/complement mediated demyelination

o Pattern III – Oligodendrocyte dystrophy with myelin protein dysregulation and apoptosis

o Pattern IV – Primary oligodendrocyte degeneration with features similar to viral infection or toxic damage – but not autoimmunity.

Epidemiology

· Female:Male 2:1

· Incidence 7 per 100,000 per year

· Prevalence 120 per 100,000

· Peak prevalence age ~50

· Peak incidence age ~30

· Lifetime risk 1/400

· Usual onset 20’s and 30’s

· Paediatric onset MS (POMS) - 2% onset less than 10yrs and 5% less than 16yrs

· Late onset MS (LOMS) – Onset >age 50

Risk Factors

· Female

· Northern European

· Increased risk further from the equator

· Increased risk if other autoimmune disease

· Family history

o Familial recurrence of 15%

o Siblings 3%

o Parents 2%

o Children 2%

o Monozygotic twins 35%

· HLA associations

o HLADRB1*1501 – most common, particularly in northern Europeans, other HLA associations in other populations.

Clinical features

Clinical categories:

· Clinically isolated syndrome (see Clinically Isolated Syndromes)

o Single clinical episode with 2 or more lesions on MRI (>6mm)

o Very high risk of subsequent disease (~85%)

· Benign Disease ~20%

o Controversial topic

o Can be defined as EDSS remaining <3.0 over a 10 year period.

Categories of clinically definite MS:

· Relapsing remitting ~80%

· Secondary progression (~60% at 10 years)

· Primary progressive ~15%

· Relapsing Progressive ~5%

Relapses

· Occur initially ~1/year

· 10% of URTIs and GIT infections in patients with MS are followed by relapse

· 30% of relapses relate to infection

· Decreased rate in pregnancy increased rate in puerperium

Initial Symptoms of MS

Symptom	%
Sensory loss	37
Optic neuritis	36
Weakness	35
Paresthesias	24
Diplopia	15
Ataxia	11
Vertigo	6
Paroxysmal attacks	4
Bladder	4
Lhermitte	3
Pain	3
Dementia	2
Visual loss	2
Facial palsy	1
Impotence	1
Myokymia	1
Epilepsy	1
Falling	1

Optic Neuritis

1. Probably the most common first symptom of MS

Clinical

Pain in or around the eye (92%) – often worse with movement

3. Abnormal visual acuity
4. Relative afferent papillary defect
5. Visual field defects – most commonly central scotoma, however any type can occur
6. Altered colour perception – often much more so than decrease in acuity
7. Papillitis may be observed acutely
8. - hyperaemia and swelling of the disc with blurring of the margins and distended veins
9. Chronic
10. Most of the above abnormalities recover to a large degree with time
11. Fundoscopy - Optic atrophy may be visible
12. Progression to MS at 10-15 years is ~40%
• 50-60% of these are diagnosed in the first 3 years

Cognitive impairment

· Frank dementia is rare (<5%) and affects only those with severe disease

· Mild cognitive impairment is much more common

· No specific treatment

Depression

· Mood disorder present in 2/3, depression most common

Fatigue

· Up to 80% of patients

· Often associated with acute attacks, may preceed focal symptoms

· Can be exacerbated by co-morbid depression and physical disability

Sexual Dysfunction

· Erectile dysfunction common

· Can be related to neural dysfunction or psycosocial issues

Bladder dysfunction

· Incontinence common

· Urge in continence most common – often due to uninhibited contraction of detrusor due to spinal cord lesion

· Sacral lesions can result in atonic bladder with overflow – requires catheterisation

· Prediction of poor prognosis

· NEJM 2002

Seizures

One study found 3x risk

Average onset to seizures - 7years after diagnosis of MS

Risk -1.1% at 5years, 1.8% at 10 years and 3.1% at 15years

Diagnosis

MacDonald Criteria 2024

Summary of differences from 2017 criteria

• RIS is MS in specific situations

• Optic nerve as a fifth topography

• DIT is not longer needed

• Updated DIS criteria

• kFLCs as a tool for diagnosis

• Same criteria for PPMS and RMS diagnosis

• Need of paraclinical evidence to diagnose MS

• More strict features for confirming diagnosis in individuals over 50 years, or with headache disorders (including migraine), or with vascular disorders

• Addition of CVS and PRLs as optional tools for diagnosis in certain situations

• Laboratory tests (MOG-IgG Ab) for confirming diagnosis in children and adolescents

In patients who are being considered for a diagnosis of MS presenting:

· at age ≥50 years and/or

· significant vascular risk factors (including hypertension, smoking, diabetes, hyperlipidemia) or known vascular disease and/or

· headache disorders,

Additional features are strongly recommended to confirm diagnosis of MS.

• A spinal cord lesion can serve as an additional feature.

• Positive CSF can serve as an additional feature.

• CVS select 6 can serve as an additional feature.

CNS Lesion topographies:

· Periventricular

· Juxtacortical

· Infratentorial

· Spinal Cord

· Optic nerve

o Involvement of the optic nerve can be assesed by MRI, VEP and OCT

§ One or more typical short segment intrinsic optic nerve lesions with no better explanation (including no prominent chiasmal involvement, perineuritis, or longitudinally extensive lesion) identified by MRI may serve as evidence of optic nerve involvement to demonstrate DIS 

§ An abnormal peak time using a full field pattern reversal visual evoked potential (significant interocular asymmetry or p100 peak time above upper limit of normal with no better explanation) may serve as evidence of optic nerve involvement to demonstrate DIS.  

§ An abnormal OCT (significant ppRNFL or GCIPL interocular thickness asymmetry, or ppRNFL or GCIPL thicknesses below lower limits of normal, with no better explanation) may serve as evidence of optic nerve involvement to demonstrate DIS.

Other supporting lesions

· Central vein sign (CVS)

o SELECT -6 criteria – Either 6 CVS or if less than 6 lesions the majority have CVS

§ Thin hypointense line or small dot

§ Visualized in at least two perpendicular planes (and appears as a thin line in at least one plane)

§ Small apparent vein diameter (<2mm)

§ Runs partially/entirely through the lesion

§ Positioned centrally in the lesion

· Paramagnetic rim lesion (PRL)

Old criteria

Clinical Attack	Clinical Evidence of lesion	2017 Criteria Additional Data	2010 Criteria Additional data	2005 Criteria Additional data
2+	2+	None	None	None
2+	1	Dissemination in space: · MRI (see below) · Another clinical attack at a different site	Dissemination in space: · MRI (see below) · Another clinical attack at a different site	Dissemination in space: · MRI (Barkhof – see below) · 2+ MRI lesions and CSF or · Another clinical attack at different site
1	2+	Dissemination in time: · MRI · A second attack · Positive OCB	Dissemination in time: · MRI · A second attack	Dissemination in time: · MRI (see below) or · Second clinical attack
1	1	Dissemination in space AND Dissemination in time (Via criteria as above)	Dissemination in space AND Dissemination in time (Via criteria as above)	Dissemination in space AND Dissemination in time (Via criteria as above)
PPMS Insidious neurological progression suggestive of MS		· One year of disease progression And two of: · Brain MRI: 1+ lesion in one characteristic area · Spine MRI: 2+ lesions in the cord · Positive OCB in CSF	· One year of disease progression And two of: · Brain MRI: 1+ lesion in one characteristic area · Spine MRI: 2+ lesions in the cord · Postive CSF	· One yr of disease progression AND Two of: · Positive MRI (nine T2 lesions or four or more T2 lesions with positive VEP) · Positive spinal cord MRI (2 focal T2 lesions) · Positive CSF
		MRI Criteria 2017	MRI criteria 2010	MRI criteria 2005
		Dissemination in space: · 1+ lesion in 2 of 4 characteristic area’s (periventricular, juxtacortical, infratentorial or spinal cord) · Typical cortical lesions can also be counted · The symptomatic lesion can be counted (except in optic nerve)	Dissemination in space: · 1+ lesion in 2 of 4 characteristic area’s (periventricular, juxtacortical, infratentorial or spinal cord) · The symptomatic lesion cannot be counted	Dissemination in space criteria: 3 of the 4 following: 1. At least one gadolinium enhancing lesion OR Nine T2 hyperintense lesions OR Eight T2 lesions plus one spinal lesion 2. At least one infratentorial lesion OR one spinal cord lesion 3. At least one juxtacortical lesion 4. At least three periventricular lesions
		Dissemination in time: Either: · New T2 (and/or Gd-enhancing) lesion at follow-up · Simultaneous presence of enhancing and non-enhancing lesions	Dissemination in time: Either: · New T2 and/or Gd-enhancing lesion at follow-up · Simultaneous presence of enhancing and non-enhancing lesions	Dissemination in time criteria Either: 1. Detection of (new) gadolinium enhancement at least 3 months after onset of initial clinical event, if not at the site corresponding to the initial event 2. Detection of a new T2 lesion if it appears at any time compared with a reference scan done at least 30days after the onset of the initial clinical event

Poser Criteria

Clinically definite multiple sclerosis

1. Two attacks plus two separate clinical lesions*

or

2. Two attacks plus one clinical lesion plus another separate paraclinical lesion

Laboratory supported definite multiple sclerosis

1. Two attacks plus one clinical lesion plus CSF, OCB, or IgG

or

2. Two attacks plus one paraclinical lesion plus CSF, OCB, or IgG

or

3. One attack plus two separate clinical lesions plus CSF, OCB, or IgG

or

4. One attack plus one clinical lesion plus one paraclinical lesion plus CSF, OCB, or IgG

Clincally probably multiple sclerosis

1. Two attacks plus one clinical lesion

or

2. One attack plus two separate clinical lesions

or

3. One attack plus one clinical lesion plus one paraclinical lesion

Laboratory supported probable multiple sclerosis

1. Two attacks plus CSF, OCB, or IgG

CSF: cerebrospinal fluid; OCB: oligoclonal banding; IgG: Immunoglobulin G.

* Clinical lesion: lesion detected on history and physical examination.

Paraclinical lesion: lesion detected by evoked response testing, MRI, or urodynamic studies.

DDx:

· Other demyelinating syndromes:

· Devic’s disease

· ADEM

· Leber’s atrophy

· Adrenoleukodystrophy

· CADASIL

Investigations

Sensitivity:

· MRI Brain/spine 70-95%

· CSF

o Oligoclonal bands 85-95%

o IgG index 90%

o Albumin 23%

· Evoked responses

o Visual (VER) 85%

o Brainstem auditory 67%

Treatment – see MS treatment

Prognosis

· Activities of daily living not affected in 25%

· 15% disabled in short period of time

· Life expectancy 25yrs from onset

· Median time to walking aid ~16years

Prognostic factors

· Good

o when sensory and visual symptoms dominate the course of the disease and there is complete recovery from individual episodes

· Poor

o Development of progressive disability (i.e. secondary progressive phase) – single worst prognostic feature.

o Motor disturbance, especially if coordination or balance are affected

o Older men

o Frequent and prolonged relapses with incomplete recovery

o Short episode between initial episode and first relapse

o Lesion load/volume on MRI probably has some correlation, however correlation is poor in later disease.

Exam

1. Confirm diagnosis

2. Assess severity of disease and co-morbidities

· Extended Disability Status Score (EDSS) which is extended version of Kurtzke disability score.

3. Consider disease benefit of disease modifying agents

4. Symptomatic treatment

· Depression/anxiety

· Spasticity

· Bladder dysfunction

5. Other management

· OT - Home assessment and modification

· Physio – Gait aids, physical training/strengthening.

· Referral to support group

· Clinical trial

6. Treatment monitoring

· EDSS

· Treatment SE

1. Interferon – flu-like Sx, injection reaction

2. Glatiramer – flushing, chest pain

7. Counselling of family and patient regarding prognosis and genetic linkage

· Consider advanced care plan