Multiple Sclerosis

This is an autoimmune disease of the central nervous system white matter. There is some evidence that the grey matter may be involved in the disease, but it is best to think of it as a type of white matter disease. The disease is multifocal i.e. it affects non-adjacent parts of the white matter. The areas of inflammation in the white matter are called plaques. Symptoms occur depending on where the plaques are. As the inflammation settles down, symptoms may resolve. However, symptoms often recur when the inflammatory system attacks the white matter again. Therefore, multiple sclerosis is typically a relapsing-remitting disease with patients having multiple episodes of neurological dysfunction that get better and then recur.
Some parts of the white matter are more important than others. Disease may occur in areas without any clinical symptoms. MR imaging has allowed assessment of disease activity in asymptomatic patients in-between relapses. Symptoms of multiple sclerosis can range from subtle and mild to disabling and severe.
The central nervous system white matter includes the optic nerves. In fact, optic neuritis is a common presentation of multiple sclerosis. There are 3-4 other classical multiple sclerosis syndromes; namely myelitis, internuclear ophthalmoplegia, ataxia and sensory disturbances. The neurologist is challenged with distinguishing between multiple sclerosis and a large range of differential diagnoses. These include other white matter diseases and psychogenic syndromes. It is important not to be dismissive of patients with mild sensory symptoms. On the other hand, labeling a patient with multiple sclerosis prematurely can have significant negative consequences as well. Even with modern MRI and clinical criteria for multiple sclerosis, not uncommonly patients may need to be observed to see if the disease evolves over time.

History taking in Multiple Sclerosis:

As with every interview, start with open-ended questions and then use close ended questions to narrow down the symptoms. It is important to ask when the symptoms first developed. Also, ask about any episodes in the past that may represent an early multiple sclerosis exacerbation for which, the patient may have not sought medical attention. Look for features of the classical syndromes (outlined below), but also realize that many patients present atypically.

  • Handedness
  • Weakness (arms, legs, face, swallowing)
  • Sensory deficits (numbness, pins & needles, pain,)
  • Headache
  • Loss of consciousness (faints/syncope & fits/seizure)
  • Brainstem & related (Vision & diplopia, vertigo, tinnitus, dysarthria)
  • Cerebellar & movement (balance, falls & tremor),
  • Spinal cord & sphincter (bowel & bladder control)

Classic Presentations of multiple sclerosis:

  • Optic neuritis: acute loss of vision with painful eye movements
  • Spinal cord involvement:
    • Spastic paraparesis
    • Bladder symptoms
    • Other patterns of weakness occur
  • Cerebellar syndrome/brainstem involvement:
    • Ataxia, nystagmus
    • Diplopia
    • Vertigo
    • Internuclear opthalmoplegia
  • Sensory alteration:
    • Parasthesia in the extremities
    • Neuropathic pain

Other points:

Signs of optic nerve damage:

  • Relative afferent papillary defect RAPD
  • Decreased visual acuity
  • Decreased colour vision
  • Central or paracentral scotoma
  • Optic atrophy
  • Note, ~75% of people presenting with optic neuritis will develop other signs of multiple sclerosis

Lhermitte’s sign a.k.a. Barber’s chair sign:

  • Electric shocks down radiating down the extremities on neck flexion is a sign of…… dorsal column lesion
  • Causes of Lhermitte’s sign:
    • Multiple sclerosis
    • Cervical stenosis
    • Subacute combined degeneration of the spinal cord

Uhtoff’s syndrome:

  • Exacerbation of multiple sclerosis due to a hot bath or exercise

Clinical categories:

  • Relapsing remitting: ~85%
    • Secondary progressive
  • Primary progressive ~10%
  • Progressive relapsing ~5%

Variants:

Please note that neuromyelitis optica (Devic’s disease) was formerly considred to be a variant of multiple sclerosis, but is now established as a separate condition: Devic’s disease: , optic neuritis in both eyes & transverse myelitis.
Tumefactive multiple sclerosis: multiple sclerosis lesions that are large and may mimic brain tumors clinically and on MRI

  • MS presenting like a tumour. MRI: T2= hyperintense >2 cm, mass effect & oedema. +/-Enhancing lesion.
  • Pathology: biopsy revealing, lipid laden macrophages, reactive astrocytes. No tumour.

Marburg type, very rare:

  • Clinically: Acute onset, rapidly progressive, monophasic (strictly speaking), fatal usually within a year.
  • Pathology: multiple plaques, may have poorly defined edges, may have mass effect. Microscopically, perivascular lymphocytes, foamy macrophage infiltrate, necrosis & cavitation can occur. Scattered reactive astrocytosis. No old plaques.

Balo concentric slcerosis:

  • very rare, pathologic variant of Multiple sclerosis. The plaque has alternating rings of demyelination leading to a concentric appearance grossly.

Multiple sclerosis Diagnosis:

Two different areas of central white matter affected at two different points in time
Criteria:

  • Poser’s criteria: 2 episodes of neurological deficit, with clinical evidence of >1 lesions in the CNS white matter
  • McDonald criteria: clinical +MRI
  • Barkhof criteria, criteria for what is a Positive MRI, 3 out of 4 of the following:
    • 1 Gd-enhancing lesion,
      or 9 T2 hyperintense lesions if no Gd-enhancing lesion
    • 1 or more infratentorial lesion(s)
    • 1 or more juxtacortical lesion(s)
    • 3 or more periventricular lesions
    • Note: 1 cord lesion can substitute for 1 brain lesion.
MRI findings in multiple sclerosis:
  • FLAIR: good for periventricular and juxtacortical lesions. Hyperintense.
  • T2 weighted: increased signal intensity in active plaques, occur in CNS white matter e.g. periventricular, optic nerve. Good for spinal cord lesions. Hypointense basal ganglia lesions can occur chronically.
  • PD: increased signal intensity in plaques
  • T1 +Gadolinium enhanced (semilunar, horseshow, incomplete or mass like), for age of the lesion: increased signal activity with active lesions. Gadolinium enhancement lasts <6 weeks. No meningeal enhancement in MS, but occurs in sarcoidosis. Lesions of different age occur with MS. Nodular or ring like.
  • Fat suppressed T1 +contrast, or STIR: detects optic neuritis
  • T1: low signal intensity indicates tissue destruction and correlates histologically with myelin loss, axonal loss and axonal swelling. If persisting greater than 6 months= “persistent black holes”. Hypointense lesions and atrophy also occurs.
    DWI: hyperintense. ADC: rims normal acutely, centre increased acutely. All increased chronically.

CNS white matter lesions:

  • Supratentorial (most common); 5-10mm but can be large in tumifactive MS. Linear, round or ovoid.
  • Dawson’s fingers (ovoid, perpendicular to ventricular surface) in corpus callosum on sagittal image.
  • Periventricular (perpendicular to the ventricle), juxtacortical & optic nerve lesions.
  • Infratentorial; cerebellar peduncles, floor of forth ventricle, superficial pons lesions.
  • Spinal cord lesions (<2 vertebral segments in length, posterolateral, Cervical >thoracic >lumbar).
  • Sparing of the CNS grey matter (cortex & basal ganglia) on 1.5 T MRI: helps with differential diagnosis
  • Cerebral atrophy is associated with worsening disability.
  • Spinal cord atrophy is associated with worsening disability.

MRS Magnetic resonance spectroscopy:

  • SPMS, PPMS Reduced N-acetyl aspartate in global white matter, axonal loss

DTI diffusion tensor imaging:

  • Normal appearing white matter NAWM: decreased fractional anisotropy occurs & is associated with disability & progression.
Other tests helping the diagnosis:

CSF analysis:

  • Oligoclonal bands: positive i.e. = or >2 bands
  • IgG index > 0.7. IgG Index= (CSF IgG/CSF albumin) / (serum IgG/serum Albumin)
  • IgG synthesis rate >3
  • Myelin basic protein >4mg/ml
  • Lymphocytosis and increased protein if close to a relapse

Evoked response/potential: a.k.a. triple evoked responses

  • Visually evoked response VER: increased latency in cortical response (most useful of the evoked responses)
  • Somatosensory evoked response SSER
  • Brainstem auditory evoked response BAER a.k.a. BSER

Test to help diagnose MS exacerbation:

  • CSF Myelin basic protein
  • MRI: T1, FLAIR

Key definitions:

Relapse:

  • The appearance of a new, or reappearance of a neurologic abnormality, separated by at least 30 days from the onset of the preceding event. Lasting >24 hours, in absence of fever or known infection

Clinically isolated syndrome:

  • Acute or subacute episode suggestive of demyelination affecting the optic nerves (optic neuritis), brainstem (INO) or spinal cord (transverse myelitis)
  • If MRI shows = or >1 lesion suggestive of MS, there is a high risk to progression within 5-20 years. [longitudinal prospective]

Benign MS:

  • Patient is fully functional in all neurologic systems at 15 years after onset

Aggressive MS:

  • At least two relapses with sequelae
  • Or an increase in the Expanded Disability Status Scale EDSS score of at least 2 points in 12 months + at least one gadolinium Gd enhancing lesion on MRI
Investigations that can be considered:

Blood tests:

  • FBC, U&E
  • ESR: vasculitis
  • ANA
  • VDRL: syphilis
  • TFT
  • LFTs
  • Serum B12: to exclude subacute combine degeneration of the spinal cord
  • Consider:
    • Borrelia serology, SS-A & SS-B, antiphopholipid antibodies, ACE, HIV tests, HTLV 1 tests, very long chain fatty acids (adrenoleukodystrophy), mitochondrial disease (lactate, muscle biopsy, mitrochondrial DNA analysis)

Lumbar puncture & CSF analysis:

  • Lymphocytic pleocytosis (usually <50 WBC) and increased protein if close to a relapse
  • CSF electrophoresis: oligoclonal bands
  • IgG index (increased IgG relative to albumin)
  • Consider Myelin basic protein

MRI: Brain & spine

  • T2 weighted
  • Gadolinium enhanced T1 weighted, for age of the lesion
  • Consider FLAIR

Evoked responses/potentials
Consider:

  • Measure urine residual volume
Measure of neurologic impairment:

Expanded disability scale EDSS:

  • 0.0 to 10.0

Disease steps in multiple sclerosis Scale:
0 = Normal
1 = Mild disability, mild symptoms or signs
2 = Moderate disability, visible abnormality of gait
3 = Early cane, intermittent use of cane
4 = Late cane, cane-dependent
5 = Bilateral support
6 = Confined to wheelchair
U = Unclassifiable

Pathology:

Gross: Plaques:

rounded sharply demarcated lesions in the white matter. May extend into grey matter. Periventricular location, scattered randomly.

Microscopically:

Recent plaque: Perivascular lymphocytes. Macrophage infiltrate, myelin filled. Loss of myelin (Luxol fast blue stain or Loyenz stain). Relatively preserved axons. Axonal spheroids. Preserved neuron bodies (if extending to grey matter). Astrocytic gliosis more prominent at the periphery. Fibrillary astrocytes in the centre.
Old plaque/chronic plaque: no or few lymphocytes or macrophages. Loss of axons centrally. More prominent gliosis.  Loss of oligodendrocytes.
Creudtzfeldt astrocytes and granular macrophages may occur and be confused for pleomorphism.

Four plaque patterns, recognised by special techniques:

Pattern I: T cell-mediated autoimmune encephalomyelitis. Centred on veins.
Pattern II: T cell plus antibody-mediated autoimmune encephalomyelitis: Pattern I with additional IgG deposition at sites of myelin destruction and in the macrophages & activated terminal complement (C9neo) deposition at sites of destruction, Centred on veins.
Pattern III: Loss of oligodendrocytes (oligodendrocytes apoptosis). T-cell lymphocytes, macrophages, microglia may be present but not centred on veins. No Ig or complement deposition.
Pattern IV: similar to Pattern III but with different borders. Loss of oligodendrocytes.

Pathology by clinical subtype:

Acute MS, AMS:

  • Active focal plaque
  • Absent/rare cortical demyelination
  • Meninges: Mononuclear cell infiltrate

RRMS:

  • Active focal plaque
  • Inactive plaques or slow expansion at the edges
  • Absent/rare cortical demyelination
  • Meninges: Mononuclear cell infiltrate

SPMS:

  • Inactive plaques or slow expansion at the edges
  • Cortical demyelination: luxol fast blue, Spares subcortical U fibres
  • Meninges: Mononuclear cell infiltrate
  • Lymphoid follicle-like structures in Meninges: contain B-cells (CD20+), T-cells (CD3+), plasma cells (CD138+) and a network of follicular dendritic cells (CD21+, CD35+). [312]
  • Normal appearing white matter NAWM: inflammation; CD8 positive cells, perivascular cuffing my mononuclear cells, microglial nodules with macrophages (CD68+), Diffuse axonal injury: neurofilament, axonal swellings & end bulbs

PPMS:

  • Inactive plaques or slow expansion at the edges
  • Cortical demyelination: luxol fast blue, Immunohistochemistry PLP, Spares subcortical U fibres
  • Meninges: Mononuclear cell infiltrate
  • Normal appearing white matter NAWM: inflammation; CD8 positive cells, perivascular cuffing my mononuclear cells, microglial nodules with macrophages (CD68+), Diffuse axonal injury: neurofilament, axonal swellings & end bulbs

Factors for poor prognosis in Multiple sclerosis:

  • Males
  • Old age of onset
  • Presentation with Motor & cerebellar signs
  • Multiple lesions on MRI T2
  • Relapses & remissions:
    • Short remissions between 1st two relapses
    • Frequent relapses with in the 1st 2 years
    • Incomplete remissions
  • Primary progressive disease

Conditions that mimic multiple sclerosis:

  • CNS infection:
    • Syphilis, brucellosis, Lyme’s disease, HIV, human lymphotropic virus type 1 HTLV 1
  • CNS inflammatory disease:
    • SLE, sarcoidosis
  • CNS microvascular disease:
    • Vasculitis
    • Diabetes mellitus
    • Hypertension
    • CADASIL cerebral autosomal dominant arteriopathy with subcortical infarcts & leukoencephalopathy
  • Vitamin B12 deficiency
  • Lymphoma
  • Structural lesions:
    • Cervical spondylosis, herniated disc, Arnold-Chiari malformation, tumour
  • Genetic disorders:
    • Leukodystrophy, hereditary myelopathy, Mictochondrial disease

Complications of multiple sclerosis:

  • Fatigue
  • Depression
  • Neuropathic pain including trigeminal neuralgia
  • Spasticity
  • Erectile dysfunction
  • Neurogenic bladder:
    • Detrusor hyperreflexia
  • Constipation
  • Pressure ulcers
  • Cognitive dysfunction:
    • Memory impairments
  • SIADH

Treatment options:

Please see pharmacology notes to learn about some of the medications.

Relapsing remitting diseases:
Acute relapses:
  • Corticosteroid short course: methylprednisolone 1000mg daily intravenous or orally for X3-5 days
  • In rare cases consider plasma exchange if no response
Disease modifying therapy, to prevent disease progression and relapses:

Injectables:

  • Interferon beta:
    • Interferon beta -1a intramuscular 30mcg once a week [MSCRG]
    • Interferon beta 1a subcutaneously 44mcg three times a week
    • Interferon beta-1b subcutaneously 0.25mg (1mL) on alternate days
    • Pegylated interferon beta-1a 125mg once every 2 weeks
  • Glatiramer acetate 20mg subcutaneously daily a.k.a. copolymer-1

Oral agents:

  • Dimethyl fumarate  240mg two times a day (trade name is Tecfidera)
  • Teriflunomide 14mg po daily (trade name is Aubagio)
  • Fingolimod  (trade name is Gilenya)

IV infusions (high efficacy agents):

  • Natalizumab 300mg intravenous infusion over 1 hour every 4 weeks (trade name is Tysabri) [AFFIRM]
  • Alemtuzumab (trade name is Lemtrada)
Clinically islated syndrome (CIS) treatment:
  • Interferon beta 1a intramuscular weekly 30 mcg (avonex): Treatment delays clinically definite multiple sclerosis at 5 years. Treatment reduces disability at 5 years. [CHAMPS]
  • Interferon beta 1a subcutaneous 3 time a week 44 mcg (rebif): Treatment delays clinically definite multiple sclerosis at 2 years. [REFLEX]
  • Interferon beta 1b subcutaneous every other day 250mg (betaseron): Treatment delays clinically definite multiple sclerosis at 2, 3, 5 and 8 years follow up. Treatment reduces disability at 3 years but effect is lost by 5 year follow up. [BENEFIT]
  • Glatiramer acetate subcutaneous 3 times per week 20mg or 40mg: Treatment delays clinically definite multiple sclerosis at 2 years, unknown effect on disability in CIS patients. [PreCISe]
  • Teriflunomide (aubagio) orally daily 14mg: Treatment delays clinically definite multiple sclerosis at 2 years [TOPIC]
Secondary progressive disease:
  • No proven therapy
  • Disease modifying therapy for RRMS is usually continued as long as relapses still occur
  • Cytotoxic: Mitoxantrone hydrochloride, is not usually used because of cardiotoxicity
Primary progressive disease:
  • Nothing has been proven effective
General supportive care:

Rehabilitation therapy:

  • Physical therapy and exercise without excessive exertion
  • Occupational therapy, as appropriate

If depressed:

  • SSRI

If fatigued consider:

  • Amantadine
  • SSRI
  • Modafinil

If neuropathic pain:

  • Amitriptyline
  • Carbamazepine
  • Gabapentin

Treat sexual dysfunction, usually erectile dysfunction:

  • Sildenafil

Consider spasticity treatment:

  • Baclofen, tizandine or diazepam
  • Multidisciplinary

Consider bladder & bowel Mx.

  • Bladder hyperreflexia:
    • Tolterodine
    • If residual >100 ml intermittent self catheterisation
  • Bowel: diet changes, softeners & stimulants

Attention to skin care/pressure ulcers

Related articles:

References:

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