Multiple Sclerosis (MS)
Dr Oliver Lily
Consultant Neurologist
Leeds General Infirmary
Multiple sclerosis
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What is MS?
What causes MS?
Symptoms and signs of MS
Making the diagnosis
Investigations
Treatments
Case Study: Ms A
• 20 year old medical student
• Presented with 3 day history of pain in the
left eye with blurred vision
• On examination:
– Reduced colour vision (Ishihara chart)
– Reduced pupillary light responses (RAPD)
– Hole in visual field (scotoma)
Case Study: Ms A
• Next day, awoke to find vision completely
gone in left eye!
• Diagnosis?
Optic Neuritis
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Inflammation of the optic nerve
Causes pain and loss of vision
Frequently not visible (retrobulbar)
Good prognosis: 95% return to visual acuity
of 6/12 or greater within 12 months
• High dose steroids speed up rate of recovery
but have no effect on final acuity
• 50% go on to develop MS within 10 years
Case Study: Ms A
• Eye completely better within 3 months with no
treatment.
• Well for 2 years
• Week of medical finals, complained of tingly
numbness starting in both feet and gradually
ascending to level around chest “like a tight band”.
Felt unsteady walking and fatigued easily.
• Electric shock sensations running down body
whenever she bent her head
• What is the diagnosis now?
Transverse myelitis
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Inflammation inside the spinal chord
Often mild with good prognosis
Often pure sensory
Lhermittes phenomenon
May affect bladder
50% go on to develop Multiple Sclerosis
Other causes of myelitis
• Infective
– Herpes Zoster
– HTLV-1
– Lyme disease
• Autoimmune
– Lupus
– Sjogrens syndrome
– Neuromyelitis optica
• Long spinal lesion (3 segments)
• Anti-aquaporin antibodies
Diagnosing MS
• Clinical diagnosis
• Relies on dissemination in time and place
• ? Is this MS
Diagnosing MS
• Clinically Definite MS
– Optic neuritis and
transverse myelitis at
different times
• Not definite MS
– Clinically isolated
syndrome (CIS)
– Myelitis and optic
neuritis at the same
time
– Recurrent myelitis
– Recurrent or sequential
optic neuritis
Supporting investigations
What is MS?
• MS is the most common cause of
neurological disability in young adults in
the UK
• 792 people with MS in Leeds
• 40 new cases of MS / year
What is MS?
• MS is a disease of the central nervous
system (CNS)
• An inflammatory reaction in the CNS
causes loss of myelin and slowing of nerve
conduction
• Areas of demyelination
• Loss of axons
Outcome: Ms A
• Treated with intravenous
methylprednisolone 1g daily for 3 days
• Improved to normal over next 6 weeks
• Told she had diagnosis of relapsingremitting multiple sclerosis
• Started on treatment with beta-interferon 1a
injections
• Remained in remission for next five years
Disease modifying treatments:
Immunomodulation
• Interferon beta 1-b
• Interferon beta 1-a
• Glatiramer acetate /
Copaxone
Interferon beta
• Reduces the number of relapses by 30%
compared to placebo
• Effective early in the disease course
• No evidence on long-term effect on
disability
Disease-modifying drugs
Site of
injection
Frequency
Betaferon
1b
sc
Avonex
1a
im
Rebif
1a
sc
Alt days
Once
week
3
Daily
times
/week
FLS, Acute
ISR
reaction
Side effects Flu-like
symptoms
ISR
FLS
Glatiramer
acetate
sc
The case of Dr A
• Now working as a GP
• 34 years old
• Noticing that when she walks, after a mile or so
her left leg tingles and begins to drag. If she stops
for a few minutes she can carry on normally.
• Referred for physiotherapy
• Returns two years later. Is limping on left leg and
carries a walking stick. Right leg also feels stiff
and wooden. Noticed urinary urgency and
occasional spasms in the legs
Case of Dr A
• On examination has weakness of flexors
more than extensors worse on the left, with
a left sided foot drop. There is increased
tone and sustained clonus in both legs with
very brisk reflexes and upgoing plantars.
• Spastic paraparesis – suggests a spinal
chord problem
• ? diagnosis
Axonal loss in MS
Disability
Time
Axonal loss in MS
Disability
Axonal loss
Inflammation
Time
The case of Dr A
• Over the next five years walking becomes more
difficult and she has to start using two elbow
crutches and then a wheelchair
• Her interferon is stopped but she continues with
regular physiotherapy
• She gets more forgetful, and eventually retires
from the health service aged 42
• 15% of MS patients are confined to a
wheelchair within 10 years of diagnosis
Newer treatments for RRMS:
the return of immunosuppression!
• Mitoxantrone
• Natalizumab
• Oral Treatments (Fingolimod)
Edan G, et al.
Therapeutic effect of mitoxantrone combined with
methylprednisolone in multiple sclerosis: a randomised
multicentre study of active disease using MRI and clinical criteria.
(n=42)
Journal of Neurology, Neurosurgery and Psychiatry 1997;62:112118.
Edan G, et al.
Therapeutic effect of mitoxantrone combined with
methylprednisolone in multiple sclerosis: a randomised
multicentre study of active disease using MRI and clinical criteria.
(n=42)
Journal of Neurology, Neurosurgery and Psychiatry 1997;62:112118.
Hartung H-P, et al.
Mitoxantrone in progressive multiple sclerosis: a placebo
controlled, double-blind, randomised, multicentre trial.
(n=194)
Lancet 2002;360:2018-2025.
Mitoxantrone
• Rapidly progressive patients
• Improvements in disability/mobility as well
as relapse rates (up to 90%)
• Prolonged improvement (up to 18m after
treatment)
• 1 in 300 chance of secondary leukaemia
• Dose related cardiomyopathy
Mitoxantrone chemotherapy
35
Disease duration
30
25
20
15
10
5
0
responders
failures
Natalizumab (Tysabri)
VCAM-1 = vascular cell adhesion molecule-1.
Lobb RR et al. J Clin Invest. 1994;94:1722-1728.
1. Connell B et al. Ann Neurol. 1995;37:424-435. 2. von Adrian UH et al. N Engl J Med. 2003;34:68-72.
1. Cannella B et al. Ann Neurol. 1995;37:424-435. 2. von Andrian UH et al. N Engl J Med. 2003;348:68-72.
3. TYSABRI® (natalizumab) US Prescribing information, 2004.
Elan shares dive on drug setback
Shares in Irish drugmaker Elan have plummeted once more after a third case
of disease linked to Tysabri, its multiple sclerosis treatment.
Elan suspended the drug after two patients were found to have caught the rare
disease, one of whom later died.
The newly revealed case - which also ended with the death of the patient - could
mean Tysabri never makes it back onto the market, analysts warned.
By the close of trading, Elan shares were down 56% to 2.43 euros.
The initial cases had involved patients taking both Tysabri and US firm Biogen
Idec's drug Avonex, and Elan had hoped that the problem was due to an
unexpected problem with the combination.
The latest, however, involves Tysabri alone.
Biogen's shares were down 11% by 1600 GMT.
Tysabri
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Rapidly evolving MS
Monthly infusions
67% reduction in relapse rate
95 cases PML worldwide (50 deaths)
Chance ranges from 1 in 10000 (JC
seronegative 1st year) to 1 in 125
• Yearly MRI surveillance
Fingolimod (Gilenya)
• Sphingosine-1-phosphate receptor blocker;
traps lymphocytes in lymph nodes
• Licenced for rapidly evolving MS (second
line)
• 60% reduction in relapse rate
• Side effects include bradycardia, macula
oedema, infections (esp herpes virus), skin
cancers
Drugs/treatments for MS with no
proven benefit over placebo
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Naltrexone
Vitamin D, E, B12, fish oils
Special diets
Venous angioplasty/stenting
Stem cell treatments (other than bone
marrow transplant)
• Sativex
Sativex
• 160 people with MS took part in this trial which compared
the effects of Sativex versus placebo on spasticity, spasms,
pain, bladder and tremor. No significant improvements
were seen in overall symptom relief
• 189 people with MS and spasticity symptoms took part in a
study which compared the effects of Sativex versus
placebo. Changes in spasticity during the six-week study
were recorded using a patient-reported scale and a clinical
measure of spasticity. Improvements were seen on the
patient-reported scale but improvements seen on the
clinical scale did not reach statistical significance.
Why do MS patients consult?
Why do MS patients consult?
• Relapses: Least likely reason
Relapses
• Onset of new neurological symptoms lasting more
than 48 hours
• Tend to come on over 1-2 days and last 2-4 weeks
• Mostly sensory
• Get better without treatment (95-100% recovery
usual)
• Affect young patients in the early stages of their
MS
Relapses II:
• High dose steroids have been shown to speed up
recovery but do not make it any more complete.
Probably a non-specific effect. They do not need
to be given urgently and in most cases do not need
to be given at all.
• Relapses are not medical emergencies and only
need to be admitted if they cannot cope at home.
• Refer to MS nurse / MS relapse clinic as
outpatient.
Why do MS patients consult?
• Relapses: Least likely reason
Why do MS patients consult?
• Relapses: Least likely reason
• Secondary problems:
– Infections: most likely reason
Infection and MS
• Disabled patient in late stages of disease
• Cause widespread and dramatic neurological
impairment (Uhtoffs phenomenon)
• Usually bladder (secondary to urinary retention)
• Occasionally pneumonia (secondary to impaired
swallow, brainstem reflexes and weak respiratory
muscles)
Why do MS patients consult?
• Relapses: Least likely reason
• Secondary problems:
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Infections: most likely reason
Pain - usually mechanical or orthopaedic
Seizures - very rare
Acute baclofen withdrawal - very dramatic!
Leg spasms
• patients with spastic paraparesis; caused by afferent
irritation eg UTI, pressure sores, blisters, ingrowing
toenails etc.
MS Care in Leeds
• MS clinic at Seacroft Hospital with 3
consultants, three MS Specialist Nurses, and
senior neuro-physiotherapist
• MS Specialist social worker/link worker
provides drop-in service
• New liaison psychology/psychiatry service
MS Care in Leeds
• Ground floor level access with disabled
parking!
• Information centre
• Full MS treatment programme including
chemotherapy and clinical trials
• MS Register and yearly newsletter
Who to call:
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MS specialist nurse (LGI)
Friendly neurology registrar
MS community team
Neurorehabilitation team
– Liaison (Prof Bhakta)
– Inpatient (CAH)
– Community (St Marys)