Multiple Sclerosis (MS)

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Multiple Sclerosis (MS)

• Dr Oliver Lily
• Consultant Neurologist
• Leeds General Infirmary

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Multiple sclerosis

• What is MS?
• What causes MS?
• Symptoms and signs of MS
• Making the diagnosis
• Investigations
• Treatments

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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)

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Case Study Ms A

• Next day, awoke to find vision completely gone in
  left eye!
• Diagnosis?

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Optic Neuritis

• 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

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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?

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Transverse myelitis

• 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

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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

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Diagnosing MS

• Clinical diagnosis
• Relies on dissemination in time and place
• ? Is this MS

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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

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Supporting investigations
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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

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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

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Outcome Ms A

• Treated with intravenous methylprednisolone 1g
  daily for 3 days
• Improved to normal over next 6 weeks
• Told she had diagnosis of relapsing-remitting
  multiple sclerosis
• Started on treatment with beta-interferon 1a
  injections
• Remained in remission for next five years

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Disease modifying treatmentsImmunomodulation

• Interferon beta 1-b
• Interferon beta 1-a
• Glatiramer acetate / Copaxone

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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

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Disease-modifying drugs
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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

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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

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Axonal loss in MS
Disability
Time
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Axonal loss in MS
Disability
Axonal loss
Inflammation
Time
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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

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Newer treatments for RRMSthe return of
immunosuppression!

• Mitoxantrone
• Natalizumab
• Oral Treatments (Fingolimod)

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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.
(n42) Journal of Neurology, Neurosurgery and
Psychiatry 199762112-118.
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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.
(n42) Journal of Neurology, Neurosurgery and
Psychiatry 199762112-118.
Hartung H-P, et al.Mitoxantrone in progressive
multiple sclerosis a placebo controlled,
double-blind, randomised, multicentre
trial.(n194) Lancet 20023602018-2025.
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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

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Mitoxantrone chemotherapy
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responders
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failures
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Disease duration
15
10
5
0
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Natalizumab (Tysabri)
VCAM-1 vascular cell adhesion molecule-1.Lobb
RR et al. J Clin Invest. 1994941722-1728.
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1. Connell B et al. Ann Neurol. 199537424-435.
2. von Adrian UH et al. N Engl J Med.
20033468-72.
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1. Cannella B et al. Ann Neurol.
199537424-435. 2. von Andrian UH et al. N Engl
J Med. 200334868-72. 3. TYSABRI (natalizumab)
US Prescribing information, 2004.
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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.
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Tysabri

• 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

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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

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Drugs/treatments for MS with no proven benefit
over placebo

• Naltrexone
• Vitamin D, E, B12, fish oils
• Special diets
• Venous angioplasty/stenting
• Stem cell treatments (other than bone marrow
  transplant)
• Sativex

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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.

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Why do MS patients consult?
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Why do MS patients consult?

• Relapses Least likely reason

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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

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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.

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Why do MS patients consult?

• Relapses Least likely reason

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Why do MS patients consult?

• Relapses Least likely reason
• Secondary problems
• Infections most likely reason

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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)

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Why do MS patients consult?

• Relapses Least likely reason
• Secondary problems
• 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.

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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

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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

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Who to call

• MS specialist nurse (LGI)

• Friendly neurology registrar
• MS community team
• Neurorehabilitation team
• Liaison (Prof Bhakta)
• Inpatient (CAH)
• Community (St Marys)

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