1. Multiple Sclerosis (MS)
Dr Oliver Lily
Consultant Neurologist
Leeds General Infirmary

2. Multiple sclerosis What is MS? What causes MS?
Symptoms and signs of MS
Making the diagnosis
Investigations
Treatments

3. 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)

4. Case Study: Ms A
Next day, awoke to find vision completely gone in left eye!
Diagnosis?

7. 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

8. 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?

10. 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

11. 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

12. Diagnosing MS Clinical diagnosis
Relies on dissemination in time and place
? Is this MS

13. Diagnosing MS Clinically Definite MS Not 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

14. Supporting investigations

15. 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

18. 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

23. 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

24. Disease modifying treatments: Immunomodulation
Interferon beta 1-b
Interferon beta 1-a
Glatiramer acetate / Copaxone

25. 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

26. Disease-modifying drugs
Betaferon 1b
Avonex 1a
Rebif 1a
Glatiramer acetate
Site of injection sc im
Frequency
Alt days
Once week
3 times /week
Daily
Side effects
Flu-like symptoms
ISR
FLS
FLS, ISR
Acute reaction

27. 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

28. 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

30. Axonal loss in MS
Disability
Time

31. Axonal loss in MS
Disability
Axonal loss
Inflammation
Time

33. 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

36. Newer treatments for RRMS: the return of immunosuppression!
Mitoxantrone
Natalizumab
Oral Treatments (Fingolimod)

37. 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:

38. 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:
Hartung H-P, et al. Mitoxantrone in progressive multiple sclerosis: a placebo controlled, double-blind, randomised, multicentre trial. (n=194)
Lancet 2002;360:

39. 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

40. Mitoxantrone chemotherapy35
responders 30
failures 25 20
Disease duration 15 10 5

41. Natalizumab (Tysabri)
The interaction of the adhesion molecules, 4-integrin on the activated leukocyte with VCAM-1 on the blood-brain barrier are the key components involved in immune cell adhesion and migration.1
VCAM-1 = vascular cell adhesion molecule-1. Lobb RR et al. J Clin Invest. 1994;94:
Lobb RR, Hemler ME. The pathophysiologic role of 4 integrins in vivo. J Clin Invest. 1994;94:

42. A closer look at the cross-section of the blood-brain barrier reveals the migration of activated immune cells into the brain and the resulting inflammatory cascade that may lead to myelin damage and nerve cell death.1,2
1. Connell B et al. Ann Neurol. 1995;37: von Adrian UH et al. N Engl J Med. 2003;34:68-72.
Cannella B, Raine CS. The adhesion molecule and cytokine profile of multiple sclerosis lesions. Ann Neurol. 1995;37:
von Andrian UH, Engelhardt B. 4 integrins as therapeutic targets in autoimmune disease. N Engl J Med. 2003;348:68-72.

43. Natalizumab is the first in a class of SAM inhibitors that prevent the migration of immune cells across the blood-brain barrier by selectively attaching to 4-integrin.1-3
1. Cannella B et al. Ann Neurol. 1995;37: von Andrian UH et al. N Engl J Med. 2003;348: TYSABRI® (natalizumab) US Prescribing information, 2004.
Cannella B, Raine CS. The adhesion molecule and cytokine profile of multiple sclerosis lesions. Ann Neurol. 1995;37:
von Andrian UH, Engelhardt B. 4 integrins as therapeutic targets in autoimmune disease. N Engl J Med. 2003;348:68-72.
3. TYSABRI® (natalizumab) US Prescribing information, 2004.

44. 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.

45. Tysabri Rapidly evolving MS Monthly infusions
67% reduction in relapse rate
95 cases PML worldwide (50 deaths)
Chance ranges from 1 in (JC seronegative 1st year) to 1 in 125
Yearly MRI surveillance

46. 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

47. 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

48. 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.

49. Why do MS patients consult?

50. Why do MS patients consult?
Relapses: Least likely reason

51. 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

52. 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.

53. Why do MS patients consult?
Relapses: Least likely reason

54. Why do MS patients consult?
Relapses: Least likely reason
Secondary problems:
Infections: most likely reason

55. 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)

56. 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.

57. 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

58. 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

59. Who to call: MS specialist nurse (LGI) Friendly neurology registrar
MS community team
Neurorehabilitation team
Liaison (Prof Bhakta)
Inpatient (CAH)
Community (St Marys)