Multiple Sclerosis (MS)

Dr Oliver Lily Consultant Neurologist Leeds General Infirmary

Multiple sclerosis

• 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

• 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

• 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

relapsing remitting 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 Alt days Side effects Flu-like symptoms ISR Avonex 1a im Rebif 1a sc Glatiramer acetate sc Once week FLS 3 times /week FLS, ISR Daily Acute reaction

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

Disability

Axonal loss in MS

Time

Disability

Axonal loss in MS

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;62:112 118.

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;62:112 118.

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

15 10 5 0 25 20 35 30

Mitoxantrone chemotherapy

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.

3. TYSABRI ® (natalizumab) US Prescribing information, 2004.

2003;348:68-72.

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

• Rapidly evolving MS • Monthly infusions • 67% reduction in relapse rate • 95 cases PML worldwide (50 deaths) • Chance ranges from 1 in 10000 (JC seronegative 1 st 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

• 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: – 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:

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