“Have I got MS?” - advice on sensory symptoms

Joe GuadagnoRoyal Victoria InfirmaryNewcastle upon Tyne

Outline

Brief reminder of MS: Incidence, dermographics Usual presenting features

Helpful basic tips? Temporal evolution of sensory symptoms

What are the typical sensory symptoms of MS? What is not typical for MS…… Other neurological conditions with sensory

symptoms New DMT’s – brief update!

Statistics

Commonest cause of acquired neurological disability in young people

Prevalence in UK (~1990s): NI 168/100 000

• (?230 2006) Tayside 184/100 000 NE England ?150/100 000

(1:650) F:M 3:1

What is MS?

Clinical diagnosis

Loosest definition:

1. At least 2 episodes of CNS dysfunction (relapses/attacks/exacerbations)

2. ‘disseminated in time and space’

3. not explained by something else

Diagnostic criteria (revised McDonald 2010)

MRI

relapsing/ remitting primary progressive

Patterns of MS

secondary progressive

85% 15%

relapsing/ remitting primary progressive

Patterns of MS

secondary progressive

85% 15%

( ‘benign’)

5%

Aetiology

genetic1 in 6 cases have affected relative

1 in 650 general population1 in 50 chance if one affected parentbut only 30% concordance in identical

twins

Aetiology: environmentalGeographical variation

UV exposure?

Genetic and environmental?

migration studies– environmental hit acquired in childhood (15yr)

– repeated or prolonged exposure

– latency

infections? EBV?

vitamin D/sunlight?

Hygiene Hypothesis – ‘idle immune system’

- acquired disease in a genetically susceptible individual: cumulative insults?

What is MS?

inflammation degeneration

What is MS?

inflammation degeneration

Common presentations (relapses)

transverse myelitis

brainstem syndromes

optic neuritis

paroxysmal symptoms

The duration of the attack should be longer than 24 hours!

And not in the context of an infection (pseudorelapse)

Helpful tip (when addressing sensory symptoms)

– remember the temporal evolution of relapses

Typical ON - RecoveryV

isua

l Fun

ctio

n

1 to 2/52 3 to 5/52

What are the typical sensory symptoms of MS?(Nb around 35% of presenting symptoms are

sensory (Olec 2005 and Paty et al 1994))

• ascending numbness starting in the feet;• bilateral hand numbness;• Hemiparesthesia (rare thalamic presentation);• dysesthesia in the whole of one limb (or non

dermatomal);• “sunburn” feeling or “itch” in a non-dermatomal

patch• MS ‘Hug’• Facial sensory disturbance and typical TN• Lhermittes phenomena

Whole body numbness or parasthesia Transient flitting sensory disturbances

(parasthesia or numbness) lasting minutes to hours

uncomplicated Bell’s palsy fatigue as isolated or predominant symptom chronic dizziness/ light-headedness “weakness” in setting of musculoskeletal

pain/tenderness atypical facial pain

What is not MS….

Sensory symptoms from other neurological disorders (and

should be referred……)

Keep in mind a little bit of neuroanatomy…………

Radiculopathies (pain!)

Entrapment neuropathies

CTS

Ulnar

Lateral Cutaneous Nerve

(meralgia parasthetica)

Common peroneal Nerve

Management of relapses

Nothing (especially sensory) Steroids

Oral 500mg methlypred for 5 days

IV 1000mg for 3 days

Disease modifying therapy - First line

Five licensed therapies Interferon-

• Avonex • Betaferon• Extavia• Rebif

Copaxone Prescribed under ABN

guidelines

† Measured as the total over 2 years‡ The Avonex trial required a sustained progression for 6 months; the Rebif trial, for 3 months; and the Copaxone trial, for 3 months

First line DMTs

Summary of results from pivotal phase 3 trials

Agent Dosage Reduction in relapses, % †

Relapse-free patients, % †

Interferon beta-1b (Betaferon)

8 mIU (250 µg)SC every other day

34 31

Interferon beta-1a (Avonex)

30 µgIM once weekly

32 38

Interferon beta-1a (Rebif)

22 µgSC 3 times weekly

29 27

44 µgSC 3 times weekly

32 32

Glatiramer acetate (Copaxone)

20 mgSC once daily 29 34

Adapted from Galetta S, et al. Arch Int Med 2002; 162; 2161-2169

Beyond one third relapse reduction…..

New Disease Modifying therapies.

Natalizumab (Tysabri)- A humanised monoclonal antibody

Leukocyte entry to the nervous system

blood

brain

firm adhesion

rolling slow rolling

capture diapedesis

chemokines (incl. MCP-1/CCR-

2)

inflammation

chemokines

selectins integrins (incl. VLA-

4)

migration

Natalizumab (Tysabri)

blood

brain

firm adhesion

rolling slow rolling

capture diapedesis

inflammation

selectins integrins (incl. VLA-

4)

Natalizumab: good things

AFFIRM Highly Active* 1 (n= 148 for TYSABRI, 61 for PBO)

81%

64%

reduction in annualised relapse rate vs. placebo over 2 years (p < 0.001)

reduction in the risk of disability progression, sustained for 24 weeks, as assessed over 2 years (p =0.008)

Patients With ≥2 Relapses in Prior Year and ≥1 Gd+ Lesion At Baseline

2010 2011

Progressive Multifocal Leukoencephalopathy (JC virus)

New Oral therapies!

Fingolimod (Gilenya)

“FDA Panel Unanimously Recommends Approval of First Oral MS Drug”A Food and Drug Administration advisory panel on Thursday unanimously

recommended approval of the first drug for multiple sclerosis (MS) that can be taken orally.

 

FREEDOMS: Annualised relapse rate (ARR) at 2 years (primary endpoint)

Kappos et al, N Engl J Med 2010; 362: 387–410; Cohen et al, Poster P901 presented at ENS 2011; Francis and Haering, April 2011; data on file Negative binomial regression model adjusted for treatment group, country, number of relapses in previous two years and baseline EDSS. Bars represent the 95% CI; ARR, annualised relapse rate; DMT, disease-modifying treatment. Based on efficacy and safety profile, fingolimod 0.5 mg/day is the only approved dose for the treatment of MS

0

0.18(0.15–0.22)

0.40(0.34–0.47)

0.1

0.2

0.3

0.4

ARR

Placebo (n=418)

Fingolimod 0.5 mg(n=425)

-54% p<0.001

Possibly not so good things about fingolimod

completely new class of drug (SIP1 inhibitor)

slows heart on first dose Macular oedema risk 2 deaths

herpes encephalitisDisseminated chicken poxno long term safety dataTeratogenicity?

31% reduction

inhibits dihydroorotate dehydrogenase (DHODH), - a mitochondrial enzyme involved in de novo pyrimidine synthesis (needed for the proliferation of activated lymphocytes).

LFT’s! – needs 2 weekly bloods for 6 months!

Hair thinning/alopecia Stays in system a long time (up to 2

years) so pregnancy effects?

Others dues soon….!

Tecfidera (dimethy fumarate - oral)

Lemtrada (Alemtuzemab – infusion)