1) Diagnosing relapses in multiple sclerosis (MS) patients can be complex, as relapses can mimic other conditions and symptoms are not always clearly MS-related. 2) It is important to properly diagnose relapses to determine the MS disease course, guide treatment decisions, and understand the patient's prognosis. 3) In addition to traditional relapses, atypical presentations must be considered, such as relapses related to MS treatments, infections, neurological conditions mimicking MS, and non-neurological or functional issues. A thorough examination is needed.

1. Diagnosing a
Relapse
MS Trust 2018
Dr Trevor Pickersgill
Consultant Neurologist
Cardiff and Vale University Health Board

2. Declarations of interest
 Conference Funding: Biogen, Novartis, Merck-Serono,
Sanofi-Aventis
 Remunerated Advisory Boards: Biogen, Teva, MedDay
 Speaker/Consultancy Fees: Novartis, Biogen, Roche,
Merck-Serono, RCGP, Migraine Association
 Member - BMA UK and Welsh Council
 Chair - Welsh Consultants Committee
 Chair - Hospital Medical Staffs Defence Trust
 Chair - BMA Organisation Committee
 Director and Trustee of BMA Pension Scheme
 Treasurer, Council member and Trustee - ABN

3. Learning Points
• Relapses – why bother?
• Relapses – how?
• Definitions
• MS-typical/MS-atypical
• Case discussions
• ‘types’ of relapse
• Varied and wide nature of alternative diagnosis
• Infection
• Treatment
• Neurological - not MS
• Not neurological – not MS

4. Importance of relapses
• Define diagnosis (usually)
• Define disease type (always)
• Define treatment (often)
• Define disability (frequently)
• Can mimic serious illness….. “it must be your MS…”
• Cause harm
• Financially, socially, physically, emotionally

5. Why do we need to diagnose relapse?
• Establishing the clinical diagnosis
• Optimising short term ability
• Guide medium term treatment decisions
• Inform the natural history of disease
• Support the patient and their family
www.multiplesclerosis.net

6. Steroids?

7. Relapse treatment
• Intravenous steroids
• Steroid tablets
• - Oral MP 500mg/day x5d
• - Pred 60/30/15 each x7d
• Wait and see
• Do not affect outcome
• Outpatient
• (Inpatient)

8. BUT…..always remembering…
Steroids do not
improve recovery
rates…only speed
Are not always
disabling
Majority recover
(not all)
Steroids have
side effects….

9. relapsing
remitting
secondary
progressive
relapsing
progressive
progressive
relapsing
relapsing
with
progression
secondary
progressive
with
relapses
primary
progressive
with
relapses
transitional
relapsing
with
sequelae

10. relapsing
primary
progressive
active
progressive
highly
active
relapsing
without
progression
worsening
relapsing
progressive
inactive
progressive
active
benign
relapsing

12. Figure 2. The net change in Expanded Disability Status Scale (EDSS) score from before an
exacerbation to after.
Fred D. Lublin et al. Neurology 2003;61:1528-1532
©2003 by Lippincott Williams & Wilkins

16. RM dob 1987….inflammation in 2005

17. ….atrophy 2012….

18. Acute relapse: definitions
• Pathophysiology: Acute inflammation and
demyelination occurring within clinically eloquent
areas of the central nervous system.

19. Demyelination
n Disturbs nerve messages
n Slows conduction
n May cause block
n Interrupts normal function
of nerves
n May be silent I.e. cause no
problems

20. Robert Carswell 1793-1857
• Pathologist
• ‘strange lesions’ in spinal
cord
Jean
Cruveilhier -
parisian
anatomist

22. CNS Inflammation
n Blood-brain barrier breached
n T Cell (white blood cell - fight
infection) sticks to lining
n Migrates in
n Attracts more inflammation
cells and cytokines (attraction
chemicals) produced
n Inflammation causes
demyelination

23. What we really need is a
medical…..

24. Stats…..
K Harding et al ENS 2012

27. Relapse rate for men and women from onset and by current age (A) from onset (n = 2477), (B) by
patient’s current age (n = 2477).
H Tremlett et al. J Neurol Neurosurg Psychiatry
2008;79:1368-1374
©2008 by BMJ Publishing Group Ltd

28. Acute relapse: what the textbooks say
• Pathophysiology: Acute inflammation and
demyelination occurring within clinically eloquent
areas of the central nervous system.
• Clinical: “patient-reported or objectively observed
events typical of an acute inflammatory
demyelinating event in the CNS, current or
historical, with duration of at least 24 hours, in the
absence of fever or infection.”1
1. Polman CH et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald
criteria. Annals of neurology 2011;69:292-302.

29. Acute relapse: what the textbooks say
• Pathophysiology: Acute inflammation and
demyelination occurring within clinically eloquent
areas of the central nervous system.
• Clinical: “patient-reported or objectively observed
events typical of an acute inflammatory
demyelinating event in the CNS, current or
historical, with duration of at least 24 hours, in the
absence of fever or infection.”1

30. Acute relapse: the reality
Acute
symptoms
in MS
Pre-morbid
function
Medication
Heat
Psychosocial
factors
Spasticity/
spasms
Other
medical
conditions
Progressive
disability

31. Acute relapse: the reality
From : Tallantyre et al. Multiple Sclerosis Journal (2015) 21 (1): 67-75.

32. Case 1: AM

33. Ideal world
• MRI same day
• Lots of time to assess/examine/measure
• Biomarkers
• Immediate infection screen results…
• CRP
• MSU
• Whole body scan…..

34. Real World….
• 30-40 min appointments
• History….
• Plausible?
• MS-typical?
• Fits with the patient…?
• Recurrent/stereotyped?
• Examination…..
• New neurological signs
• Need old records (database?)
• Impairments – walking distance/speed

35. And….
• Temperature?
• MSU/dipstick
• General medical examination

36. Acute relapse and infection
• At risk period
• Relapse rate ↑ x 2
• More often prolonged and sustained
1. Sibley WA et al, Lancet 1985;1:1313-5. 2. Andersen O, et al. Journal of neurology 1993;240:417-22.
3. Edwards S, et al. JNNP 1998;64:736-41. 4. Panitch HS. Annals of neurology 1994;36 Suppl:S25-8.
5. Buljevac D, et al. Brain 2002;125:952-60. 6. Correale J, Fet alNeurology 2006;67:652-9.
Infection
Weeks

37. Case 2: SE

38. Case 2
31y lady, known relapsing-remitting MS
• 2 week history:
• Headaches
• Palpitations
• Short of breath on exertion
• On examination:
• Pansystolic murmur
• Bilateral pitting leg oedema
Questions:
• Is this a relapse?
• Would you treat with steroids?
• What else would you do?

39. Case 2
Questions:
• Is this a relapse?
• No
• Would you treat with steroids?
• No
• What else would you do?

40. Case 2- continued
• TFTs: FT4 37.3, TSH
<0.02
• CTPA: no pulmonary
embolus
• Carbimazole
• Radio-iodine
Diagnosis: pulmonary hypertension due to autoimmune
thyrotoxicosis (related to alemtuzumab)

41. Treatment related effects
• Alemtuzumab
• Autoimmunity
• ITP – not suitable relapse clinic
• Thyroid – great mimic
• Renal - monitoring
• Natalizumab/ TEC/ Fingolimod
• PML – know your patient’s titres and STRATIFY risk
• Interrogate scans
• 3-4monthly ‘PML protocol’

42. Alemtuzumab side-effects
• Prospective follow-up of 100 patients (mean 6y)
• Thyroid disease 35%
• Other autoimmunity 16%
Willis et al. (2015) Multiple Sclerosis Journal.

43. Name that DMT…..

44. Natalizumab and possible relapse
Guidance for evaluation of new neurological symptoms in patients receiving TYSABRI.
Biogen Idec. 2015

45. Guidance for evaluation of new neurological symptoms in patients receiving TYSABRI.
Biogen Idec. 2015

46. Examples of MRI findings in asymptomatic patients with natalizumab-associated progressive
multifocal leukoencephalopathy (PML; left column) and the lesion evolution during follow-up
after the patients have become symptomatic (right column).
Wattjes M P et al. J Neurol Neurosurg
Psychiatry doi:10.1136/jnnp-2014-
308630
©2014 by BMJ Publishing Group Ltd

47. Reference axial T2-weighted images (A and B) and follow-up axial T2-weighted (C and D) images,
and contrast enhanced T1-weighted (E and F) images of a natalizumab-treated patient with MS from
our study.
Martijn T Wijburg et al. J Neurol Neurosurg Psychiatry
2016;87:1138-1145
©2016 by BMJ Publishing Group Ltd

48. • 3 years – 241 patient 371 reviews
• 79% seen within a week
• Mean symptoms duration 26d
• 75% RRMS
• 58% in relapse
• Of which 26% had another contributory factor

51. Case 3: KL

53. Fig 2 Assessing severity of relapses. “Severe” and “disabling” are used interchangeably, as are
“moderate” and “clinically significant”.
Ian Galea et al. BMJ 2015;350:bmj.h1765
©2015 by British Medical Journal Publishing Group

54. Case 4: CM

55. The difficult…..
• Non-physical – eg fatigue, cognition (linked..?)
• Minor – sensory, vision with normal acuity
• Infection-related /infective relapse
• New inflammatory activity
• Progression as a chameleon for relapse…
• Relapse as a mimic of progression…
• Paroxysmal clustering (TN, tonic spasms)
• The unusual…..

56. .....of course it’s not....is it..?
• 45m Asian
• PMH - ON
• New hemiparesis
• Confusion
• disinhibited

57. Not relapse….
• Pseudorelapse – stuck record
• Brief symptoms
• Very brief symptoms..
• Bad day syndrome
• Functional/medically unexplained
• Neurological but not MS…
• Discs
• Carpal tunnel
• migraine

58. Acute relapse: the reality
From : Tallantyre et al. Multiple Sclerosis Journal (2015) 21 (1): 67-75.

59. Musculoskeletal comorbidity in MS
• Greater trochanteric bursitis1
• Fibromyalgia2
• Arthritis
• Adverse neural tension
1. Sloan RL, Practical neurology 2009:9: 163-5.
2. Marrie, R. Multiple Sclerosis and Related Disorders. 2012: 1 :162.

60. Non-organic
39 year old lady with RRMS
• Diagnosed with MS 2004
• Optic neuritis 2004
• Trigeminal neuralgia
• Earlier this year: giddy/ unsteady, partial improvement
with steroids
• New loss of vision left eye

61. “Her walking is a bit wobbly and she has to hang on to
somebody’s arm.
Examining her today her acuity is 1/60 left, counting
fingers right, but despite this apparent complete
blindness she was able to walk in heels reasonably well
and her pupils had really quite brisk reactions. Her
discs were pale, she seemed reluctant to check eye
movements, she couldn’t or wouldn’t close her eyes to
test facial power.
Although she walked up and down the corridor 45
metres or more, when she got on the bed she couldn’t
move her legs. She would only twitch her toes when I
asked her to lift her legs up and both plantars were
definitely flexor. Her gait was rather odd and shuffling.”

62. From : Tallantyre et al. Practical Neurology (2015)

63. Acknowledgments
• Relapse Clinic Team:
Jackie Smee
Rachel Wallbank
Lynn Kelly-Jones
Gail Clayton
Sian Locke
Rhiannon Jones
Annabelle Price
Rhian O’Halloran
Emma Tallantyre
James Hrastelj
Ray Wynford-Thomas
Ania Crawshaw
Katharine Harding
Mark Willis
• Slides/Data:
• Dr Emma Tallantyre
• Dr Ray Wynford-Thomas
• Prof Neil Robertson
• Dr Claire Hirst