This document summarizes key points from a presentation on accurately diagnosing relapses in multiple sclerosis (MS) patients. It discusses the clinical definition of an MS relapse according to textbooks and reality, and highlights factors like pre-morbid function and medication that can influence relapse diagnosis. Several clinical scenarios are then presented where attendees must determine if new symptoms represent a relapse or have alternative causes like infection, autoimmune conditions from MS treatments, musculoskeletal issues, or functional neurological symptoms. Accurately diagnosing relapses is important for treatment decisions and understanding the natural disease course.

1. MS Trust Conference
Differential diagnosis in a relapse clinic
Dr Emma Tallantyre
Post-doctoral Research Fellow
Rachel Wallbank
Occupational Therapist MS Team
University Hospital of Wales, Cardiff.

2. Learning objectives
• To appreciate the clinical definition of an MS relapse
• To understand the reasons for accurately classifying
relapse
• To recognise the common mimics of relapse and the
pitfalls of relapse diagnosis
• To use clinical examples to gain confidence in
accurately diagnosing and managing relapses
• To appreciate key issues in relapse management and
service design

3. Acute relapse: what the textbooks say
• Pathophysiology: Acute inflammation and
demyelination occurring within clinically eloquent
areas of the central nervous system.

4. 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.

5. 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.

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

7. Acute relapse: the reality

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

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

10. CLINICAL SCENARIOS

11. Scenario 1
32 year old lady with RRMS, three weeks post-
partum.
• Blurred vision left eye. Mild pain on eye
movements. Has seen optician and told she has
optic disc swelling.
• Visual acuity: left 6/24; right 6/6
Questions:
• Is this a relapse?
• Would you treat? If so, what with?

12. Scenario 1
Questions:
• Is this a relapse?
– YES: acute optic neuritis
• Would you treat? If so, what with?

13. 2. Sellebjerg F et al. Neurology. 1998; 51: 529-34.
3. Sellebjerg F et al. Neurology. 1999; 52: 1479-84. 4. Burton et al. Cochrane Database 2012.
5. Ramo-Tello et al. Mult Scler. 2014; 20: 717-25.
Acute relapse and steroids: who to treat, and how.
WHO?
• Optic Neuritis Treatment Trial (ONTT)1:
– 457 individuals with ON: IV methylpred vs oral pred vs placebo:
significant improvement in speed of recovery with IV
methylpred, no impact on long term vision.
• NICE guidance (2014): “Assess and offer treatment for relapses of
MS, that affect the person's ability to perform their usual tasks”
HOW?
• High dose oral steroids effective2,3
• Oral and IV steroids thought to have equivalent efficacy4
• One RCT showed non-inferiority of oral methylprednisolone5
• NICE: Oral methylprednisolone 500mg od for 5d
1. Beck et al, (1992) NEJM. 326 (9): 581-588.

14. Scenario 2
30 year old lady with RR MS
– One week history of difficulty walking.
– No symptoms of infection.
– Legs weak and stiff on examination.
– Urine dipstick:
• Leucocytes: +
• Nitrites: +
Questions:
• Is this a relapse?
• What, if any, treatment would you give?
• When would you follow her up?

15. Scenario 3
30 year old lady with RR MS
– One week history of difficulty walking.
– Dysuria and frequency to micturate.
– Temp 37.5C.
– Legs weak and stiff on examination.
– Urine dipstick:
• Leucocytes +
• Nitrites: trace
• Protein 1+
• Blood 1+
Questions:
• Is this a relapse?
• What, if any, treatment would you give?
• When would you follow her up?

16. Acute relapse and infection
Questions:
• Is this a relapse?
– “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.”
– Pseudo-relapse: Heat/ infection can cause transient
neurological deterioration.
– But infection can also trigger relapse.
• Relapses associated with infection: worse
outcome

17. 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

18. Scenario 2/3
• What, if any, treatment would you give?
• When would you follow her up?

20. • What, if any, treatment would you give?
– Scenario 2: Antibiotics and steroids.
– Scenario 3: Antibiotics initially.
• When would you follow her up?
– Scenario 3: In 1 to 2 weeks to reassess neurology
and consider steroids.

21. Scenario 4
24 year old lady
• Resident in Saudi until 2/52 previously
• March 2014 : headaches, blurred vision, arm and leg
numbness
• August 2014: visual loss left eye
• Began with central blurring
• Progressed over 1-2/52
• At worst sliver of retained temporal field
• Pressure feeling in eye worse on eye movement
• Some improvement over last 1 week but still little useful
vision in left eye
• Right eye unaffected

22. Scenario 4
• VEP delayed left side

23. Scenario 4 - imaging

24. Scenario 4
Questions:
• Is this a relapse?
• Would you treat with steroids?
• What else would you do?

25. Ophthalmology
• Corneal oedema
• Intra-ocular pressures 40 (Normal: 12-22)
• Deep cupped optic discs
• Marked optic atrophy
• Diagnosis: acute angle-closure glaucoma
• Cause of ON signal change ? Ischaemia
• VEPs?
• Rx Diamox
• Recovery unlikely

26. Scenario 4
Questions:
• Is this a relapse?
– No
• Would you treat with steroids?
– No
• What else would you do?
– Refer to ophthalmology

27. Acute relapse: ON mimics
Unusual clinical features:
• Persistent or absent pain
• Severe visual loss
• Visual disturbance continues to progress after one
month
• Bilaterality
• Steroid response, followed by a relapse when stopped
Differential diagnosis
• Uveitis
• Glaucoma
• Ischaemic optic neuropathy including vasculitis
• Neuroretinitis e.g. syphilis, TB, toxoplasma.
• Leber hereditary optic neuropathy.
• Other inflammatory optic neuropathy e.g. NMO,
sarcoid

28. Scenario 5
31y lady, known relapsing-remitting MS
• 2 week history:
– Headaches
– Palpitations
– Short of breath on exertion
• On examination:
– Pansystolic murmur
– Bilateral pitting oedema
Questions:
• Is this a relapse?
• Would you treat with steroids?
• What else would you do?

29. Scenario 5
Questions:
• Is this a relapse?
– No
• Would you treat with steroids?
– No
• What else would you do?

30. Scenario 5 - 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)

31. Treatment related effects
• Alemtuzumab
– Autoimmunity
• Natalizumab/ BG-12/ Fingolimod
– PML

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

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

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

35. Scenario 6
54 y man progressive MS
• 3 month history
– R leg numbness
– R sided lower back pain
• Weak left leg with brisk reflexes
• Loss of sensation dorsum right foot
Questions:
• Is this a relapse?
• Would you treat with steroids?
• What else would you do?

37. Scenario 6
• Diagnosis:
– Spinal stenosis and nerve root compression
• Management:
– Referral for surgical opinion
– Physiotherapy
– Pain management

38. 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.

39. Scenario 7
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

40. Scenario 7 (examination)
“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.”

41. Scenario 7
Questions:
• Is this a relapse? If not, what would you call it?
• Would you treat with steroids?
• What else would you do?

42. Functional neurological symptoms
• AKA: non-organic, hysterical, psychogenic,
medically unexplained.
• How to recognise functional symptoms:
– Discrepancy with functional ability
– Discrepancy with neuroanatomy
– Objective tests (bedside or investigation)
1. Merwick, A. The International MS Journal 2008; 15: 47–51

43. Scenario 7 (examination)
“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.”

44. Scenario 7 (examination)
“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.”

45. Scenario 7 (examination)
“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.”

46. Scenario 7 (examination)
“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.”

47. Functional neurological symptoms
Wong SH, et al. Interpretation of
Visual Fields. Practical Neurology
2015; 1–8.
Stone J, et al. Hoover’s Sign.
Practical Neurology 2011; 50–53.

48. Functional neurological symptoms

49. Functional neurological symptoms
• What else would you do?
– Explain the symptoms to the patient
• Demonstrate discrepancies
• Use it to reassure
– Recognise the impact of the symptoms
• “Although these symptoms are not caused by MS, they are still very real
and I can see how they are really impacting on life at the moment.”
• “We see these sort of symptoms quite a lot and often find that people can
feel quite confused by not being able to firmly identify the underlying
cause. So it’s important that you know that I agree these symptoms are
real; you are not imagining them or making them up.”
– Minimise investigations : positive diagnosis
– Practical solutions
• Physiotherapy
• Social support
• Functional goals e.g. engagement with groups/ activities

50. Scenario 8
29 year old man
• Three weeks of worsening mobility.
• Needing unilateral assistance (previous EDSS 3).
• Numbness in the fingers. Vertigo in the mornings.
• Two steroid courses so far this year.
Questions:
• Is this a relapse?
• Would you treat with steroids?
• What else would you do?

51. Steroids: how often is too often?
• Common side-effects:
– headache, mood disturbance, fatigue, insomnia,
metallic taste, weight gain and skin changes.
• Other considerations:
– Diabetes/ hypertension
– Gastrointestinal complications
• Rare unless co-adminsitered with NSAIDS1
• Give PPI if history of peptic ulcer disease
– Bone health
• Pulsed steroids not thought to ↑ risk osteoporosis2
• Osteonecrosis is a cumulative risk3
1. Piper et al. Annals of internal medicine. 1991; 114: 735-40.
2. Zorzon et al. European journal of neurology 2005; 12: 550-6.
3. Ce et al. European journal of neurology 2006; 13: 857-61.

52. Consideration for disease modifying
therapy
• Consideration for disease modifying therapy
– Active MS
• 2 relapses within 2 years
– Ongoing relapses on existing therapy
• In the clinic
– Provide written information
– Order relevant investigations
– Enquire about patient preference
– Explain process of consideration

53. Acute relapses: other mimics
• Failed recovery from a previous relapse
• Progressive disability
• Paroxysmal MS symptoms
• Ensuring the original diagnosis is secure

54. Why do we need a dedicated relapse
service?
• Research shows:
– shortens delay in accessing specialist care
/receiving treatment
– reduces inpatient admissions
– minimises the psychological impact of MS relapses
• National recommendations

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

56. Relapse clinic issues
• Telemedicine
• Do patients benefit from RAC?
• Brain imaging

57. Thank you
Any questions?