This case study describes a patient with relapsing-remitting MS who was treated with natalizumab (Tysabri) between 2010-2011. In March 2011, she had an abnormal brain lesion detected on a surveillance MRI. Over the next few months her condition progressively declined, with developing weakness and sensory symptoms. Further MRIs and lumbar punctures were consistent with a diagnosis of progressive multifocal leukoencephalopathy (PML) induced by her treatment with natalizumab. She underwent plasma exchange treatment but continued to deteriorate clinically.

1. PML – Case Study
Sharon Letissier
MS Nurse
Queen Elizabeth Hospital
Birmingham

2. Patient Details
• Patient diagnosed in 2011 aged 31, Extensive
enhancing lesions in the brain and spinal cord
• Pre treatment EDSS 3.5
• February 2010 – dizziness, vertigo, loss of balance,
visual disturbance of right eye
• July 2010 – tingling and numbness in hands and feet
• January 2011 – loss of balance
• April 2011 – loss of balance and sensory symptoms
• July 2011 – loss of balance, generalised numbness

3. • Reviewed by Consultant July 2011 – diagnosis of
MS confirmed and recommended Tysabri based
on relapse history and MRI findings
• Reviewed by MS nurses July 2011 – MS diagnosis
discussed and Tysabri
• Tysabri commenced August 2011 -JC virus tested
(Positive) – JC index test not available at the time
• Retested Oct 2013 – index value 3.8

4. MRI Scan pre treatment,
T2, postcontrast
Jan 2011
T2
postcontrast

5. 2011 - 2014
• Stable on Tysabri
– Ongoing fatigue and intermittent short lasting
right eye visual disturbance
• March 2014
– EDSS 0
– No relapses since Tysabri commenced
– Discussion regarding switching to Fingolimod

6. Oct 2014
• Attended Fingolimod discussion group and screening
• Had a chest infection, asthmatic prior to screening
• Reported ongoing fatigue
• By Mid Oct-
• Gradual deterioration in right hand function with poor coordination
• Slurred speech intermittent
• Right hand and arm weakness intermittent
• Increase in fatigue
• Mobile independently

7. Late Oct 2014
• CSF sent to reference lab USA
• Positive results received (low titre)
• Seen in clinic next day
• MRI same day
• Admitted to neurology ward

8. Inpatient stay
• Prescribed initially
– Cidofovir (per BNF guidelines for CMV retinitis in
HIV)
– Plasma exchange for 5 days
– Mirtazapine
– Mefloquine
– Keppra
Weekly MRI scans – observing for IRIS

9. End Nov -Inpatient stay
– Continued deterioration of previous symptoms:
• New onset of double vision
• Worsening of the right sided weakness
• Worsening mobility
– Prescribed:
• Granulocyte-colony stimulating factor (GCSF) – twice
(Stefoski, Chicago)
• Maraviroc (to decrease chance of IRIS)
• IV methylprednisolone (mild IRIS) -twice

10. Beg – mid Dec – inpatient stay
• Rapid deterioration of the right sided weakness,
abnormal eye movements, speech
• Repeat LP, JC virus titre increased > 600 cop/ml
• Frequent myoclonic jerks
• EEG – no obvious discharges, activity originating
? from brain stem
• Commenced further medication for seizures

11. MRI Scan Dec - 2014

12. Mid Dec – inpatient stay
• Transferred to ITU due to myoclonic status
epilepticus
• Deep sedation and ventilation 2 weeks
• Regular EEGs

13. Jan- 2015
• Back on Neurology ward
• NG Fed
• Not verbalising, obeying simple commands
• Right side no movement
• Rehab commenced

14. Jan – April 2015
• Gradual improvement
• Eating normal diet
• Dysphasic
• Cognition – disinhibited
• Right arm no use, right leg starting to move
• Mobile with support short distances
• Vision – poor, double vision

15. Ongoing
• Discharged April 2015 (on Maraviroc for 1 year
and Keppra)
• Not working
• Registered partial sighted (visual agnosia)
• Mobile short distances with one crutch
• No functional use right arm
• Cognition has improved
• Word finding improved

16. MRI scan Oct 2015

17. Future Plan
• 2 years post diagnosis
• No evidence of MS disease activity (clinically
or radiologically)
• No DMT as yet (patient’s decision)
• Still on Keppra
• Attending Rehab
• Fatigue is an ongoing issue

18. Tysabri-induced PML
Paul Talbot
Greater Manchester Neuroscience Centre
Salford Royal NHS Foundation Trust

19. Number on DMDs in GM by end of year
4,067 PwMS in Greater Manchester Sept 2016 (55% RRMS). Lusher et al. ECTRIMS 2016

20. % of new starters in GM by end of year

21. Number of new starters in GM by end of year
0
5
10
15
20
25
30
35
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
Lemtrada
Tysabri
Mitoxantrone

22. 0
50
100
150
200
250
2007 2008 2009 2010 2011 2012 2013 2014 2015
Number on Tysabri in GM by end of year

23. Tysabri-induced PML
• Tysabri
• PML-IRIS
– Diagnosis
– Prognosis
– Treatment
– Risk Management

24. Tysabri
• Humanised monoclonal Ab
– Binds α4 integrin on lymphocytes
– Blocks migration across BBB
• 4-weekly infusion
• Clinical activity (+/- ‘rebound’) returns at 10-
12 weeks

25. Benefits
0
0.5
1
1.5
2
2.5
Baseline Year 2
Placebo
Tysabri
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
Baseline Year 1 Year 2
68% reduction
81% reduction
At least 1 relapse
in 12 months
(‘active MS’)
At least 2 relapses in 1 year
AND at least 1 new or enhancing lesion
(‘RES MS’)
Disability progression 42% reduction 64% reduction
Annualisedrelapserate
Polman et al. AFFIRM. New Eng J Med 2006; 354: 899-910, Hutchinson et al. Subgroup analysis of AFFIRM and SENTINEL. J Neurol 2009; 256 (3)
405-1.

26. Benefits
• 90% second-line therapy
• 18 PML cases
• No additional safety concerns
Butzkueven et al. JNNP 2014; 85: 1190-97. Open label ‘real-world’ 10 year Tysabri Observational Program (TOP).

27. PML
• Presence of JCV
• Viral factors
– mutations
• Host factors
– peripheral immune function
– genetics
• Drug effects
– reduced CNS immune surveillance

28. PML risk
37,249 PwMS: 156 PML cases
JCV Ab +ve
Tysabri
exposure
PML risk
No prior IS use Prior IS use
No index value <0.9 >0.9 <1.5 >1.5
Year 1 1/10,000 1/10,000 1/10,000 1/5,000 1/3,333
Year 2 1/1,667 1/20,000 1/3,333 1/1,111 1/2,500
Year 3 1/625 1/5,000 1/1,250 1/385 1/278
Year 4 1/244 1/2,500 1/500 1/147 1/120
Year 5 1/208 1/2,000 1/417 1/127 1/119
Year 6 1/167 1/1,667 1/333 1/100 1/182
Koendgen et al. ECTRIMS 2016.
JCV Ab -ve
PML risk
1 in 10,000

29. PML diagnosis
• Clinical features evolve over weeks
– Cognitive (50%)
– Motor (40%)
– Language (30%)
– Visual (25%)
– Ataxia (20%)
– Seizures (15%)
• MRI
• LP
– 50% <500 copies/ml
• Cerebral biopsy
Biogen. Based on first 35 cases.
Slowly evolving stroke-like
syndrome vs
anything unusual/not MS

30. FLAIR DWI
PML diagnosis
‘Look high
and wide’

31. PML at diagnosis

32. PML at -4 months

33. PML at -8 months

34. PML prognosis
024
EDSS
−30 −24 −18 −12
020406080100
Mont
KarnofskyScore
−30 −24 −18 −12
Symptomatic
Asymptomatic
Carrillo-Infante et al. ECTRIMS 2016.
Outcome Asymptomatic
(n=62)
Symptomatic
(n=504)
All
Death 3 (5%) 130 (26%) 133 (24%)

35. PML treatment
• Immune reconstitution
– PLEX
• Antiviral drugs
– Mirtazepine
– Mefloquine
• IRIS-therapy
– Steroids
– Maraviroc
• MS DMDs (?)

36. Risk management
• Consent
– Informed
• Documented consultations
• Individualized risk
• Standard paragraphs
• PILs & MS Decisions website
– Written (?)
– Repeat at 2 years and 5 years

37. Risk management
• Clinical vigilance
– Infusions
– MS Nurse
• Help-line
• Relapse clinic
– DMD clinic review
– GP
• Action for GP

38. Risk management
• MRI vigilance
– Annual or 4-monthly MRI
• Compare
• Look high and wide
• DWI
– Report prior to infusion
• PML risk
– Neuroradiologist
‘with an interest’

39. Risk management
• Use less Tysabri
• Continue Tysabri
– PML risk reduction strategy
• Switch to another DMD
– Risk of MS relapse (+/- ‘rebound’)
– Risk of ‘carryover’ PML

40. Risk management
• Serum concentration declines to
– 3μg/ml for 4 weeks (>80% saturation)
– 1μg/ml 4-8 weeks (50-80% saturation)
– <1μg/ml after 8 weeks (<50% - desaturation)
• Clinical activity returns at 10-12 weeks
– Does submaximal receptor saturation exclude
autoreactive T-cells (‘MS protective’) and allow
normal lymphocyte scavenging (‘PML protective’)?

41. Risk management
• Extend dose interval
– Non-randomized switch
%patients
Ryerson et al. JNNP 2016; 87: 885-89.
n=1080 n=246 n=269 n=379
4 PML cases 0 PML cases
0
5
10
15
20
25
4 weeks 6 weeks 8 weeks 4-8 weeks
Relapse
New T2 lesions
Gd-enhancing lesions
*

42. Risk management
• Switch to another DMD
– Non-randomized
– Clinically stable
– Stop/switch due to PML risk
Continuing Tysabri (n=196)
Stop/switch Tysabri (n=122)
[No DMD = 12, Gilenya = 55,
Copaxone = 36, IFNβ = 12,
Mitox = 2, AZA = 2, CYC = 2,
Rituximab = 1]
Prosperini et al. MSJ 2015; 21 (13) 1713-22.

43. Risk management
• Switch to Gilenya?
– 64% reduction in risk of relapse vs BRACE DMDs1
– NICE
– PML
– Washout2
1Iaffaldano et al. Brain 2015. 2Kappos et al. Neurology 2015; 85: 29-39.

44. Risk management
• Switch to Lemtrada?
– At least as efficacious as Tysabri
– NICE
– PML
– Washout
– Immune reconstitution

45. Risk management
Giovannoni et al. Pract Neurol 2015. doi:10.1136/practneurol-2015-001355.

46. My thoughts…
• Use less Tysabri
– Use more Lemtrada first-line
– Increase Tysabri dose interval1
• If doing well @ 2 years
– Switch to Gilenya2
• Washout 4-8 weeks3, 4-monthly MRI for 1 year
• If clinical or MRI activity, switch to Lemtrada
• If bad MS or not doing well @ 2 years
– Switch to Lemtrada4
• Washout 4-8 weeks3, 4-monthly MRI for 1 year
• LP immediately before starting Lemtrada
1Ryerson et al. JNNP 2016; 87: 885-89. 2Kappos et al. Neurology 2015; 85: 29-39. 3Weinstock-Guttman et al. JNNP 2016; 87: 937-43. 4Giovannoni et al. Pract
Neurol 2015. doi:10.1136/practneurol-2015-001355.

47. The End

48. Case study
Carmel Wilkinson
MS Specialist Nurse
Royal Victoria Infirmary
Newcastle upon Tyne

49. ► 2001 – 21 yrs of age, presented with one
year history of intermittent right arm and
leg numbness
► 2006 – 2 relapses, IV steriods
 Rebif 22mcg, EDSS 1.0
 Father diagnosed with MS
► 2008 – new spinal lesion

50. ► 2009 – pregnant; stopped interferon
 spinal cord relapse during pregnancy;
sensory disturbance of hands with ‘clawing’
and pseudoathetosis
 Rebif post partum - further relapse soon
after – right leg weakness
 Significant transverse myelitis (20m walking)

51. ► 2010 – MRI showed GAD-enhancing
brain lesion with increased T2 lesion load
► 2010 - commenced Natalizumab (PML
risk quoted at that time as 1:1000)
► Ongoing hand sensory symptoms (R > L)

52. ► 5 infusions; improved energy and reduced
fatigue. Hand symptoms improving
► 11 infusions; similar story - even better
► Surveillance scan 23rd March 2011
 Subtle odd lesion high up in the left post
central gyrus – "unusual in presentation, not
thought to be PML" -advised to repeat scan
within next 2 months.
 Attended for 13th infusion informed of the scan
results – no new symptoms

53. March 23rd 2011
(12 infusions)

54. ► 13th infusion (no new symptoms – still
parasthesia of right hand)
► Before 14th Infusion had increased sensory
disturbance of her hand but claimed she
was stressed and this occurred commonly;
day unit staff proceeded with infusion
► Over next 3 weeks developed progressive
weakness of hand, especially pincer grip
► MRI on 26th May – progression of lesion
?PML

55. 26th May 2011 (14 infusions)

56. ► LP performed that day (CSF 1)
 CSF JCV DNA not detected
► HPA Colindale lab < 50 DNA copies, and BIOGEN
recommended lab in USA (FOCUS labs) <50 DNA
copies
 CSF sent to NINDS research lab (< 10 DNA
copy count) – JCV DNA negative although
cannot be confirmed as sample volume < 150
microlitres)
 CSF JC Virus antibody also not detected
 Other CSF viral PCR studies (VZV, HSV,
Adenovirus, parechovirus, CMV, EBV,
enterovirus, and HHV-6) – all negative

57. ► Plasmaphoresis commenced next day (5
cycles over 5 days)
► Further investigations including HIV and CT
chest/abdo/pelvis all normal
 Minor improvement of wrist function
► Further MRI 14/06/2011 (non contrast) –
small increase in size of lesion

58. 14th June 2011
(1 month and 9 days from last infusion)

59. ► June 21st 2011 Re-admitted (nearly 4
weeks after Plasmaphoresis) with a rapid
decline;
 Expressive dysphasia, right hemiparesis
(UL>LL)
► MRI 21st June – progressive increase in size
with no contrast enhancement.

60. 21st June 2011
(7 days after
last scan)

61. ► Repeat CSF (CSF 2 performed 23/06/2011)
 WCC 0, protein 0.55
 JC Virus DNA again negative (HPA Colindale and Focus
Labs)
► Thought probable IRIS (owing to rate of decline, despite
lack of enhancement)
 1g of methypred for 3 days
 Oral pred 60 mg
► Developed focal motor seizures of right side of face and
arm
 Commenced CBZ 100mg bd and clobazam 10mg bd

62. ► 5th July 2011 – progression of right sided
paresis despite steriods
 Commenced Mefloquine (following loading
dose) 250mg/week
 Mirtazepine 30 gm
► 13th July 2011 - Repeat MRI shows
worsening lesion with now definite IRIS

63. 13th July 2011 (around 6 weeks after Plasmaphoresis – IRIS)

64. PML – profound T1 hypointensity

65. PML/IRIS

66. ► 26th July 2011 – plateaued (leg slightly
better?)
 Steriods reduced down to 30 mg.
► 9th August 2011 – Improvement. Speech and
right leg much better. Shoulder abduction and
elbow flexion now possible, subtle finger
flexion movements
► 9th August 2011 - 3rd LP (CSF 3)
 WCC 3, protein 0.41
 JC virus DNA not detected in NINDS or Colindale.

67. ► 23rd August 2011 – Continued
improvement. Right UL better strength but
increased spasticity. Pred reduced from 10
to 8 mg.
► 13th September – Deterioration. Increased
spasticity. Decreased finger movements.
Myoclonic jerks.

68. Sept 27th 2011

69. ► Brain biopsy discussed – declined
► 13th Sept 2011 - 60 mg of pred for 2 weeks then
decreasing dose….
► 4th Oct 2011 – Improved again. Extending fingers
voluntarily again.
► 1st Nov 2011 – continued improvement,
increasing strength of R UL but fine motor control
of hand poor.
► 19th Dec 2011 – MRI improved and clinically
improved (better control and less spastic). Pred
reduced from 15mg to 10mg

70. ► 17th Jan 2012 – plateaued
► 31st Jan 2012 – secondary generalized
tonic-clonic seizure
 Resulted in increased spasticity and mild
speech disturbance for some weeks
 CBZ slightly increased
 Pred increased to 20 mg
► Feb to April 2012 – increasing spasticity
with occasional focal seizures of r face and
arm

71. July 2012

72. ► Married in Dec 2012….
► Jan 2013 – May 2013: worsening spasticity
right arm and leg
 intensive physio
 antispasmodics and botox
 Walking distance decreasing (200m then drags
leg)
 Attempting to go back to work
 No MS related activity on MRI (or clinically)

73. Jan 2013

74. Changes to practice
►Protected hours for governance
►Change in checklist to include:
 Date of last scan
 JC ab status (if negative date of last check)
 Last consultant review
 Increase in training of NDU staff
 Increased presence on NDU