PML – Case Study

Sharon LetissierMS Nurse

Queen Elizabeth Hospital Birmingham

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

• 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

MRI Scan pre treatment, T2, postcontrast

Jan 2011

T2

postcontrast

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

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

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

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

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

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

MRI Scan Dec - 2014

Mid Dec – inpatient stay

• Transferred to ITU due to myoclonic status epilepticus

• Deep sedation and ventilation 2 weeks

• Regular EEGs

Jan- 2015

• Back on Neurology ward

• NG Fed

• Not verbalising, obeying simple commands

• Right side no movement

• Rehab commenced

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

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

MRI scan Oct 2015

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

Tysabri-induced PML

Paul TalbotGreater Manchester Neuroscience Centre

Salford Royal NHS Foundation Trust

Number on DMDs in GM by end of year

4,067 PwMS in Greater Manchester Sept 2016 (55% RRMS). Lusher et al. ECTRIMS 2016

% of new starters in GM by end of year

Number of new starters in GM by end of year

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 20150

5

10

15

20

25

30

35

LemtradaTysabriMitoxantrone

2007 2008 2009 2010 2011 2012 2013 2014 20150

50

100

150

200

250

Number on Tysabri in GM by end of year

Tysabri-induced PML

• Tysabri• PML-IRIS

– Diagnosis– Prognosis– Treatment– Risk Management

Tysabri

• Humanised monoclonal Ab– Binds α4 integrin on lymphocytes– Blocks migration across BBB

• 4-weekly infusion• Clinical activity (+/- ‘rebound’) returns at 10-

12 weeks

Benefits

Baseline Year 20

0.5

1

1.5

2

2.5

PlaceboTysabri

Baseline Year 1 Year 20

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

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

Annu

alise

d re

laps

e ra

te

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.

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).

PML

• Presence of JCV• Viral factors

– mutations• Host factors

– peripheral immune function– genetics

• Drug effects– reduced CNS immune surveillance

PML risk37,249 PwMS: 156 PML cases

JCV Ab +veTysabri 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 -vePML risk

1 in 10,000

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

FLAIR DWI

PML diagnosis

‘Look high and wide’

PML at diagnosis

PML at -4 months

PML at -8 months

PML prognosis

Carrillo-Infante et al. ECTRIMS 2016.

Outcome Asymptomatic (n=62)

Symptomatic(n=504)

All

Death 3 (5%) 130 (26%) 133 (24%)

PML treatment

• Immune reconstitution– PLEX

• Antiviral drugs– Mirtazepine– Mefloquine

• IRIS-therapy– Steroids– Maraviroc

• MS DMDs (?)

Risk management

• Consent– Informed

• Documented consultations• Individualized risk• Standard paragraphs• PILs & MS Decisions website

– Written (?)– Repeat at 2 years and 5 years

Risk management

• Clinical vigilance– Infusions– MS Nurse

• Help-line• Relapse clinic

– DMD clinic review– GP

• Action for GP

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’

Risk management

• Use less Tysabri• Continue Tysabri

– PML risk reduction strategy• Switch to another DMD

– Risk of MS relapse (+/- ‘rebound’)– Risk of ‘carryover’ PML

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’)?

Risk management• Extend dose interval

– Non-randomized switch

% p

atien

ts

Ryerson et al. JNNP 2016; 87: 885-89.

n=1080 n=246 n=269 n=379 4 PML cases 0 PML cases

4 weeks 6 weeks 8 weeks 4-8 weeks0

5

10

15

20

25

RelapseNew T2 lesionsGd-enhancing lesions

*

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.

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.

Risk management

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

Risk management

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

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.

The End

Case studyCarmel Wilkinson

MS Specialist NurseRoyal Victoria InfirmaryNewcastle upon Tyne

► 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

► 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)

► 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)

► 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

March 23rd 2011 (12 infusions)

► 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

26th May 2011 (14 infusions)

► 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

► 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

14th June 2011

(1 month and 9 days from last infusion)

► 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.

21st June 2011

(7 days after last scan)

► 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

► 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

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

PML – profound T1 hypointensity

PML/IRIS

► 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.

► 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.

Sept 27th 2011

► 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

► 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

July 2012

► 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)

Jan 2013

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