Upload
ms-trust
View
61
Download
3
Embed Size (px)
Citation preview
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