MS case Conundrum Dr Bindu Yoga Mid Yorkshire Hospitals NHS Trust - - PowerPoint PPT Presentation

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MS case Conundrum Dr Bindu Yoga Mid Yorkshire Hospitals NHS Trust - - PowerPoint PPT Presentation

Jul 12, 2023 351 likes •640 views

MS case Conundrum Dr Bindu Yoga Mid Yorkshire Hospitals NHS Trust 50 F Symptoms onset ~2000 with vertigo, unsteady gait diagnosed as Labrynthitis. Other documented relapses 2008 left sided tingling and numbness 2009 severe

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MS case Conundrum

Dr Bindu Yoga Mid Yorkshire Hospitals NHS Trust

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  • 50 F
  • Symptoms onset ~2000 with vertigo, unsteady gait diagnosed as

Labrynthitis.

  • Other documented relapses

– 2008 left sided tingling and numbness – 2009 severe disabling unsteady gait and vertigo with improvement – May 2010 again significant unsteady gait and vertigo, left with residual ataxia – MRI brain privately in July 2010 prior to NHS referral, showed multiple high signal changes consistent with demyelination.

  • Relapsing remitting MS diagnosis made in 2010
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  • Repeat MRI brain with contrast and spine Sep 2010
  • 3 enhancing lesions and one thoracic cord lesion
  • EDSS 2.5
  • Treated with Natalizumab/Tysabri since Nov 2010
  • JCV positive since 2011

– 0.73 in 2014 – 1.02 in 2015 – 1.24 in 2017 – 1.23 in 2018 – 1.12 in 2019

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SLIDE 4
  • 2011:
  • progressively worsening with walking, walking with a stick

and can walk up to 100meters.

  • EDSS 4.0 with spastic ataxic paraparesis
  • Same year reported possible relapse not definite – short

lived intermittent postural vertigo in the summer.

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SLIDE 5
  • 2012:
  • Further progression without relapse, left leg dragging,

walking with stick, can walk up to 20mts.

  • Self caring
  • EDSS 6.0
  • 2 years since Tysabri, JCV +ve so offered to step down to

Fingolimod but declined.

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SLIDE 6
  • 2013:
  • Spastic ataxic paraparesis worse in left LL with increased tone and
  • stiffness. Extensor spasms. No relapses.
  • Baclofen started.
  • EDSS 6.0
  • Later in the year ? Relapse, c/o rotational vertigo with no other BS

symptoms.

  • Further progression with walking, needed 2 crutches and mobility
  • scooter. EDSS 6.5
  • MRI spine – no new lesions and no cord compression
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SLIDE 7
  • 2014:
  • MRI brain and spine- no new lesions, several spinal cord

lesions with cord atrophy.

  • Disability progression, severe disability with spastic lower

limb weakness.

  • Diagnosis of SPMS made.
  • Explained Tysabri is of no help in SPMS but continued as

patient insisted and she had upper limb good function.

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SLIDE 8
  • 2015:
  • Further progression, cannot mobilise anymore
  • Wheel chair dependent, can transfer.
  • EDSS noted as 6.5.
  • Referred for baclofen pump
  • JCV 1.02, MRI brain –no new changes.
  • Pt enquired about HSCT – significant disability, SPMS

and not suitable.

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SLIDE 9
  • 2015:
  • Offered to step down to Gilenya or 8 weekly Tysabri
  • 2016:
  • MRI spine – no new changes.
  • Wheel chair dependent.
  • Baclofen pump inserted.
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SLIDE 10
  • 2017:
  • Practically paraplegic with no power in lower limbs.
  • Baclofen pump in situ since 2016
  • EDSS 7.5
  • Started 8/52 Tysabri.
  • MRI brain stable.
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  • She was having yearly MRIs as the JCV titres were below

1.5 and difficult to organise the MRIs with baclofen pump.

  • She had carers and needed assistance with transfers.
  • Indwelling catheter as not keen for Suprapubic catheter.
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SLIDE 12
  • 2018: Last infusion Oct 2018
  • MRI brain showed increased size of right periventricular

lesion.

  • Seen by Visiting Leeds consultant as Local consultant

had retired.

  • ?PML and Tysabri stopped.
  • Also explained that with EDSS 8.0, SPMS diagnosis

Tysabri is not funded by NHS England.

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SLIDE 13

October 2018

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SLIDE 14
  • Jan 2019:
  • Repeat MRI brain with Contrast requested by the visiting

consultant finally occurred in collaboration with spinal unit.

  • No change and the lesion in question is unlikely PML.

Suspected new cortical lesion.

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Oct 18 and Jan 2019 scan

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  • I saw the patient and explained that restarting Tysabri is

not an option

– no evidence in SPMS (ASCEND study) and – PML risk remains with JCV positivity. – Met the stopping criteria by NHS England.

  • Discussed with a Leeds consultant as it has to be

discussed with MS MDT to re-prescribe Tysabri.

  • Advised not to restart.
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  • April 2019:
  • Repeated MRI brain with contrast while she was having

her baclofen pump refilling.

  • Main purpose was to make sure no signs of PML
  • Scan showed 12 multiple small enhancing lesions.
  • Clinically stable.
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  • What to do next?
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  • Discussed with another Leeds Consultant for MDT opinion.
  • Advised not to restart.
  • It is usual to see rebound activity post NTZ cessation.
  • Reassuring fact is no suspicion of PML.
  • Patient received 3 day IV MEP 1gm to prevent any worsening
  • f the radiological activity – no evidence.
  • Referred for 4th Opinion - awaited
  • ? Can siponimod be an option but not NICE approved yet.
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Natalizumab discontinuation

  • Several potential scenarios that warrant discontinuation:

– Mostly related to risk benefit ratio for continued use of the drug (PML risk) – Some start with JCV +ve with the knowledge that at some point risk of PML will

  • utweigh the benefit of staying on NTZ

Factors considered during discontinuation include: – Frequency & severity of relapses – Disability level – Previous therapies have failed or not tolerated – Eligibility status for high efficacy therapies for MS – As with MS therapy, discontinuation is considered if efficacy is suboptimal or switching therapy or adverse effects/allergic reactions – Pregnancy planning

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Potential issues with discontinuation of NTZ

  • There has been concern about the potential for worsening
  • f clinical and radiological activity after cessation of NTZ,

including

– increased relapse rate, – relapse severity,and – number of new T2 and gadolinium-enhancing lesions, possibly attributable to an IRIS-like phenomenon.

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Rebound activity post NTZ cessation

  • several hypotheses have been proposed to explain the rebound

phenomena including that

– the increase in circulating proinflammatory CD4+ and CD8+ T cells with NTZ therapy leads to attack on the CNS when the drug is discontinued and there is removal of α4 integrin blockade. – There is also speculation that NTZ may have an “arresting effect” on the natural maturation of the immune system that typically causes MS patients to have a less inflammatory course in older age.

  • debate as to whether some of the clinical worsening after NTZ withdrawal

is caused by CNS-IRIS like phenomenon or worsening of their MS.

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Rebound activity post NTZ cessation

  • The rebound rate varies among studies between 10% and

30% of patients

  • The reactivation of the disease activity occurs frequently

within the 3-6 months after NTZ cessation

  • Biomarkers of NTZ treatment (lymphocyte counts,

alpha4-integrin saturation, sVCAM, and CD49d expression) 4 months after discontinuation returns to the same levels as in untreated patients (Cree et al.2013)

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Rebound activity post NTZ cessation

  • A post hoc analysis from the AFFIRM, SENTINEL, and GLANCE studies showed a

return of disease activity independently of receiving alternative treatment or not (O'Connor et al., 2011).

  • RESTORE study, a randomized 24-week NTZ treatment interruption study,
  • bserved that up to 29% of patients after NTZ discontinuation showed an MRI

disease recurrence and 15% had a clinical relapse (Fox et al., 2014).

  • The TY-STOP, an observational study, revealed that in the first year after NTZ

cessation, up to 35% of patients had a relapse (Clerico et al., 2014).

  • None of these studies described a rebound phenomenon.
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Treatment for rebound activity

  • There are no randomized controlled trials or established guidelines about the correct

treatment in a rebound.

  • Frequent used Rx pulsed IV MEP
  • PLEX therapy is controversial with some worsening as rapid clearance of NTZ from

peripheral blood results in rapid flux of lymphocytes into the brain.

  • Close monitoring and early initiation of alternative therapy in RRMS
  • It is grey area for SPMS - ?Siponimod in the future.
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SLIDE 27

References

  • I. Gonzlex-suarez et al; Catastrophic outcome of patients with a rebound after Natalizumab treatment

discontinuation; Brain Behav. 2017 Apr; 7 (4): e00671.

  • Gueguen A, Roux P, Deschamps R, et al. Abnormal inflammatory activity returns after natalizumab cessation in

multiple sclerosis. J Neurol Neurosurg Psychiatry. 2014;85(9):1038–1040.

  • Vellinga MM, Castelijns JA, Barkhof F, Uitdehaag BM, Polman CH. Postwithdrawal rebound increase in T2 lesional

activity in natalizumab-treated MS patients. Neurology. 2008;70(13 Pt 2):1150–1151.

  • Rachel Brandstadter, Ilana Katz Sand.The use of natalizumab for multiple sclerosis, Neuropsychiatr Dis Treat.2017;

13: 1691–1702.

  • N'gbo N'gbo Ikazabo R et al. Immune-reconstitution Inflammatory Syndrome in Multiple Sclerosis Patients Treated

With Natalizumab: A Series of 4 Cases. Clin Ther. 2016 Mar;38(3):670-5. doi: 10.1016/j.clinthera.2016.01.010. Epub 2016 Feb 5.