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

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 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

• 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

• 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.

• 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.

• 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

• 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.

• 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.

• 2015: • Offered to step down to Gilenya or 8 weekly Tysabri • 2016: • MRI spine – no new changes. • Wheel chair dependent. • Baclofen pump inserted.

• 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.

• 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.

• 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.

October 2018

• 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.

Oct 18 and Jan 2019 scan

• 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.

• 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.

• What to do next?

• 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 of the radiological activity – no evidence. • Referred for 4 th Opinion - awaited • ? Can siponimod be an option but not NICE approved yet.

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 outweigh 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

Potential issues with discontinuation of NTZ • There has been concern about the potential for worsening of 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.

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.

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)

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, • observed 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.

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.

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.