Multiple Sclerosis — Viva Defence

Long case viva — highly active relapsing-remitting MS

Candidate's opening statement (SASPOP)

"Doctor, my patient is a 29-year-old woman with a 3-year history of relapsing-remitting multiple sclerosis. Her problems are: highly active disease with four relapses in 18 months despite interferon beta-1a, indicating treatment failure; incomplete recovery from the last two relapses with residual left leg weakness and a T10 sensory level; a high MRI lesion burden (15 brain lesions with 3 gadolinium-enhancing, plus two cervical cord lesions) confirming ongoing inflammatory activity; JC virus antibody positivity, which constrains the DMT choice; and a desire to start a family within 2 years, requiring reproductive planning. My priorities are to escalate to a high-efficacy DMT to achieve no evidence of disease activity and prevent further disability, while managing her residual symptoms and planning a safe transition through pregnancy." [1]

Problem list

1. Relapsing-remitting MS, highly active — failing interferon beta-1a (four relapses in 18 months, 3 enhancing lesions).
2. Residual neurological deficit — left leg weakness, T10 sensory level (incomplete recovery from recent relapses).
3. JC virus antibody positive — constrains natalizumab use (PML risk).
4. Pregnancy planned within 2 years — requires DMT washout and reproductive planning.
5. Symptom burden — spasticity, possible bladder dysfunction, fatigue, risk of depression.
6. Vitamin D status to be assessed and supplemented. [1]

Integrated management plan

Confirm the diagnosis and exclude mimics. Before escalating, I would confirm that this is truly MS and not neuromyelitis optica spectrum disorder or MOG-antibody disease. I would check serum AQP4-IgG and MOG-IgG. If AQP4-IgG is positive, the diagnosis and treatment plan change entirely — MS DMTs may be harmful, and the patient would need rituximab, mycophenolate, or azathioprine [1]. Assuming the diagnosis is confirmed as MS, I would proceed with DMT escalation.

DMT escalation. This patient has highly active RRMS failing first-line therapy. The options are natalizumab, ocrelizumab, and alemtuzumab. Given her JC virus positivity, I recommend ocrelizumab (600 mg IV every 6 months) — it has comparable efficacy to natalizumab (OPERA trials showed 46 to 47 per cent reduction in annualised relapse rate versus interferon) without the PML risk that is critical in a JCV-positive patient [5]. Pre-treatment screening includes hepatitis B surface antigen and core antibody, hepatitis C, quantiferon, and immunoglobulin levels. If she declines infusion therapy, cladribine or dimethyl fumarate are oral alternatives.

Acute relapse management. For future relapses with functional impairment: methylprednisolone 1 g IV daily for 3 to 5 days first-line; plasma exchange (5 to 7 exchanges) for steroid-refractory severe relapses. I would not repeat steroid courses for a relapse that has already failed. [1]

Symptom management. Spasticity: physiotherapy, oral baclofen, botulinum toxin for focal spasticity. Bladder: check post-void residual, anticholinergics or intermittent catheterisation. Fatigue: amantadine, energy conservation. Depression: PHQ-9 screening, SSRIs. Vitamin D supplementation to target above 75 nmol per litre. [1]

Monitoring. Clinical review every 3 to 6 months. MRI brain and spine with gadolinium at 6 to 12 months after starting ocrelizumab, then annually. Target: NEDA (no relapses, no new MRI lesions, no disability progression). [1]

Reproductive planning. Ocrelizumab depletes B cells for 6 to 12 months after the last dose — discontinue 6 to 12 months before conception. If ongoing DMT is needed during pregnancy, glatiramer acetate is the safe option (category B). The PRIMS study showed relapse rate drops in pregnancy (lowest in third trimester) and rises postpartum (first 3 months), so DMT should be restarted promptly after delivery [7].

Examiner probing questions

Examiner: "Why ocrelizumab over natalizumab in this patient?" Because she is JC virus antibody positive. Natalizumab carries a PML risk that is stratified by JCV positivity, prior immunosuppression, and treatment duration. For a JCV-positive patient without prior immunosuppression, the risk after 24 months is approximately 1 to 2 per 1000, rising with the JCV index and duration [6]. Ocrelizumab has comparable efficacy (OPERA trials: 46 to 47 per cent reduction in annualised relapse rate versus interferon, versus natalizumab's 68 per cent reduction versus placebo) [5] and no PML risk. The trade-off is a possible signal for malignancy and infection risk, but for a young JCV-positive patient, the PML-free profile of ocrelizumab is the deciding factor.

Examiner: "What is the McDonald 2017 criterion that this patient satisfies for dissemination in time?" The simultaneous presence of gadolinium-enhancing (acute) and non-enhancing (older) lesions on her current MRI. This demonstrates that lesions have occurred at different points in time on a single scan. The 2017 revision also allows CSF oligoclonal bands to substitute for DIT when DIS is met, and counts symptomatic and cortical lesions [1].

Examiner: "How would you manage a severe relapse that does not respond to steroids?" Plasma exchange — 5 to 7 exchanges over approximately 2 weeks. The mechanism is removal of pathogenic antibodies and inflammatory mediators. It benefits approximately 40 to 50 per cent of patients with steroid-refractory demyelinating attacks. Repeating steroid courses is not effective and should not be done. [1]

Branching scenario — neuromyelitis optica spectrum disorder

Examiner: "Now consider a 35-year-old woman who presents with bilateral simultaneous severe optic neuritis (visual acuity counting fingers in both eyes) and, two months later, develops a T2 spinal cord lesion spanning 5 vertebral segments with severe paraparesis and urinary retention. What is the likely diagnosis, the critical investigation, and how does management differ from MS?" [1]

This is neuromyelitis optica spectrum disorder (NMOSD) until proven otherwise. The cardinal features distinguishing it from MS are: bilateral simultaneous optic neuritis with severe visual loss and poor recovery, longitudinally extensive transverse myelitis (more than 3 vertebral segments), and the possibility of area postrema syndrome (intractable hiccups and vomiting). The critical investigation is serum AQP4-IgG, which is positive in approximately 70 to 90 per cent of NMOSD patients. MOG-IgG should also be checked (MOG-antibody disease can present similarly but has a better prognosis and is typically steroid-responsive). The management differs fundamentally from MS: first, MS DMTs may be harmful — interferon-beta is associated with increased NMOSD relapse, and natalizumab has been associated with disease worsening. Second, the treatment is immunosuppression — rituximab (anti-CD20) is first-line, with mycophenolate, azathioprine, or eculizumab (anti-C5 for AQP4-positive NMOSD) as alternatives. Acute attacks are treated with methylprednisolone and plasma exchange, often more aggressively than in MS. The distinction between MS and NMOSD is one of the most important in neurology, because the wrong DMT can worsen the disease [1].

Branching scenario — primary progressive MS

Examiner: "What if the patient were a 45-year-old man with progressive leg weakness, stiffness, and urinary urgency over 2 years, no relapses, and MRI showing periventricular and spinal cord lesions with no gadolinium enhancement. CSF shows oligoclonal bands. What is the diagnosis, and what DMT is indicated?" [1]

This is primary progressive MS (PPMS) — insidious progressive neurological decline from onset without relapses or remissions, with characteristic MRI and CSF findings. PPMS accounts for approximately 15 per cent of MS, has an equal sex ratio (unlike the female predominance in RRMS), older onset (around 40 years), and worse prognosis. The 2013 Lublin phenotype revisions classify this as PPMS, inactive (no gadolinium enhancement), with progression [2]. The only DMT with demonstrated efficacy in PPMS is ocrelizumab — the ORATORIO trial (Montalban 2017) showed a 24 per cent reduction in confirmed disability progression at 12 weeks compared to placebo [4]. No other DMT (interferon, glatiramer, natalizumab, fingolimod) has shown efficacy in PPMS. Siponimod has shown modest benefit in SPMS (EXPAND trial) but not PPMS. The patient should also receive aggressive symptom management (baclofen for spasticity, bladder management, rehabilitation) and multidisciplinary care.

Branching scenario — natalizumab-associated PML

Examiner: "A patient on natalizumab for 3 years, JCV-positive, presents with progressive right hemiparesis and cognitive change over 2 weeks. What is your immediate differential, investigation, and management?" [1]

The immediate concern is progressive multifocal leukoencephalopathy (PML) — a life-threatening brain infection caused by JC virus reactivation. The patient has all three PML risk factors: JCV positivity, treatment duration over 24 months, and (depending on history) possible prior immunosuppression. However, I must also consider an MS relapse (though the subacute progressive course over 2 weeks is more typical of PML than a relapse) and other infections. [1]

Investigation: urgent MRI brain with gadolinium and diffusion-weighted imaging (DWI). PML lesions are typically multifocal, asymmetric, T2-hyperintense, involve the subcortical white matter (often frontal or parietal), show restricted diffusion on DWI (acute phase), and have minimal or no gadolinium enhancement (unlike MS relapses, which enhance). Lumbar puncture for CSF JCV PCR — a positive result confirms PML. Blood JCV index may be elevated. [1]

Management: immediately stop natalizumab. The mainstay of treatment is immune reconstitution — but this carries the risk of immune reconstitution inflammatory syndrome (IRIS), a paradoxical worsening as the immune system recovers and attacks the JSV-infected cells. Plasma exchange may be used to accelerate natalizumab clearance. Mirtazapine has been used (blocks JCV entry) but evidence is limited. Steroids may be needed for IRIS once it develops. The prognosis is poor — mortality is 20 to 30 per cent, and survivors often have significant residual disability [6].

Examiner: "How do you distinguish PML from an MS relapse on MRI?" PML lesions are typically large, confluent, multifocal, asymmetric, subcortical white matter lesions with restricted diffusion on DWI and minimal gadolinium enhancement. MS relapse lesions are smaller, discrete, often periventricular, and typically show gadolinium enhancement (active inflammation with blood-brain barrier breakdown). The clinical course also differs: PML is subacute and progressive over weeks, while a relapse evolves over days. When in doubt, CSF JCV PCR is definitive. [1]

Short-case discussion — neurological examination

Examiner: "Examine this patient's cranial nerves. She has MS with a brainstem lesion." [1]

My routine: general inspection for ptosis, facial asymmetry, nystagmus; visual acuity (Snellen chart), visual fields (confrontation), colour vision (Ishihara plates or red desaturation); fundoscopy (disc pallor from previous optic neuritis, papilloedema); pupils (size, symmetry, direct and consensual reflexes, swinging flashlight test for RAPD); eye movements (pursuit and saccades in all directions — looking for internuclear ophthalmoplegia: impaired adduction on the side of the MLF lesion with contralateral abducting nystagmus; also check for gaze-evoked nystagmus, skew deviation); trigeminal nerve (sensory in V1, V2, V3; corneal reflex; motor — masseter); facial nerve (upper and lower facial strength, taste not routinely); hearing (whispered voice, Rinne and Weber); gag reflex and palate elevation; tongue protrusion (looking for fasciculations, deviation); shoulder shrug and tongue protrusion against resistance (accessory and hypoglossal). [1]

Presentation: "Doctor, on cranial nerve examination, there is a left internuclear ophthalmoplegia — impaired adduction of the left eye on rightward gaze, with right abducting nystagmus. There is also gaze-evoked nystagmus on leftward gaze. Pupils are equal and reactive with no RAPD. Fundoscopy is normal. The remaining cranial nerves are intact. These findings localise to a lesion in the left medial longitudinal fasciculus in the brainstem, consistent with demyelination. I would review the MRI, assess the full neurological examination including motor and cerebellar systems, and consider the DMT history." [1]

Examiner: "What is the significance of bilateral INO?" Bilateral internuclear ophthalmoplegia in a young patient is highly suggestive of multiple sclerosis. The MLF is a heavily myelinated tract in the brainstem that is particularly vulnerable to demyelination. Bilateral involvement strongly suggests a demyelinating process rather than a vascular or structural lesion. [1]

Examiner: "How would you assess for the Lhermitte sign?" I would ask the patient to flex their neck forward and ask if they feel an electric shock or tingling sensation radiating down the spine or into the limbs. A positive Lhermitte sign indicates cervical cord demyelination — it is not specific to MS (it can occur with cervical spondylosis, B12 deficiency, radiation myelopathy) but is highly characteristic. I would also distinguish it from the Uhthoff phenomenon — transient worsening of existing symptoms with heat or exercise, which is conduction block in previously demyelinated axons, not a new lesion. [1]