Multiple Sclerosis — DCE Clinical Case

Long case

Patient scenario

Ms LR is a 29-year-old woman referred to the MS clinic for management of highly active relapsing-remitting multiple sclerosis. She was diagnosed 3 years ago after presenting with left optic neuritis (painful visual loss with a relative afferent pupillary defect, reduced colour vision, and delayed P100 on VEP). Brain MRI at diagnosis showed 8 periventricular and juxtacortical T2-hyperintense lesions with 2 gadolinium-enhancing lesions. CSF showed oligoclonal bands not present in matched serum. She was started on interferon beta-1a 44 micrograms subcutaneously three times weekly. [1]

Over the last 18 months, she has had four relapses despite interferon therapy: a right leg sensory relapse (numbness from the waist down, T10 sensory level), a brainstem relapse (vertigo and internuclear ophthalmoplegia), a cerebellar relapse (ataxia and scanning dysarthria), and a motor relapse (left leg weakness). The last two relapses were treated with methylprednisolone 1 g IV for 5 days, with incomplete recovery — she now walks with a single point stick and has residual left leg weakness (4+/5 hip flexion and knee extension), a T10 sensory level, and mild scanning dysarthria. Her EDSS is 3.5. [1]

Recent MRI shows 15 T2-hyperintense lesions (periventricular, juxtacortical, and infratentorial) with 3 gadolinium-enhancing lesions, and two cervical cord lesions (C3 and C5). Her JC virus antibody index is 1.8 (positive). AQP4-IgG and MOG-IgG are negative. Full blood count, liver function, and renal function are normal. Vitamin D is 42 nmol per litre (low). She has no other past medical history. She takes interferon beta-1a, oral contraceptive pill, and occasional paracetamol. She smokes 10 cigarettes per day. She works as a graphic designer and is planning to start a family with her partner within the next 2 years. [1]

Examination findings

The patient is alert, oriented, and conversational with mild scanning dysarthria. Visual acuity is 6/6 bilaterally (recovered from optic neuritis). There is a left relative afferent pupillary defect on the swinging flashlight test (residual from the original optic neuritis). Fundoscopy shows bilateral temporal disc pallor. Eye movements reveal a left internuclear ophthalmoplegia (impaired adduction of the left eye on rightward gaze, with right abducting nystagmus) and gaze-evoked nystagmus on leftward gaze. Facial sensation and strength are normal. The remaining cranial nerves are intact. [1]

Motor examination of the upper limbs is normal (tone, power 5/5, reflexes 2+, coordination intact). In the lower limbs, tone is increased in the left leg (modified Ashworth 1+ in the quadriceps and hamstrings), power is 4+/5 in the left hip flexors and knee extensors (right leg 5/5), reflexes are 3+ bilaterally with sustained clonus at the left ankle, and both plantars are extensor. There is a sensory level at T10 for pinprick and temperature. Vibration sense is impaired at the left ankle. Coordination is impaired on left heel-shin testing (dysmetria). Gait is broad-based and ataxic with a circumduction component on the left; she uses a single point stick. Romberg is positive. [1]

Candidate's opening statement (SASPOP)

"Doctor, my patient is Ms LR, a 29-year-old graphic designer 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 with residual disability — left leg weakness, increased tone, extensor plantars, a T10 sensory level, and an ataxic gait (EDSS 3.5); a high MRI lesion burden with 3 active gadolinium-enhancing lesions, confirming ongoing inflammation; a left internuclear ophthalmoplegia and bilateral optic atrophy from brainstem and optic nerve involvement; JC virus antibody positivity, which constrains the DMT choice; vitamin D deficiency; cigarette smoking, which accelerates disease progression; and a desire to start a family within 2 years, requiring reproductive planning. My priorities are to confirm that this is truly MS by excluding NMOSD, escalate to a high-efficacy DMT to achieve no evidence of disease activity, manage her residual symptoms, address modifiable risk factors, and plan a safe reproductive pathway." [1]

Problem list

1. Relapsing-remitting MS, highly active — failing interferon beta-1a (four relapses in 18 months, 3 enhancing lesions on MRI).
2. Residual neurological deficit — left INO, left leg weakness and spasticity, T10 sensory level, ataxic gait (EDSS 3.5).
3. JC virus antibody positive (index 1.8) — constrains natalizumab use.
4. Pregnancy planned within 2 years — requires DMT washout and reproductive planning.
5. Vitamin D deficiency (42 nmol per litre).
6. Cigarette smoking (10 per day) — accelerates progression to SPMS.
7. Risk of bladder dysfunction, fatigue, and depression. [1]

Integrated management plan

Confirm the diagnosis. AQP4-IgG and MOG-IgG are already negative, confirming that this is MS and not NMOSD or MOGAD. The McDonald 2017 criteria are met (DIS: periventricular, juxtacortical, infratentorial, and spinal cord lesions; DIT: simultaneous enhancing and non-enhancing lesions) [1].

DMT escalation. The patient has highly active RRMS failing first-line therapy. Given her JC virus positivity, my recommendation is ocrelizumab 600 mg IV every 6 months. The OPERA trials demonstrated that ocrelizumab is superior to interferon beta-1a in RRMS (46 to 47 per cent reduction in annualised relapse rate, 40 per cent reduction in disability progression) [5], and it carries no PML risk (unlike natalizumab, which in a JCV-positive patient carries a risk of 1 to 2 per 1000 after 24 months) [6]. Pre-treatment screening: hepatitis B surface antigen and core antibody, hepatitis C, quantiferon, immunoglobulin levels, baseline CBC and liver function. Premedicate with methylprednisolone, antihistamine, and paracetamol before each infusion. If she prefers an oral agent, cladribine (3.5 mg per kg total over 2 years) is an alternative with high efficacy but requires varicella vaccination and carries a risk of severe lymphopenia.

Acute relapse management. For future relapses with functional impairment: methylprednisolone 1 g IV daily for 3 to 5 days. For steroid-refractory severe relapses: plasma exchange (5 to 7 exchanges over 2 weeks). I would not repeat steroid courses for a relapse that has already failed. If relapses continue on ocrelizumab, I would reassess adherence, reconsider the diagnosis, and consider alemtuzumab or HSCT for refractory disease. [1]

Symptom management. Spasticity: physiotherapy, oral baclofen (5 mg three times daily, titrate), botulinum toxin for focal spasticity in the left quadriceps. Bladder: check post-void residual — if detrusor overactivity, solifenacin or mirabegron; if retention, intermittent self-catheterisation. Fatigue: rule out sleep apnoea and anaemia, amantadine 100 mg twice daily. Neuropathic pain: gabapentin or pregabalin. Depression: PHQ-9 screening, SSRI if indicated. Vitamin D supplementation 2000 IU daily to target above 75 nmol per litre. Smoking cessation counselling — smoking accelerates progression to SPMS and reduces DMT efficacy. [1]

Monitoring. Clinical review every 3 to 6 months (EDSS, relapse assessment, symptom review). MRI brain and cervical spine with gadolinium at 6 months after starting ocrelizumab, then annually. Target: NEDA (no relapses, no new MRI lesions, no disability progression, no brain volume loss) [2].

Reproductive planning. Ocrelizumab depletes B cells for 6 to 12 months after the last dose. Plan to discontinue 6 to 12 months before conception. If she needs ongoing DMT during pregnancy, glatiramer acetate is the safe option (category B, no teratogenicity, safe in breastfeeding). The PRIMS study showed relapse rate drops in pregnancy (lowest in the third trimester) and rises postpartum (first 3 months), so DMT should be restarted promptly after delivery [7]. Breastfeeding may be protective. Folic acid 5 mg daily should be started preconception. A concrete plan for DMT restart postpartum should be agreed before delivery.

Discussion questions

Examiner: "How do the McDonald 2017 criteria apply to this patient's diagnosis?" The original diagnosis met both dissemination in space (DIS) and dissemination in time (DIT). DIS is demonstrated by lesions in multiple characteristic locations (periventricular, juxtacortical, infratentorial, and spinal cord — only two of four are required). DIT is demonstrated by the simultaneous presence of gadolinium-enhancing (acute) and non-enhancing (older) lesions on a single MRI scan. The 2017 revision added that CSF oligoclonal bands can substitute for DIT (which her CSF OCB also satisfy), and that symptomatic and cortical lesions now count. The 2017 criteria allow earlier and more confident diagnosis [1].

Examiner: "Why not natalizumab in this patient?" Natalizumab is one of the most effective DMTs (approximately 68 per cent reduction in relapse rate), but it carries a PML risk in JC virus-positive patients. This patient is JCV-positive (index 1.8) with no prior immunosuppression. Her PML risk after 24 months of natalizumab is approximately 1 to 2 per 1000 (or higher depending on the JCV index), and it rises with treatment duration [6]. Ocrelizumab offers comparable efficacy without PML risk, making it the preferred choice. If natalizumab were the only option, I would use it with intensive MRI surveillance (every 3 to 4 months) and consider switching to ocrelizumab after 12 to 24 months, but ocrelizumab is the better first choice.

Examiner: "What is the EBV connection, and does it affect management?" The 2022 study by Bjornevik in Science demonstrated that EBV seroconversion is associated with a 32-fold increased risk of MS, using a cohort of more than 10 million US military personnel — all but one of 801 MS cases were EBV-positive before diagnosis [3]. This suggests EBV is a necessary trigger for MS. While it does not directly affect this patient's immediate management (she is already EBV-positive, as are essentially all MS patients), it has profound implications for the future: an EBV vaccine could theoretically prevent MS, and anti-EBV therapies may become a treatment strategy. For now, the practical implication is counselling the patient about the autoimmune/infectious aetiology and the rationale for immunomodulatory therapy.

Examiner: "How would you manage her pregnancy plan?" I would plan a structured pathway. First, achieve disease stability on ocrelizumab (NEDA for at least 6 to 12 months) before attempting conception. Then discontinue ocrelizumab 6 to 12 months before conception (B-cell depletion persists for that long after the last dose). During the washout and pregnancy period, if she needs ongoing DMT (given her highly active history), switch to glatiramer acetate (category B, safe throughout pregnancy and breastfeeding). Counsel her on the PRIMS data: relapse rate drops in pregnancy (particularly the third trimester) and rises in the first 3 months postpartum, but 72 per cent of women do not have a postpartum relapse [7]. Plan to restart ocrelizumab promptly after delivery (or after weaning if breastfeeding). Ensure folic acid 5 mg preconception and vitamin D supplementation throughout. Epidural analgesia is safe. The key message is that MS does not affect fertility and pregnancy does not worsen long-term disability, but DMT planning is critical to avoid both fetal exposure and postpartum relapse.

Short case — focused neurological examination

Instruction

"Examine this patient's cranial nerves and gait. She has multiple sclerosis." [1]

Systematic examination routine

1. End of bed inspection. Assess for ptosis, facial asymmetry, nystagmus, use of walking aids, general body habitus. Observe speech pattern for scanning dysarthria.
2. Visual system. Visual acuity (Snellen), visual fields (confrontation), colour vision (Ishihara or red desaturation — a key early sign of optic nerve involvement), fundoscopy (disc pallor from chronic optic neuritis, papilloedema).
3. Pupils. Size, symmetry, direct and consensual reflexes, and the swinging flashlight test for a relative afferent pupillary defect (paradoxical dilatation of the affected eye when light is swung to it from the normal eye — indicating optic nerve conduction delay).
4. Eye movements. Pursuit and saccades in all six cardinal directions. Look specifically for: internuclear ophthalmoplegia (impaired adduction of the eye on the side of the MLF lesion, with contralateral abducting nystagmus — bilateral INO in a young patient is highly suggestive of MS); gaze-evoked nystagmus; skew deviation; sixth nerve palsy.
5. Trigeminal nerve. Sensory testing in V1, V2, V3 distributions; corneal reflex; motor (masseter bulk and strength).
6. Facial nerve. Upper and lower facial strength (ask to raise eyebrows, close eyes tightly, show teeth, puff out cheeks).
7. Lower cranial nerves. Hearing (whispered voice, Rinne and Weber); palate elevation (symmetry); gag reflex; tongue protrusion (fasciculations, deviation); sternocleidomastoid and trapezius strength.
8. Gait. Observe normal gait, heel-toe (tandem) gait for cerebellar ataxia, and Romberg test (positive in sensory ataxia from dorsal column involvement). [1]

Key signs this patient demonstrates

• Mild scanning dysarthria (cerebellar involvement).
• Left relative afferent pupillary defect and bilateral temporal disc pallor (residual from previous optic neuritis).
• Left internuclear ophthalmoplegia (impaired adduction of the left eye on rightward gaze, with right abducting nystagmus) — a classic MS brainstem sign.
• Gaze-evoked nystagmus on leftward gaze (brainstem/cerebellar involvement).
• Broad-based ataxic gait with circumduction of the left leg.
• Positive Romberg (sensory ataxia from dorsal column involvement). [1]

Presentation template

"Doctor, I examined Ms LR's cranial nerves and gait. There is mild scanning dysarthria. On visual examination, there is a left relative afferent pupillary defect on the swinging flashlight test, and fundoscopy reveals bilateral temporal disc pallor, consistent with previous optic neuritis. Eye movements reveal a left internuclear ophthalmoplegia — impaired adduction of the left eye on rightward gaze with right abducting nystagmus — and gaze-evoked nystagmus on leftward gaze. The remaining cranial nerves are intact. Gait is broad-based and ataxic with a circumduction component on the left, and Romberg is positive. These findings are consistent with multiple sclerosis with brainstem, cerebellar, optic nerve, and dorsal column involvement. I would review the MRI to assess current disease activity, confirm the DMT history, and assess the full motor and sensory examination." [1]

Discussion — DMT selection, monitoring, and the Uhthoff phenomenon

Examiner: "How would you choose between ocrelizumab and alemtuzumab?" Both are high-efficacy agents, but ocrelizumab is preferred first. Ocrelizumab (anti-CD20, 600 mg IV every 6 months) has demonstrated superior efficacy to interferon in the OPERA trials with a favourable safety profile — infusion reactions, infections, and a possible malignancy signal, but no PML risk and no secondary autoimmunity [5]. Alemtuzumab (anti-CD52, two annual infusion courses) has very high efficacy but carries a significant risk of secondary autoimmunity — thyroid disease in approximately 30 per cent, immune thrombocytopenia in approximately 2 per cent, and Goodpasture syndrome in less than 1 per cent — requiring monthly blood monitoring (CBC, creatinine, urinalysis) for 48 months. Alemtuzumab is reserved for patients who have failed or cannot tolerate other high-efficacy agents. For this patient, ocrelizumab's simpler monitoring, favourable safety profile, and lack of secondary autoimmunity make it the preferred choice.

Examiner: "What monitoring does ocrelizumab require?" Pre-treatment: hepatitis B surface antigen and core antibody (reactivation risk — if positive, prophylactic antiviral therapy is required), hepatitis C serology, quantiferon-gold (tuberculosis), immunoglobulin levels (if IgG is very low, consider the risk-benefit), baseline CBC and liver function. Before each infusion: CBC, liver function, infection screen, pregnancy test. During each infusion: observe for infusion reactions (premedicate with methylprednisolone 100 mg IV, antihistamine, and paracetamol; the first dose is split into two 300 mg infusions 2 weeks apart). After infusion: monitor for delayed infections. Annual MRI to assess for NEDA. Ongoing surveillance for malignancy (the breast cancer signal in the ORATORIO trial requires vigilance). [1]

Examiner: "What is the Uhthoff phenomenon, and how do you distinguish it from a relapse?" The Uhthoff phenomenon is the transient worsening of pre-existing neurological symptoms (such as visual blur, weakness, or fatigue) when body temperature rises — from exercise, a hot bath or shower, fever, or environmental heat. The mechanism is reversible conduction block in previously demyelinated axons: demyelinated axons conduct nerve impulses only marginally, and a small increase in body temperature raises the threshold for action potential propagation, causing a temporary conduction block and re-emergence of old symptoms. It is NOT a new relapse — it is not new inflammation or new demyelination, and the symptoms resolve completely when body temperature normalises. A relapse, by contrast, is a new or worsening neurological deficit lasting more than 24 hours (typically evolving over days to weeks), caused by new inflammatory demyelination. Distinguishing the two is critical: the Uhthoff phenomenon requires no treatment (just temperature management — cooling, avoiding hot environments), while a relapse requires high-dose steroids. The patient should be counselled on this distinction to avoid unnecessary steroid courses. [1]