This document presents three case studies. Case Study 1 involves a 38-year-old woman with double vision and headaches that are worse when looking left. Examination finds failure of left eye adduction. Case Study 2 is a 32-year-old woman with blurred vision, leg weakness, and urinary incontinence. Case Study 3 is a 45-year-old man with shortness of breath, fevers, weight loss, fatigue, unsteady gait, and memory problems.

2. Bryan Ceronie

3. Case Study 1
 38F
 2/7 history of blurred and double vision
 First noticed it at the gym
 At first thought she had got something stuck in it but she
saw the opticians who referred her to ED
 Worse when she looks to the left, has to crane her neck
to correct it

4. CASE STUDY 1
 Examination:
 A – patent
 B -
 C – HS I + II + O
 CRT 2s
 JVP <->
 Euvolaemic
 ECG: SR
• Eye Examination:
• Visual acuity 6/6 right 6/9 left
• Normal fundi
• CNs:
• Failure of adduction on left
lateral gaze
• Contralateral nystagmus
• Normal tone, power,
coordination, reflexes and
sensation in all four limbs

5. Differential diagnosis
Autoimmune
•Multiple Sclerosis
•Neuromyelitis Optica
•Sarcoidosis
•SLE
Vasculitides
•Wegener’s
Infective
•HSV
•HIV
•Lyme Disease
Toxic
•Methanol/Ethylene Glycol
•Ethambutol/Isoniazid
•Amiodarone
•Cimetidine
•Vincristine/ciclosporin
Metabolic
•B12/folate
•B1, B2, B,3 B6
Vascular
•Central Retinal Artery
Occlusion

6. Further history
 Suffered glandular fever as a child
 Diagnosed with hypothyroidism in her late teens,
treated with levothyroxine
 Last year diagnosed with carpal tunnel syndrome for
parasthesiae in her right hand, resolved spontaneously
after two weeks

7. Investgations
 ECG,
 Urine dip
 Bloods:
 FBC, ESR
 U&E, LFTs, CRP, TFTs,
B12/folate
 ANA, ENA, ANCA, ACE,
dsDNA, C3/C4
 HIV, Borrelia, VDRL
 Aquaporin-4, MOG
• Imaging:
• CT Head
• MRI Head
• CSF:
• Biochemistry
• MC&S
• Oligoclonal bands
• Neurophysiology:
• Visual evoked potentials
• Somatosensory evoked
potentials
• Brainstem auditory evoked
potentials

9. Multiple sclerosis
 Autoimmune condition of the brain and spinal cord
 Antibody-mediated damage to myelin proteins leads to
demyelination and neurodegneration
 Characterized by discrete attacks of demyelination, followed by
remyelination, in a relapsing-remitting pattern (RRMS)
 Ultimately leads to progressive neuronal loss and permananent
disability (progressive MS)

10. MS: classification
 Relapsing Remitting (RRMS): most common type (85%).
Recurrent attacks of neurological deficits in different parts of
CNS which resolve or partially resolve over time.
 Clinically Isolated Syndrome: single episode of neurological
deficit. Also sometimes called possible MS
 Secondary Progressive MS (SPMS): progressive
accumulation of neurological deficit and disability. 50% of
RRMS will develop this within 10-15 years.
 Primary Progressive MS (PPMS): 10% of patients heavily
steadily progressive disease from outset.

11. MS: Epidemiology
 Affects 2.1 million people worldwide
 Prevalence: 50-100 per 100 000
 Age range: 15 – 45 years. Mean age at diagnosis 29 years.
 Sex: 2:1 female preponderance
 Geography: prevalence increases with latitude (highest in
Northern europe). High rates in Sardinians, Parsis and
Palestinians. Rising in Latin Amrerica.

12. MS: Aetiology
 Genetics: MZ concordance 20-35%
 EBV: higher association of MS individuals with serum
antibiodies and CSF antigens
 Vitamin D: low levels may contribute to latitude hypothesis
and explain protective effects of some diets
 ?Cerbrospinal venous insufficiency

13. Pathophysiology
 Demyelination:
 Antigen presenting to T cells outside of the CNS then results in trafficking
through the BBB
 Decreased function of T regulatory cells (Tregs)
 Increased expression of IL-17 and IL-23 cytokines, mediated by Th17 cells
 Activation of autoreactive B cells to develop into a pathogenic phenotype,
secreting antibodies against myelin proteins
 Therapeutic data suggest memory B cells may play a crucial role
 Neurodegeneration
 Loss of myelin leads to accumulation of metabolic insults with neurons, as
well as direct inflammation-mediated damage

15. MS: clinical features
 Sensory loss and
paraesthesiaes
 Motor symptoms: pyramidal,
extrapyramidal, cerebellar
 Bladder, bowel and sexual
dysfunction
 Diplopia
 Optic neuritis
• Trigeminal neuralgia
• Heat intolerance
• Pain
• Cognitive: attention,
memory, concentration,
judgement
• Depression or euphoria
• Fatigue

16. MS: Clinical features

17. MS: eye signs
 Optic neuritis:
 Decreased visual acuity
 Decreased colour vision
 Pain on eye movement
 Swollen optic discs
 Uthoff phenomenon
 Pulrich effect
 Oscillopsia: sensation of
objects in visual field
oscillating
• Opthalmoplegia
• CNVI most common
• CNIII and IV uncommon
• Bilateral INO
• One and a half syndrome
• Pulfrich effect: lateral motion
of an object has the illusion of
depth
• Uthoff phenomenon:
exacerbation of symptoms by
exercise, hot meal or hot bath

18. INO

19. INO

20. INO
 https://youtu.be/YBDg5VMsux4
 https://youtu.be/tIOyFsBwUuY

21. One and a half syndrome
 Lesion to PPRF and ipsilateral MLF
 Conjugated horizontal gaze palsy in one direction and
INO in other

22. MS: Diagnosis

23. MS: Imaging
 MRI abnormalities in 90-95% of patients with MS
 T2: oedema and chronic lesions
 T1: cerebral atrophy and ‘black holes’ of of degeneration
 FLAIR: high-signal intensity lesions, highly sensitive

24. MS: Special tests
 Lumbar Puncture:
 Used when MRI or clinical syndrome non-diagnostic
 Oligoclonal bands in 90-95% of patients with MS
 Intrathecal IgG in 70-90% patients
 Neurophysiology:
 VEPs – patient focuses on reversing black and white
checkerboard. Delays in latencies suggestive of MS.
 SSEPs – examine posterior column of spinal cord, brainstem
and cerebral cortex. Delays indicate demyelination.
 BAEPs – evaluate asymptomatic ipsilateral lesions in auditory
pathways. Less sensitive than VEPs and SSEPs.

25. MS: managing relapses
 Goals: stabilise life-threatening conditions, initiate supportive
care and seizure precautions, monitor for rising ICP
 Methylprednisolone: hastens recovery from exacerbations,
no effect on overall progression
 Plasma exchange: for severe attacks or if steroids
contraindicated or ineffective
 Other: treat precipitating infections with antibiotics,
normalise body temperature with anti-pyretics, ensure
urinary drainage and skin care

26. MS: Disease modifying therapy
 Beta interferon and glatiramer acetate: not recommended
on basis of cost and efficacy
 Dimethyl fumarate and terflunomide: only if not highly active
or rapidly evolving RRMS
 Alemtuzumab: active RRMS
 Fingolimod: highly active RRMS if unchanged or increased
relapse rate
 Natalizumab: rapidly evolving severe RRMS
 2+ disabling relapses in 1 year, one or more gadolinium-
enhancing lesions or increase in T2 lesion load

29. DMTs: adverse effects
 DMF: anaphylaxis, PML, lymphopenia
 Fingolimod: bradyarrythmias/AV block, PRES, macular
oedema, BCC, hypertension, teratogenic
 Terflunomide: hepatotoxcity, teratogenicity, leucopenia,
infection, no live vaccines, malignancy, AKI, hyperkalaemia,
hyperuriceamia, SJS
 Alemtuzumab: autoimmunity, infections, malignancy,
pneumonitis
 Natalizumab: PML, hepatotoxicity, HSV and VZV meningo-
encephalitis, immunosuppression

30. Other treatments
 Emotional lability: amitryptiline (unlicensed)
 Neuropathic pain
 Physiotherapy and rehabilitation
 Spasticity: baclofen, gabapentin, BDZs, ?cannabinoids
 Oscillopsia: gabapentin
 Mobility: rehabilitation, mobility aids and environmental
modification, FES, DBS
 Fatigue: amantadine, physiotherapy, CBT, mindfulness, yoga

31. Newer treatments for RRMS
 Cladribine: anti-leukaemia drug.
 CLARITY – 55% reduction in relapse rate
 Daclizumab: anti-CD25 antibody.
 DECIDE trial – 79% patients relapse-free at 96 weeks
 Ocrelizumab
 OPERA I and OPERA II – 46% reduction in relapses, 40%
decrease in disease activity. 50% acheived NEDA.
 Ongoing trials in primary progressive MS

32. Treatments for progressive
MS
 Currently no licensed DMTs
 Beta IFN may delay disease progression
 Phase 3 trials currently underway for ocrelizumab,
MD1003, masitinib and fingolimod in PPMS
 Phase 3 trials underway for siponimod, MD1003 and
masitinib in SPMS

33. Therapeutic considerations
 No evidence of disease activity (NEDA): emerging
therapeutic target in clinical practice
 Defined as no relapses, no increase in disability and no
new or active (enhancing) MRI lesions
 Patients with MS treated-to-target of NEDA have better
long term outcomes than those with breakthrough
disease
 May be a consideration for future therapeutic trials

34. Therapeutic studies of
memory B cells
 Traditional dogma of MS being a primarily T cell
mediated autoimmune disease
 Th17 and CD4+ T cell-driven activation of autoreactive
B cells lead to secretion of antibodies by plasmablasts
 Evidence from therapeutic studies, including
alemtuzumab (anti-CD52) rituximab (anti-CD20),
suggest memory B cells may be key effectors in driving
disease activity

35. MS Prognosis
 Untreated, over 30% will develop significant disability
within 20-25 years
 5-10% have a milder phenotype with no accumulation
of disability
 Males with PPMS have the worst outcome
 Shortened life expectancy which correlates with
disability. Mostly secondary complications
 Marburg variant: severe fulminant form leading to death
and coma within days

36. MS in Art
Hannah Laycock

37. MS in Art
Bryony Birkbeck

38. Case Study 2
 32F
 3/7 history of blurred vision, colours appearing washed
out, pain on eye movement. Does not improve on
closing either eye. Worse on eating hot water.
 This morning she woke up feeling weak in both legs
and incontinent of urine
 Background: Raynaud’s phenomenon, mother has
rheumatoid arthritis

39. CASE STUDY 2
 Examination:
 A – patent
 B -
 C – HS I + II + O
 CRT 2s
 JVP <->
 Euvolaemic
 ECG: SR
• Eye Examination:
• VA 6/21 right, 6/21 left
• Bilateral RAPD
• Reduced colour vision
• Pain on eye movement
• Swollen discs
• CNs intact
• Upper limbs normal
• Lower limbs:
• 3/5 power bilaterally
• Increased tone
• Brisk reflexes
• T10 sensory level

40. NMO Diagnosis
 MRI: high-signal intensity lesions spanning several
sections of spinal cord on T2 +/- gadolinium
 MRI brain relatively normal cf. MS
 Radiological evidence of optic neuritis
 CSF: mildly elevated protein and pleocytosis of
polymorphonucleocytes. OCBs less common.
 Serology: antibodies to aquaporin 4 (60-70%
sensitivity) and anti-myelin oligodendrocyte associated
glycoprotein (MOG) and

41. Neuromyelitis Optica
 AKA Devic’s disease
 Acute unilateral or bilateral optic neuritis with concurrent
acute myelitis
 Monophasic or multiphasic course
 No disease outside optic nerve or spinal cord
 Distinct neuropathological features and fulminant clinic
course compared to MS
 Associated with other immune disorders including
rheumatoid arthritis, SLE, giant cell arteritis, Wegener’s
disease, mixed connective tissue disorders

42. NMO Treatment
 No proven effective therapies
 High dose glucorcorticoids may be beneficial
 Plasma exchange in those unresponsive to steroids
 Secondary prevention: no recommended effective
treatment. Immunosuppressants may be beneficial e.g.
azathioprine, MMF, mitoxantrone, cyclophosphamide,
IVIG,
 Rituximab has been shown to yield good results.

43. Acute Disseminated
Encephalomyelitis (ADEM)
 Inflammatory demyelinating condition of CNS
 Acute-onset encephalopathy with polyfocal neurological
deficits
 Close pathological resemblance to MS
 Significant overlap with other inflammatory
enecephalitides, vasculitides and Guillain-Barre
Syndrome
 Higher proportion of younger people affected, with 22%
occuring in people under the age of 18
 Typically preceded by febrile infection (viral or bacterial)
or vaccine

44. ADEM Features
 Monophasic attacks associated with fevers, prominent
cortical signs (mental state changes, seizure), relative
absence of posterior column abnormalities, especially
children under 12
 Motor deficit more common than sensory deficit, ataxia
in up to 50% of cases
 Treatment: high dose IV corticosteroids or IVIG
 Course: typically monophasic attacks with remission.
Less commonly may be multiple attacks. Rarely
converts to MS.

45. Case Study 3
 45M
 2/12 history of worsening SOBOE, fevers, weight loss
and fatigue
 Now feeling unsteady on his feet and clumsy
 His wife reports that his concentration and memory
have been worse, and that he seems to drink water
excessively

46. CASE STUDY 3
• Cervical lymphadenopathy
• CNs: dysarthria, nystagmus
• Normal tone, power, reflexes
and sensation in all four
limbs
• Gait: broad-based
• Past-pointing with intention
tremor
• Bloods: Ca 2.7, serum
ACE raised
• CXR: bilateral hilar
lymphadenopathy
• MRI: T2 high signal
lesions bilaterally in
cerebellum

47. Neurosarcoidosis
 Multisystem inflammatory diease of unknown aetiology
characterised by noncaseating granulomas
 Wide range of neurological presentations including
sensorimotor neuropathies, multifocal neuropathies
(similar to MNN), mononeuropathies (especially CNVII)
 CNS effects include cortex, cerebellum or
hypothalamus / pituitary inovlvement

48. Neurosarcoidosis
 Diagnosis:
 Bloods: FBC, ESR, B12, Ca, LFTs, ANCA, ACE
 Imaging: CXR, MRI
 CSF: pleocytosis, high protein, ACE (normal in 30%)
 Neurophysiology: EMG, evoked potentials
 Biopsy: lymph node or active lesions
 Treatment: corticosteroids, immunosuppressants, IVIG

49. Case Study 4
 35F
 4/12 history of headache and difficulty concentrating,
poor memory and attention span
 3/52 low mood, anhedonia, lack of energy and difficulty
in sleeping
 PMH: Sjogren’s disease

50. CASE STUDY 4
 Examination:
 Erythematous rash over
cheeks, sparing
nasolabial folds
 ACE-R: Subtle cognitive
impairment, especially
attention and memory
domains
 Otherwise neurology
intact
 Investigations:
 Bloods: raised ESR,
normal CRP, low C4
 Antibodies: ANA, ENAs,
ANCA, dsDNA awaited
 CSF: normal
 MRI: high intensity T2
signal in periventricular
regions

51. CNS Lupus
 Most commonly (45-75%) presents as acute or
subacute encephalopathy with altered mental state
 Seizures in 14-25% of cases
 Cranial nerve involvement: 10%, usually transient
 Stroke: 5-10%, small – large vessel involvement
 Peripheral neuropathy: 18%, usually distal
polyneuropathy
 Myopathy: 3-5%

52. CNS Lupus
 Diagnosis:
 Raised ESR with low CRP, raised ANA and dsDNA,
antiphospholipid antibodies
 CSF: 20% have oligoclonal bands and raised IgG
 MRI: 65% have T2 signal intensity, typically favouring
grey-white junction or grey matter. May also show cortical
or subcortical infarcts
 EEG: diffuse encephalopathy
 SPECT, PET, MRA, nerve studies, biopsy

53. CNS Lupus
 Management:
 High dose corticosteroids
 Antimalarials – hydroxychloroquine
 Cytotoxics: cyclophosphamide, azathioprine,
methotrexate, rituximab
 Experimental: MMF, epratuzumab