Multiple sclerosis by Dr. Basil Tumaini, presented during the residency in internal medicine at Muhimbili University of Health and Allied Sciences

1. Multiple sclerosis
Dr. Basil Tumaini
Resident in Internal Medicine
August 2018
Muhimbili University of Health and Allied Sciences

2. Outline
• Introduction
• Etiology and pathophysiology
• Epidemiology
• Clinical presentation
• Diagnosis
• Treatment
• Prognosis
• Eponyms

3. Multiple sclerosis (MS) introduction
• MS is an autoimmune disease of the CNS
characterized by chronic inflammation,
demyelination, gliosis (scarring) and
neuronal loss; the course can be relapsing-
remitting or progressive
Reich DS, Lucchinetti CF, Calabresi PA. Multiple Sclerosis. N Engl J Med 2018
Jan 10;378(2):169–80.
Available from: https://doi.org/10.1056/NEJMra1401483

4. Multiple sclerosis (MS) introduction
• Lesions of MS typically develop at different
times and in different CNS locations (i.e., MS
is said to be disseminated in time and space)

5. Cause
• Discrete plaques of demyelination occur at
multiple CNS sites
• T-cell mediated immune response
• Trigger is unknown
• Has been associated with low vitamin D levels
• Demyelination heals poorly, causing relapsing and
remitting symptoms
• Prolonged demyelination causes axonal loss and
clinically progressive symptoms

6. Epidemiology
• Prevalence: commoner in temperate areas
 England ≥42:100,000
 SE Scotland 200:100,000
 Rarer in Africa/Asia.
 Lifetime UK risk 1:1000
• Adult migrants take their risk with them
• Children acquire the risk of where they settle
• Mean age of onset: 30yrs. F:M ≥3:1

7. Association with vitamin D
• Early exposure to sunlight/vitamin D is important
• Vitamin D status relates to prevention of MS, and
fewer symptoms and fewer new lesions on MRI in
established MS

8. Pathophysiology of MS
An autoimmune disease
B cells are the central player

9. Pathophysiology of MS

11. Presentation
• Usually monosymptomatic
unilateral optic neuritis (pain on eye movement and
rapid reduction of central vision)
numbness or tingling in the limbs
leg weakness
brainstem or cerebellar symptoms (e.g. diplopia, ataxia)
• Symptoms may worsen with heat (e.g. hot bath) or
exercise.
• Rarely polysymptomatic

12. Six MS eponyms
• Loss of motor, sensory, autonomic, reflex, and
sphincter function below the level of a lesion
indicates transverse myelitis
• Longitudinal myelitis also occurs
• Devic’s syndrome (neuromyelitis optica—NMO) is
an MS variant with transverse myelitis, optic
atrophy and NMO-IgG antibodies

13. • Lhermitte’s sign: neck flexion causes
‘electric shocks’ in trunk/limbs
• Also +ve in cervical spondylosis cord tumours
and subacute combined degeneration of the
cord (B12 deficiency)
• Along with dysaesthetic pain, trigeminal
neuralgia, and painful tonic MS spasms, it
comprises the MS-related central pain disorders

14. • Optic neuritis symptoms:
• Acuity/temporary blindness ± complex visual
hallucinations of faces

15. • Charles Bonnet syndrome (rare)
• Uhthoff ’s phenomenon
• vision on exercise, hot meals, hot baths;
• Phosphenes (flashes) on eye movement
• Pulfrich effect (unequal eye latencies, causing
disorientation in traffic as straight trajectories seem
curved and distances are misjudged on looking
sideways)

16. • Efferent, afferent or relative afferent pupillary
defects:
• An Argyle Robert son-type pupil is rarer: syphilis, DM,
MS or sarcoidosis - lesion in or near the Edinger–
Westphal nucleus

20. Video of INO

21. Progression
• Early on, relapses (which can be stress induced)
may be followed by remission and full recovery
• With time, remissions are incomplete, so disability
accumulates
• Steady progression of disability from the outset
also occurs, while some patients experience no
progressive disablement at all

22. Diagnosis & Investigations
• This is clinical, as no test is pathognomonic
• It requires lesions disseminated in time and space,
unattributable to other causes; thus after a 1st
episode further evidence is needed
• Early diagnosis and treatment reduce relapse rates
and disability

23. • A careful history may reveal past episodes, e.g.
brief unexplained visual loss, and detailed
examination may show more than 1 lesion
• MRI is sensitive but not specific for plaque
detection (McDonald criteria)

24. McDonald criteria

25. McDonald criteria
• MS remains a clinical diagnosis!
• These criteria may give too much weight to
MRI
• Attacks must last >1h, eg weakness, with
>30d between attacks

26. • MRI is sensitive but not specific for plaque
detection
~90% presenting with an MS-like 1st
episode and consistent MRI lesions go on
to develop MS
MRI may also exclude other causes, e.g.
cord compression
MRI

36. MRI abnormality
3 out of 4:
• Gadolinium-enhancing or ≥9 T2 hyperintense
lesions if no Gd-enhancing lesion
• 1 or more infratentorial lesions
• 1 or more juxtacortical lesions
• ≥3 periventricular lesions (1 spinal cord
lesion = 1 brain lesion)

37. MRI evidence of dissemination in
time
• A Gd-enhancing lesion demonstrated in a
scan done at least 3 months following onset
of clinical attack at a site different from
attack, or
• if no Gd-enhancing lesions at a 3-month
scan, follow-up scan after another 3 months
showing Gd-lesion or new T2 lesion

38. CSF
• Oligoclonal IgG bands in CSF electrophoresis
(absent in serum) or
• Increased IgG index

41. Evoked Potentials (EP)
• This counts if delayed but well-preserved
waveform
• Delayed visual, auditory, and somatosensory
EP

42. Serology
• NMO–IgG antibodies are highly specific for
Devic’s syndrome
• MOG and MBP antibodies in those with a
single MS-like clinical lesion can predict time
to conversion to definite MS

43. Treatment
• Encourage a happy, stress-free life if possible
(Reduced stress can reduce development of
new lesions)
• Minimize disability (disabled living
foundation)
• If poor diet or reduced sun exposure, give
vitamin D to achieve serum 25(OH)D
levels of ≥50nmol/L

44. Treatment of 1acute exacerbation
• Steroids: Methylprednisolone, e.g. ½–
1g/24h IV/PO for 3d shortens acute
relapses
use sparingly (twice/yr; steroid SE)
It doesn’t alter overall prognosis

45. 2Controlling progression: DMT
• Interferons (IFN-1 & IFN-1)
Reduces relapses by 30% in active RRMS and
lesion accumulation on MRI
Their power to delay disability is modest at
best, as is their role in progressive MS
SE: flu symptoms, depression, abortion
NB: new gadolinium-enhancing lesions on IFN
correlate with severe disability 15yrs later

46. DMT: Monoclonal antibodies
• Alemtuzumab acts against T cells in RRMS
• 2 trials show it’s better than INF
• SE: infections, while the immune system
reconstitutes itself; autoimmune disease
(thyroid, skin, kidney)
• Natalizumab acts against VLA-4 receptors
that allow immune cells to cross the BBB
• It decreases relapses in RRMS by 68% and
reduces MRI lesions by 92%
• SE: PML; antibody-mediated resistance

47. DMT: Non-immunosuppressives
• Glatiramer; mitoxantrone (doxorubicin
analogue; helps in SPMS; safety is an issue)

48. Other drugs
• Azathioprine may be as good as IFNs for RRMS
and is 20 x cheaper
• NB: there are no good drugs for PPMS

49. Treatment of complications
symptomatically
• Spasticity: choices
• Baclofen 5–25mg/8h PO
• Diazepam 5mg/8–24h PO (addictive);
• Dantrolene 25mg/24h (max 100mg/6h);
• Tizanidine 2mg/24h PO, every 4d in steps of
1mg/12h (max 9mg/6h)
• Endocannabinoid system modulation (Sativex®)
has a role

50. Symptomatic treatment
• Tremor:
• Botulinum toxin type A injections improve arm
tremor and functioning

51. Symptomatic treatment …
• Urgency/frequency:
If post-micturition residual urine >100mL,
teach intermittent self-catheterization
If <100mL, try tolterodine

52. Poor prognostic signs
• Older M
• Motor signs at onset
• Many relapses early on
• Many MRI lesions
• Axonal loss.

53. Recommendation for further reading