Symptomatic treatment included: Spasticity, Pain, Fatigue, Ataxia, Cognition , Sphincteric control, Sexual dysfunction

1. SYMPTOMATIC TREATMENT IN MULTIPLE SCLEROSIS
Hatem Samir Shehata, M.D
Prof of Neurology
Cairo University

2. Management
Tactics of RRMS
Treatment ofacute
relapses
DMDs
Baseline
therapies
(first line)
IFN, GA,
Teriflunamide
Escalation
therapies
Fingolimod and
Natalizumab
Other therapies
Almituzumab,
Daclizumab, Fumarate,
Immunosuppressant,
others
Symptoms
Management
Hierarchy of management of
RRMS
SYMPTOMATIC TREATMENT
• SPASTICITY
• PAIN
• FATIGUE
• ATAXIA AND TREMOR
• COGNITIVE AND DEPRESSION
• BOWEL AND BLADDER
• SEXUAL DYSFUNCTION
2

3. WHY Treat MS
Symptoms ??
– Have great impact on f-QoL and i-QoL
– Very common in MS patients
– Manageable !!! Generally improved/managed by
symptomatic treatment
– Despite great advances in DMDs; yet, symptomatic
treatments are still lagging behind DMDs
– An important factor in adherence
– Doctors’ ethical obligations !!!
3
‘THE ONLY DISABILITY IN
LIFE IS A BAD ATTITUDE’
SCOTT HAMILTON

4. 4
Starts by inflammation
Ends by degeneration
?? EDSS 3

5. Cumulative disability
progression
5

6. 6
A wheel-chair bound
patient !!!
Is it a hopeless scenario ????

7. 7
After 4 months

8. 8
After 8 months

9. • It occurs in 60% of MS patients
• It can be classified into:
– Tonic (persistently elevated muscle tone) and
– Phasic form (intermittently elevated muscle tone), which is often associated
with painful cramps
9
Complications
Disability(1) Disability: weakness / dexterity
(2) Mask actions of antagonists
(3) Seating and postural problems
(4) Pains, stiffness and spasms (discomfort–
contractures)
(5) Hygiene and self care problems
(6) Mood changes and loss of self-esteem
(disfigurement –sexuality problems)
(7) Fatigue – Sleep disruption
Spasticity
Consequences

10. 10
Spasticity and MS
513 Patient from registrant at the North American
Research Committee on MS (NARCOMS)
Frequently affects ADL
Forced to modify ADL
Prevents ADL

11. Gait mechanics in MS
• Up to 50% of patients reported problems with some aspects of mobility
in the first year following diagnosis of MS
• Up to 90% have mobility problems within 10 years of diagnosis
11

12. Gait mechanics in MS
• Patients with MS develop changes in mechanics of ambulation that
are 2ry to: (1) weakness, (2) spasticity, (3) diminished proprioception
and (4) disorder in motor integration
• The most common abnormal pattern involves
1. Reduced hip flexion (iliopsoas paresis) Abnormal swing
phase ‘ignition’
2. Decreased dorsiflexion (weak tibialis anterior and tendoachilles
tightness) Toe drag
3. Excess knee extension during single limb support phases of walking
Genu recurvatum
4. Circumduction gait and pelvic tilt
12
Walking more energy consuming and slow

13. 13
[ I ] Motor cortex: planning for voluntary movement
[ II ] Corticospinal tracts
carry orders to LMN
[III] Impulses from cortex
also pass to BG
Correct the
timing of
movement and
force of muscle
contraction
[IV] The corrective
impulses from the EPS are
sent to interneurons in
medulla spinalis
[V] Cerebellum coordinates the
speed and direction of
movement
[VI] Interneurons send
inhibitory or excitatory
impulses to the LMN to
regulate its activity
[VII] Final common pathway: LMN sends contraction impulse to the
muscle via peripheral nerve
Feed back: muscle spindles, golgi
tendon organs mechanoceptors in
joints send info on the degree of
contraction to the medulla
spinalis, cerebellum and
somatosensory cortex
Spasticity –
Pathophysiology
Neural pathways
regulating muscle
contraction

14. 14
Loss of cortical drive after
spinal / supra spinal lesion
Loss of descending inhibitory spinal
circuits (Dorsal RST)
Increase muscle SR by intact Medial
reticulospinal and vestibulospinal tracts
II/
Muscle SpindleTendon
Ib afferent

15. Goals of Therapy
• Increase functionality (improve QoL): ROM, ambulation
• Postural benefits: modify body image
• Ease pain – Decrease spasms
• Prevent or decrease contractures
• Facilitate Rehab/Orthosis
• Hygiene
15

16. Spasticity Management
Options
Physical therapy
Regular exercises
Physiotherapy
16
Surgery
Severe
spasticity
Medical
therapy
Generalized
Oral agents
Regional
Intra-thecal baclofen
Focal
BTX-A injection
Phenol blockade
Consider each in combination with others

17. Pharmacologic
Management
• Systemic
– Baclofen (30-90 mg/d), diazepam (5-15 mg/d), dantrolene sodium
(100-400 mg/d), clonidine (0.3-0.9 mg/d), tizanidine (< 36 mg/d),
cannabinoids (Sativex)
Limitations: non-selective; large dosages often required which
may result in intolerable side effects (sedation, weakness, GIT
disturbances and hepatotoxicity)
17
FAMBYRA
In January 2010, FDA approved (dalfampridine or 4-aminopyridine)
It increases walking speed in 35% of people with multiple sclerosis
It is a K-channel blocker that enhances conduction in damaged nerves

18. Commonly used muscle
relaxants and Fambyra
18
In January 2010, FDA approved (dalfampridine or 4-aminopyridine)
It increases walking speed in 35% of people with multiple sclerosis
It is a K-channel blocker that enhances conduction in damaged nerves

19. 19
• Patients goals
• Risks
• Compare goals
• Therapeutic goals
• Benefits
1. Action potential at the presynaptic
2. Neurotransmitter (NT) release
3. Glutamate and GABA
4. Binding to GABA-R and iGlu-R
5. Inhibitory …………… Excitatory
6. Activated Glu
7. Increase Calcium
8. ECBs bind to pre-synaptic cannabinoid
receptors (CB1-R)
9. Net result is inhibition of further Ca
influx, and so inhibition of NT release
stimulates
endocannabinoid
(ECB) synthesis
ECB. ‘Retrograde’ inhibition of
nerve impulse transmission

20. • Local treatment options.
– Motor point and nerve blocks: aqueous phenol (Neurolysis
by coagulate proteins)
Limitations: tissue necrosis, pain and dysesthesia; variable duration of effect;
often irreversible
– Local injections of BTX-A
20
Pharmacologic Management (Cont’d)

21. 21
Indications: generalized moderately severe
spasticity (not adequately treated with oral
medications and BTX).
The spasticity reduction in LL (+/-) UL depends
on the catheter position in the spinal fluid.
Low catheters (T 10-12): improve mainly the
legs. Higher catheters (T 1-2): arm spasticity is
targeted.
■ Regional treatment options. Intra-thecal Baclofen (ITB)
Pharmacologic Management (Cont’d)
Test dose: 50 ug baclofen injection in spinal fluid.
Then evaluate for 4-8 hours (response)
A catheter is inserted through a needle
intrathecally and is threaded upward, then
tunneled under the skin to the abdomen and is
connected to a programmed pump under
abdominal muscles.

22. Surgical Management
• Selective dorsal rhizotomy
• Selective Neurotomy: partial section of motor nerve
branches
• Orthopedic surgery as tendon release (depending on
age of patient)
Limitations: invasive; irreversible; parathesia; effectiveness varies
22

23. 23
Selective Dorsal Rhizotomy (SDR)
1. Exposing LL nerve roots through a midline
lumbar incision.
2. Sensory roots are divided into 3 – 5 rootles, that
are electrically stimulated to identify and cut
nerves with abnormal responses.
Commonly in young patients with LL spasticity
(with relative good strength and good back
extensors power) or (to improve hygiene).
Prerequisites: No contractures.
Complications rate: 5 – 10%

24. • Both bony and soft tissue surgeries
• The major soft tissue procedure involves lengthening the muscle-tendon
unit (tenotomy) – and (tendon transfer)
• Other surgeries include:
– Capsulotomy
– Fascial arthroplasty
– Removal of excessive callus formation
24
Orthopedic surgeries

25. Overview of Rehabilitation
Intervention
• Early start – better outcome.
1. Positioning‘bed, wheelchair, splinting with increased angles of
extension, casting, AFO)
2. Stretching and PROM to prevent long-term soft tissue contractures or
adaptive shortening
Full stretch for 2 hours / 24 hours (Medical Disability Society, 1988)
3. Re-educate ‘Relearning’ and facilitate balance/equilibrium
• Gait training: progressing assertive device ‘e.g., from quad cane to
straight cane’. Strengthening
1. Heat “relaxation”, cold “inhibition”, U/S, E.S
25

26. Constraint-induced
movement therapy (CIMT)
• CIMT is a form of therapy that helps unilaterally affected victim to
regain the use of affected limbs
• The focus: force patient to use the
affected limb by restraining the
unaffected one. The affected limb is
then used intensively for 3 – 6 hours
a day for at least 2 weeks.
• As a result; the brain grows
new neural pathways
26

27. Pain
• Estimated prevalence of MS-related pain ranges widely from 26 to 86 %
• Pains in multiple sclerosis can be classified into:
– Neuropathic pains:
(A) Dysesthetic limb pain (thalamic or cortical deafferentiation pain by lesions
along the spino-thalamo-cortical pathways)
(B) Trigeminal neuralgia (high-frequency ectopic discharges generated by
trigeminal primary afferents demyelination)
(C) Lhermitte’s (dorsal column primary afferent demyelination)
(D) Pain with optic neuritis
– Nociceptive pain (musculoskeletal pains and headaches, whether migraine
or TTH
– Treatment-induced pains
27

28. Pain
• Pharmacological treatment:
– First-line trials of AEDs, tricyclic antidepressants, and SNRI
– In refractory cases; opioids (e.g., methadone) used by experienced
clinicians
– More recent, less-supported therapies include; BTXfor V and
Dronabinol (Marinol), a cannabinoid (CB) 1 receptor agonist
(delta-9-THC), is suggested to be effective against neuropathic pain
in patients with MS
28

30. • Incidence ranging from 60 to 95%
• A subjective lack of physical and/or mental energy (perceived by
patient/caregiver) that interfere with usual or desired activity
30
During the initial screening of fatigue
consider: iron studies, thyroid and 25-
OH vitamin D levels
Fatigue

31. – Primary mechanisms. Related to direct immune-related CNS
affection:
• Increase pro-inflammatory cytokines (TNF-α, TNF-α, and IFN-γ levels) in
fatigued MS patients
• Endocrine influences (lower levels of de-hydro-epi-androsterone ‘DHEA’ in
fatigued MS patients)
• Axonal loss, and altered patterns of cerebral activation
– Secondary mechanisms:
• Sleep disorders (RLS, sleep disordered breathing, insomnia, …)
• Depression and disability status
• Iatrogenic mechanisms (IFN-β , immunosuppressive, pain medications
and muscle relaxants
31
Fatigue (mechanisms)

32. • Amantadine. Several RCT have shown favorable results; yet, a Cochrane
Database Review demonstrated potential bias of these studies, which
preclude formal FDA approval
• Pemoline. It is CNS stimulant with dopaminergic effects [black box
warning: liver toxicity]
• Modafinil (Provigil), and its (R)-enantiomer Armodafinil (Nuvigil), are
wake-promoting agents approved for narcolepsy, shift-work sleep
disorder, and OSA with EDS despite use of CPAP
• SSRI (fluoxetine)
• Non-pharmacologic treatment: including CBT, aerobic exercises,
rehabilitation regimens and yoga
32
Fatigue (treatment)

33. Ataxia and Tremor
• 80% of MS patients suffer from disabling ataxias (cerebellar, spinal or
sensory)
• Specific Treatment
– The cornerstones of treatment are PT and OT (tone regulation, stabilization
of the trunk and ataxia-inhibiting techniques). Recently, video-games based
treatment
– A significant reduction of intention tremor may be achieved by short-term (1
min) local application of ice (class III evidence)
33

34. Ataxia and Tremor
• Drug Treatment
– β-blockers (propranolol) can help patients with severe intention tremor
– AEDs. Primidone may be effective in ET but sedative side effects limit its use.
GBP ameliorates orthostatic tremor. CBZ and TPX may help
– Clonazepam, oxitriptan (5-hydroxytryptophan) and IV Ondansetron (class III
evidence)
– Surgical Treatment. With stereotactic operations, e.g. VIM thalamotomy and
VIM (DBS)
34

35. Cognitive Dysfunction
• The estimate of cognitive impairment in MS ranges between 40% and
65%
• Not only in long-standing MS patients, but also in earlier disease stages
• Impairments include attentional domains, memory, executive functions
and visuo-spatial skills
• Evolving evidence that early treatment with IFN-beta may also have a
protective effect on the cognitive function
35

36. Cognitive Dysfunction
36
After the first MS-related clinical event, 55.3% of patients showed
distinct cognitive deficits
Specifically, 6% in working memory, 14.9% in focusedattention,
25.5% in figurallearning and up to 14.9% in executive function

37. • Treatment
– Structured Memory Training (class I evidence )
– Simple tasks such as crossword riddles and other games training
memory skills may help
– Cholinesterase inhibitors like donepezil may ameliorate
memory functions, especially verbal learning and memory (class
I evidence)
– 4-AP and amantadine have been studied with respect to their
effect on cognitive dysfunction
37
Cognitive Dysfunction

38. Depression
• MS patients can be afflicted with a range of psychiatric disorders
• Depression is the most common illness (50% of patients)
• It can (1) markedly impair QoL, (2) reduce adherence to treatment and
REHAB strategies, (3) pseudo-attacks, (4) worsen other symptoms
(fatigue, cognition, pains, etc..,)
• Goals of treatment are (1) early detection, (2) avoid offenders “IFN,
steroids, .. Etc.,), (3) referral to psychiatrists
• Pharmacological treatment + CBT (class II evidence)
38

39. Bladder and bowel dysfunction
• Bladder Dysfunction: It affects up to
90% of MS patients (damage to
central autonomic pathways)
39
3 MAJOR FORMS
Storage Dysfunction: due to
overactive detrusor
muscle (hyperreflexia):
precipitancy, urgency,
urinary frequency and
nocturia
Emptying
dysfunction: include
urinary hesitancy
and retention with
overflow
Combined Dysfunction (detrusor
– external sphincter
dyssynergia): resulting in
urgency combined with
hesitancy when voiding, and
incomplete voiding

40. Management
40
Correct Voiding
Improper Timing
No
dysenergia
detrusor
sphincter
dyssynergia
(DSD)
Acontractile detrusor with
incompetent sphincter
Acontractile detrusor
with OA sphincter
Acontractile detrusor with
normal sphincter

41. Management
• Initial evaluation includes history, physical exam, urinalysis, and UDS with a
post-void residual (PVR)
• Untreated, bladder dysfunction leads to many complications (UTI,
urolithiasis, hydronephrosis, and renal failure)
41
(1) Oxybutynin and tolterodine (class I evidence)
(2) Trospium chloride [Spasmex ‘Ferring’] (30 mg b.i.d)
(3) Propiverine [Mictonorm ‘Schering-Plough’] (15 mg t.d.s)
(4) Flavoxate [Genurine] (class II evidence)
(5) Solifenacin (class I evidence)
FOR Over Active Bladder (OAB)
Medical treatment

42. Management
α-blocking agents Alfuzosine (Xatral), Doxazocin (Cardura), and Tamsulosine (Omnic)
(0.4 to 0.8 mg/d) (class II evidence)
Desmopressin [Minirin], the ADH, effectively reduces nocturnal micturition
frequency (class II evidence). Tablet: 0.1 mg, spray: 10 ug, melt: 60 ug)
42
FOR EMPTY DYSFUNCTION AND “COMBINED FORM”
FOR NOCTURNAL MICTURITION FREQUENCY
TIMED VOIDING
Surgical options augmentation cystoplasty (in OAB), sacral
neuromodulation, and BTX
Rehabilitation. Pelvic floor muscle training
In cases of high post-void residuals, regular clean intermittent self-
catheterization may prevent further complication

43. • Surgical options augmentation cystoplasty (in OAB), sacral
neuromodulation, and BTX (it may lead to increased post-void residual and
therefore increase the need for self-catheterization)
• Rehabilitation. Pelvic floor muscle training, biofeedback, and
neuromuscular electrical stimulation
• In cases of incomplete voiding with high post-void residuals, regular clean
intermittent self-catheterization may prevent further complication
43
Management

44. Bowel dysfunction
• Pathophysiology. Dysfunctional extrinsic autonomic control of bowel
function
• It may worsen due to medications (as anticholinergics, antidepressants,
or medications used for spasticity), or due to other MS symptoms
• Approaches: (1) dietary modifications (dietary fibers), (2) laxatives such
as lactulose syrup, polyethylene glycol and enemas, but they carry the
risk of dependence, (3) bowel biofeedback therapy
44

45. Sexual Dysfunction
• During the course of MS, sexual dysfunctions eventually occur in up to 80%
of patients [can lead to conflicts within the partnership]
• Causes:
(I) Primary due to MS-related demyelination
(II) Secondary to medications, or specific symptoms as spasticity and fatigue
(III) Tertiary dysfunctions (psychological reactions due to disabilities)
45
Females Males
Reduced libido and lack of orgasm Predominantly ED (70%)
Retrograde/delayed/absent ejaculation (50%)
Reduced desire
Reduced semen quality/sperm count ’motility’

46. Sexual Dysfunction
• RISK FACTORS. (1) Disease duration. (2) Age. (3) Level of physical
disability. (4) Depression and fatigue
• Treatment.
(1) D.C of drugs which may interfere with sexual function
(2) Targeting MS symptoms which may impair sexual intercourse like
adductor spasticity or bladder incontinence
46

47. Management
• Drug Treatment
– Phosphodiesterase-5 inhibitors sildenafil, vardenafil and tadalafil (class I
evidence). Significant improvement of ED ranging from 73% to 95% especially
with UMNL with residual reflexogenic erection
47
Psychogenic ED Yohimbine may ameliorate erection
In cardiac patients Sublingual apomorphine (6 mg) is used PRN as
its effect starts 20 min after ingestion (class II evidence)
In females with reduced lubrication and dyspareunia Livial (Tibolone)
a selective estrogen activity regulator is recommended (class III evidence )

48. Drug Treatment (Cont’d)
48
Organic anejaculation in Multiple Sclerosis MIDODRINE . α1-adrenergic
receptor agonist prodrug of desglymidodrine
Other drugs include; pseudoephedrine, ephedrine, phenylpropanolamine Hcl and
neostigmine
Management

49. • Invasive and Surgical Treatments
• ICI of alprostadil 2.5–20 ug (PG) (class II evidence ).
Superior to PDE5-i in patients with LMNL lacking
reflexogenic erections
• ICI of papaverine (success rates up to 92%), but with
high dosages (80 mg), with higher risk of priapism
• Vacuum pumps may be considered
(class III evidence).Adequate vaginal
penetration was 93% at 3 mo with
partner satisfaction rate (83%)
49
Management

50. • Penile vibratory stimulation [success rate 60%]. First-line
treatment in men with SCI who fail to ejaculate during sexual
intercourse.
Viberect is used to provoke penile erection in men who
experience ED, and to provoke ejaculation in men with SCI
50
Management

51. 51
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