by sanjay kumar(pt)

1. What is MND?
Motor Neurone Disease (MND) is a
progressive neurodegenerative disease that
attacks the upper and lower motor neurones.
Degeneration of the motor neurones leads to
weakness and wasting of muscles, causing
increasing loss of mobility in the limbs, and
difficulties with speech, swallowing and
breathing.

2. How it presents
 Often insidious onset clumsiness mild
weakness slurred speech
 There is no definitive symptom which leads
to diagnosis
 Does not usually affect the senses or the
bowels or bladder
 Effects differ greatly between individuals
regarding symptoms, severity, rate and
progression and survival time.

3. Typical features
• Progressive, Incurable and Rare
• Group of related diseases
• Motor neurones are affected
• Upper and lower limb weakness
• Speech and swallowing difficulties
• Breathing difficulties

4. Symptoms
Muscle wasting and weakness
Fasciculation (twitching)
Cramps
Spasticity (stiffness)
Respiratory problems
Speech and swallowing problems
Saliva and mucus problems
Weight loss
Fatigue
Pain
Emotional Lability
Cognitive changes
Psycho-social aspects

5. Rarely affected
Senses: touch, taste, sight, smell and hearing
Bowel and bladder function
Sexual function and sexuality
Eye Muscles
Heart muscles

6. Primary Signs
 Muscle weakness
 Atrophy
 Stiffness
 Cramps
 Fasciculations

7. Secondary Signs
 Dysphagia – Difficulty in swallowing
 Dysarthria – Difficulty in speech
 Dysphonia – Change in voice quality
 Respiratory Insufficiency
 Emotional Labiality

8. Late Signs
 Weight loss
 Depression
 Anxiety
 Memory loss
 Fatigue
 Pain
 Drooling of saliva

9. Typical signs
 Spontaneous motor activity
 Cramps
 Fasciculations
Wasting of hands
& arms in ALS

10. Different Types
 Lots of overlap
 Classified
1) in terms of the motor neurones affected
2) Symptoms
Bulbar –refers to face/speech/swallowing

11. Amyotrophic lateral sclerosis
(ALS
 Most common
 Upper and Lower motor neurones affected
 Weakness and wasting of the limbs
 Average life expectancy 2-5 years from
onset of symptoms

12. Progressive bulbar palsy
 Quarter of people
 Upper and Lower motor neurones involved
 Slurring speech/difficulty swallowing
 Life expectance between 6 months and 3 years
from diagnosis

13. Progressive Muscular atrophy
 Small number of people 5%
 Lower motor neurones
 Sometimes slower progression
 Early symptoms are sometimes weakness
and clumsiness in the hands
 Most people live for more than 5 years from
diagnosis

14. Primary Lateral Sclerosis
 Rare 0.5%
 Affects only upper motor neurone
 Mainly weakness in the lower limbs
 Can get symptoms in the hands or slurred
speech
 Life span could be normal
 Can develop into ALS

15. Demography
 Over 40 usual age between 50 and 70
 Men slightly more than women
 2 per 100 000
 Cause remains a mystery

16. Tests
 Bloods see if raised CK – can be raised in MND
but not diagnostic
 EMG – Taken from each limb and the
bulbar(throat) muscles- abnormal in MND as the
electrical activity of the muscles is changed
 Nerve conduction tests
 Transcranial magnetic stimulation – tests upper
motor neurones
 MRI – eliminates other diseases
 May do Lumbar puncture or muscle biopsy

17. Treatment
 Riluzole
 Beneficial prolongs survival of people with
MND
 Slows down the progress by a few months
 Inhibits the amount of Glutamate released
in nerve impulses
 Glutamate is a neurotransmitter in excess
causes nerve damage

18. Medications for symptoms
 Muscle cramps – Carbamazepine and
Phenytoin
 Muscle Stiffness – Muscle relaxants
Botox and intrathecal baclofen
• Drooling – Hyoscine, Glycopyrrolate,
atropine
• Pain – usual analgesia/Gabapentin

19.  Respiratory support
 NIV
 This provides the most pressure when
breath in when breath out still have positive
pressure to splint the airway open
 Extends survival increase QOL

20. MND/ALS Management
 A multidisciplinary approach
 Physical/Occupational Therapy
 Speech Therapy
 Nutrition Assessment and Swallow evaluation
 Respiratory therapy/pulmonology
 Home Health
 Social Worker
 Palliative Care

21. Symptomatic Management
 Important part of ALS treatment
 Several recent advances for symptom
management
 Increase in survival and quality of life in
patients seen in ALS centers

22. Symptomatic Management
 Emotional lability (Pseudobulbar affect)
- Associated frequently with bulbar dysfunction
- Amitriptyline (TCA) Forshew and Bromberg 2003
- Fluvoxamine (SSRI)
- Dextromethorphan/Quinidine
- Patient and caregiver education
( AAN Practice Parameter - Guidelines for symptomatic
management of ALS )

23. ALS Management
 Spasticity
- Baclofen – 10 mg po bid/tid and titrate
up as tolerated
- Tizanidine- 4 mg po bid/tid
- Valium – 20-40 mg po at bedtime
- Stretching of the muscles
- Baclofen pump for severe spasticity

24. ALS Management
 Cramps and Fasciculations
-Difficult to treat generally
-Magnesium –Slow Mag
-Tonic water (quinine)
-Chamomile tea ?
-Low dose baclofen
-Low dose benzodiazepines

25. ALS Management
 Treatment of Pain
- Can occur at any stage in the disease
- Neuropathic, Musckulosketetal,
immobility
- Combination of drugs
- NSAIDS, Gabapentin, Pregabalin, TCAs
- Severe Pain – Narcotics

26. ALS Management
 Treatment of Fatigue
- Amantidine – dose 100 mg Po twice or
three times daily
- Modafinil (Provigil)- 100 mg 1-2 times a
day
- Treatment of other underlying causes
( thyroid dysfunction, anemia etc.)

27. ALS Management
 Insomnia
- Ambien
- Sedating antidepressants- Trazadone,
Remeron
- Correcting underlying factors –
nocturnal hypoventilation, pain etc.
- Sleep hygeine

28. ALS Management
 Bowel and Bladder Dysfunction
-Bladder Urgencies - Oxybutinin (detrol),
Catheters
-Constipation – increase fiber in diet,
hydration, stool softners, laxatives,
enema if severe

29. Drooling / Sialorrhea Management
 Glycopyrrolate (Robunil)- 1-2 mg every 4
hours
 Benztropine, Amitriptyline
 Transdermal hyoscine patch
 Topical atropine drops - 1% every 4 hours
 Botox or Myobloc injection into the salivary
glands
 Radiation therapy – if very severe
(AAN Practice Parameter- R. G Miller and Colleagues,
revised Nov, 2006)

30. Drooling/Sialorrhea
Management

31. ALS Management
 Thick Mucus Production in respiratory
tract
- Increase Hydration
- Guiafenesin (robitussin) liquid or pill
form
- Propananol ?
- Suctioning and cough assist device

32. ALS Management
 Goal of therapy – Maximize function
 Establish safe exercises without overexertion
 Improvement of quality of life
 Prevention of contractures
 Patient transfers and assistive devices/aids
 Fall precautions

33. ALS Management
 Tremendous advances in technology
 Newer communication devices
 Sophisticated power wheel chairs
 Stair climbers
 Portable ramps
 Other durable medical equipments

34. Management of Dysphagia
 Speech and swallow evaluation
periodically in clinic
 Assessment of nutritional status
 High protein and high calorie diet
 Barium swallow, video swallow study
 Early discussion about PEG tube
 Referral to GI specialist

35. G Tube

36. Management of Dysphagia
 Indications for G-tube
- Moderate to severe dysphagia
- Significant weight loss
- Recurrent pneumonia
- Declining respiratory status

37. Management of Respiratory Failure
 FVC checks q 3 months in clinic by RT
 BIPAP if FCV < 50 PPV
 Invasive ventilation/Tracheostomy when
FVC < 30 PPV
 Treating underlying infection
 Management of patient anxiety

38. Palliative Care
 Palliative services involved early
 Hospice for patients with end stage ALS
 Comfort care and pain management
 Early Decision making
 Advanced Directives

39. Upcoming Clinical Trials

40. Arimoclomol
 Oct 2005, Phase IIa study completed. 80
patients participated, 10 centers (NorthEast
ALS Consortium)
 Study Goal- safety and tolerability profile for
the drug
 Thought to work by upregulating the heat-
shock proteins and“molecular chaperones” in
cells under oxidative stress
 Increased survival by 5 weeks in SOD-1 mouse
model (by Univ of London)

41. Nature Medicine, 2004


42. Arimoclomol
 Results presented at the International
ALS/MND meeting in Japan.
 Phase 2a study showed that the compound
entered the BBB and CSF
 Phase 2b study with Arimoclomol planned, to
begin in summer 2008
 390 patients, 30-35 sites

43. Ceftriaxone
 Ceftriaxone study –Phase II
 Goal- tolerability and safety when given over
long periods of time
 Shown in animal models to increase survival by
few weeks.
 Mechanism- crosses the BBB and increases the
level of glutamate transporter carrier protein
to decrease the level of glutamate and cellular
excitotoxicity

44. Ceftriaxone
 60 patients initially, 10 US Centers
 First Stage- to study the level of drug in CSF
 Second stage to assess the safety profile when
used over 16 weeks
 Third Stage – Additional 540 patients will be
enrolled to study efficacy (ongoing)
 Drug is given IV through a central venous
catheter

45. Negative Drug Trials
 Vitamin E
 TCH346
 Celebrex
 Creatine
 Indinavir
 Topiramate(topamax)
 Neurontin
 Minocycline

46. Manganoporphyrin
 a novel antioxidant (AEOLUS)
 38 percent increase in survival in SOD mouse
 large study underway.
 Small study with 30 patients showed safety. SC
injection, 75 mg once a day.

47. Lithium for ALS Treatment
 A small Italian study – 44 pts
 Lithium and Riluzole vs Riluzole and
placebo
 Slows progression of disease and 16
patients in lithium arm alive at 15 month
follow up
 29 % of patients died in placebo arm

48. Lithium and ALS
 Mechanism of action
 Increases autophagy
 Increase in number of mitochondria-
spinal cord of SOD1 mouse model
 Increased motor neuron density

49. Fig. 5. Effects of lithium treatment on disease symptom progression
and survival in patients with ALS
Fornai, Francesco et al. (2008) Proc. Natl. Acad. Sci. USA 105, 2052-
2057

50. Lithium for ALS
 A larger multicenter trial on the way
 250 patients- NEALS, CALS
 NIH sponsored
 Expect to start this summer
 Double blinded placebo controlled randomized
study
 Dosage- 150 mg po BID, upto 450 mg a day
 To maintain a serum drug level 0.4-
0.8meq/litre

51. Lithium for ALS
 Primary outcome- disease progression
 A 6 point drop in ALSFRS
 FVC decline
 If lithium is effective, then placebo
patients will be switched to the drug

52. Lithium and ALS
 Side Effects
Nausea, vomiting, fatigue, diarrhea,
dizziness, weight gain, weakness, tremor,
drowsiness and seizure at toxic levels,
irregular heart beat, renal failure,
hypothyroidism

53. Other Studies
 Diaphragm Pacing for respiratory muscle
weakness to improve breathing (Cleveland)
Larger clinical trial on the way
 Nutrition in ALS (phase 2 study, university of
Kentucky)

54. Psychosocial Impact
Breaking bad news
Assessment
Maintaining Hope
Loss
Control and choice
Fears of death and dying
Coping strategies
Family, carers and friends

55. Multidisciplinary approach
Counsellor/Clinical psychologist
Specialist nurse MND Care centre co-ordinator Clinical nurse specialist
Specialist palliative care
Occupational therapist
Physiotherapist
Speech and language therapist
Dietician
Social worker/care manager
Respiratory physician
Neurologist
District nurse
General Practitioner
Gastroenterologists
Consultant in rehabilitative medicine
Community Matron
MND Association & other Voluntary services

56. Conclusions
 Unprecedented number of clinical trials in ALS
in one time
 Marked diversity in technology and targeting
different disease mechanisms.
 We need to improve patient access in
multidisciplinary clinics and establish more
clinical trials with the best study designs.
 Work with different organizations more closely
– ALSA, NIH, MDA and corporate sectors

57. Lou Gehrig
 “Fans, for the past two
weeks you have been
reading about the bad
break I got.Yet today I
consider myself the
luckiest man on the face
of earth…. I may have
had a tough break, but I
have an awful lot to live
for”

58. Thank you for your patience