1. ALS-Management and Upcoming Clinical Trials
Abi Muthukumaran, MD
Director of the ALS Program
Cedars-Sinai Medical Center
Los Angeles.

2. ALS Symptoms
Muscle weakness
Atrophy
Stiffness
Cramps
Fasciculations

3. ALS Symptoms Dysphagia – Difficulty in swallowing
Dysarthria – Difficulty in speech
Dysphonia – Change in voice quality
Respiratory Insufficiency
Emotional Lability

4. ALS Symptoms Weight loss Depression Anxiety Memory loss Fatigue Pain
Drooling of saliva

5. ALS Spontaneous motor activity Cramps Fasciculations
                  Wasting of hands & arms in ALS

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

7. Medical Management Riluzole
The only FDA approved drug for ALS treatment
AAN Practice Advisory- Neurology 1997
Approved for use in the US, Europe and Canada –2000
Safe, fairly well tolerated
Moderate efficacy
Expensive ($10,000/year !!)

8. Riluzole

9. Riluzole
Monitor LFTs at baseline and every month for first 3 months, followed by every 3 months long term
Reduces damage to motor neurons by decreasing the release of glutamate
Prolongs survival by 3-4 months, Cochran review 2005
Side effects include fatigue, nausea, diarrhoea and liver toxicity

10. 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

11. 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 )

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

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

14. 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

15. 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.)

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

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

18. 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)

19. Sialorrhea Management

20. ALS Management Thick Mucus Production Increase Hydration
Guiafenesin (robitussin) liquid or pill form
Propananol ?
Suctioning and cough assist device

21. 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

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

23. 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

24. G Tube

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

26. 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

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

28. Upcoming Clinical Trials

29. 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)

30. Nature Medicine, 2004

31. 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, sites

32. 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

33. 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

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

35. 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.

36. 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

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

38. 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,

39. 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 meq/litre

40. 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

41. 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

42. 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)

43. Exercise in ALS Mahoney,2004
There is emerging evidence that regular exercise helps the rate of decline
Still some conflicting data
SOD mouse in treadmill 10 weeks increase in survival Vs no exercise
But high intensity exercise is bad
Mahoney,2004

44. 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

45. 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”

46. Thank you for your patience