Dr. Patrick Treacy Medical Director of the Ailesbury Clinics lectures on "Botox and Migraine" to the Migraine Association of Ireland in Ennis 2007

1. Using BOTOX ® as an adjunct in the treatment for MIGRAINE by Dr. Patrick Treacy Medical Director Ailesbury Clinics Ireland

4. WHAT EXACTLY IS BOTOX ® ?

5. History of Botox starts in the new century 1900 German chemical warfare brought new means of killing people

6. Ypres April 22 nd 1915 Non specific method. 5,000 British troops died on the first day and 5,000 Germans on the second

7. Next year Ireland strikes for freedom. Dublin 1916

8. 1916 British built a new chemical warfare complex 7000 acres of scrubland in Porton Down Wiltshire

9. Porton Down Research Centre Research experiments on Botulinum by scientist Dr. Paul Fides gave rise to DysPORT

11. Porton Down is still active today

12. First victim of experiments Aircraftman Ronald Madison died in May 1953

13. Reinhard Heydrich Assassinated by Czech agents in Prague on 27 th May 1942 by use of Botulinum toxin

14. 1953 US built chemical warfare plant at Fort Detrick American experiments by Edward Schantz gave rise to Botox

16. Strabismus The various muscles of the eye that might be affected by strabismus. Demonstration of the various inflictions of strabismus

17. How did Botox reach such popularity?

18. The use of BOTOX cosmetically Pictures courtesy of Ailesbury Clinics

19. Same patient 5 days later

20. When did Botox become so popular? 1987 Canadian ophthalmologist Jean Carruthers noted that frown lines disappeared following the use of Botox to treat patients for blepharospasm. She told her dermatologist husband Dr. Alastair Carruthers 1990 , The Carruthers published their findings “ The treatment of glabellar furrows with Botulinum-A exotoxin” Carruthers JDA, Carruthers JA. J Dermatol Surg Oncol. 1990;

22. Botox and Headaches 1992 The headache and Botox connection began emerging in 1992 when a California physician noted his patients who got Botox injections said they were having fewer headaches.

23. Where does Botox come from? Botulinum toxin (BTX) is produced by a bacterium called Clostridium botulinum , The clinical syndrome of botulism can occur following ingestion of contaminated food from this bacterium Botulinum toxin is broken into 7 neurotoxins ( types A, B, C [C1, C2], D, E, F, and G ), which are distinct but structurally similar. Human botulism is mainly due to types A, B, E, and, rarely, F,G. Types C and D cause toxicity only in animals.

24. What does the Botox look like? Botox is a single chain that can split to form a dichain molecule with a disulfide bridge. The light chain is similar to tetanus toxin The heavy chain can bind the toxin to nerve receptors

25. Scientific History of Botox 1822 German doctor Justinus Kerner published symptoms of "sausage poison" in 200 cases of gastroenteritis in Stuttgart in medical journal . He suggested the idea of a possible therapeutic use of “sausage poison“ in St. Vitus dance 1870 , German doctor Muller coined the name botulism for the symptoms. Botulus is Latin for sausage. 1895, Microbiologist Prof. Emile Van Ermengem checked 3 deaths from food poisoning outbreak in Ellezelles and isolated the bacterium Clostridium botulinum .

28. FDA approved uses of BTX-A 1. Cervical dystonia 2. Blepharospasm 3. Cranial nerve 11 disorders 4. Facial spasm 5. Glabellar frown lines

32. How does Botox work? At a normal neuromuscular junction, a nerve impulse triggers the release of acetylcholine , which causes the muscles to contract.

33. How does Botox work? Botox acts by binding to receptor sites on the nerve terminals blocking the release of ACETYLCHOLINE This mechanism laid the foundation for the development of the toxin as a therapeutic tool.

34. Mechanism of BLOCKING of BTX-A The Botox light chain stops ACETYLCHOLINE release by cleaving a protein called SNAP-2 SNAP-2 is required for the docking of acetylcholine vesicles on the inner side of the nerve terminal plasma membrane.

37. Why does Botox stop working? Clinical effect lasts about 2-6 months and then resolve Recovery occurs through formation of new nerve terminals Study by De Paiva suggests that regeneration of the original neuromuscular junction can take place.

38. The Migraine Story

39. Triggers and Risk Factors Migraine headaches are often triggered by specific things

40. Triggers: Changes in Daily Cycles

41. Triggers: Environment or Diet

42. Triggers: Mental

43. Migraine Takes Time Out From Your Life In the past 3 months in the US alone... Missed family or leisure activity Functioned less than half as well at household chores Were unable to do chores/household work Functioned less than half as well at work/school Missed Work or School 9 million 14 million 21 million 18 million 16 million

44. How Migraine Stacks Up Against Other Common Diseases From the Centers for Disease Control and Prevention, the US Census Bureau, and the Arthritis Foundation. 1% 5% 6% 7% 12% Rheumatoid arthritis Asthma Diabetes Osteoarthritis Migraine Affected Patients

45. The Stages of a Migraine Attack

47. How do Migraines happen? 1 Migraine originates deep within the brain 2 Electrical impulses spread to other regions of the brain. 3 Changes in nerve cell activity and blood flow may result in visual disturbance, numbness or tingling, and dizziness. 4 Chemicals in the brain cause blood vessel dilation and inflammation of the surrounding tissue 5 The inflammation irritates the trigeminal nerve , resulting in severe or throbbing pain

48. Chemicals irritate Trigeminal Nerve

49. This triggers other nerves

50. Arterial Activation Release of Neurotransmitter Worsening of Pain How does Botox help?

51. Botox blocks these neurotransmitters cGRP Sub P Glut

52. The blocking effects of BOTOX Motor Nerve Alpha/Gamma Sensory Nerve Type C, A-delta, A-Beta SP, cGRP, Glu Autonomic Cholinergic Smooth Muscle SNARE BOTOX Ach Ach * BTX/A->SNAP-25; BTX/B -> VAMP SNARE complex Single site of action = SNARE protein via SNAP-25

53. How Botox into Muscle stops Headache Pain Sub-P cGRP Bk K+ His Sub-P cGRP Central Sensitization: An increase in responsiveness of neurons within CNS Peripheral Sensitization: -Increase in excitability of peripheral nociceptors Response to Stimulus VESICULAR release of mediators stimulate nociceptors Antidromic Stimulation Neurogenic Inflammation: Dilation of arterioles, leakage of plasma from venules (edema) Chronic Inflammation and Pain: Wind-up Feedback loop Proposed Effects of BTX Direct inhibition of inflammatory mediators` Peripheral Sensitization Antidromic Stimulation: AP’s travel both centrally, and peripherally, invading branches of the same neuron outside the area of injury Vesicle mediated release BTX BTX Central Sensitization

56. The Scientific Proof

65. Migraine Injection Points

66. Any side effects of Botox? Flulike syndrome has been reported, generally short-lived. Other s/e muscle soreness, headaches, light-headedness, fever, chills, hypertension, weakness, diarrhoea, and abdominal pain are not necessarily a result of BTX-A treatment. They include . Since the mechanism of action of BTX-A is so specific, side effects are uncommon and systemic effects rare.

67. What about the famous droopy eyelids? Patient with eyelid ptosis

68. ANATOMY OF FOREHEAD MUSCLES FRONTALIS Action: Elevates eyebrows and the skin of the forehead Action: Elevates eyebrows and the skin of the forehead

69. ANATOMY OF FOREHEAD MUSCLES CORRUGATOR SUPERCILII Action: Depresses eyebrows and wrinkles forehead

70. ANATOMY OF FOREHEAD MUSCLES ORBICULARIS OCULI Action:Depresses eyebrows Closes the eyelids Helps drainage of tears

71. REMEMBER final brow position is a balance between DEPRESSORS and ELEVATOR PROCERUS MUSCLE CORRUGATOR MUSCLE ORBICULARIS OCULI FRONTALIS FINAL BALANCE DEPENDS ON SKILL OF DOCTOR

72. Contraindications to Botox injections Treat patients with diseases of the neuromuscular junction (eg, myasthenia gravis) cautiously because underlying generalized weakness can be exacerbated, and local weakness at injection sites can occur more than otherwise expected

73. IF YOU DO NOT KNOW WHAT YOU ARE DOING YOU PAY THE PRICE NOW! HOW DO I GET BACK UP?

76. THE MIGRAINE INJECTION POINTS INJECT ONLY CORRUGATOR, PROCERUS AND FRONTALIS MUSCLES DANGER : AVOID INJECTING 1CM ABOVE MID-PUPILLARY LINE

77. BOTULINUM-A TOXIN formulations Botox® is an American form of BTX-A produced from the Hall strain of C botulinum Botox ® is distributed by Allergan Inc. Headquarters Irvine California Manufactured Westport Co. Mayo BOTOX ®

78. BOTULINUM-A TOXIN formulations Dysport ® is a British form of BTX-A made in England and mostly available in Europe. Dysport ® is produced by Speywood Pharmaceuticals in England (Dysport) DYSPORT ®

79. BOTULINUM-A TOXIN formulations Myobloc™ is BTX-B (botulinum toxin type B) is also used to treat facial wrinkles. FDA approved for the use of cervical dystonia in Dec 2000 Myobloc™ is distributed by Elan Pharmaceuticals in Athlone, Ireland MYOBLOC ®

80. Peripheral Sensitization Leads to Central Sensitization Peripheral Stimulation Release of Neuropeptides Peripheral Sensitization Increased afferent signals Lack of sensitivity of nerve endings Release of Glutamate and Peptides in CNS Antidromic Activation CNS Central Sensitization Additional Activation Decreased Inhibition at the dorsal horn

82. PNS CNS Peripheral Sensitization Glu , Sp , cGRP, NA, NGF BK, PGs, HA, 5-HT, H + Adenosine, NO Central Sensitization Glu Sp C-fiber/ A delta A  fiber Spinal Cord or Nucleus Trigeminal Caudalis DRG or TGG Impulses Increase WDR Peripheral Sensitization, leading to Central Sensitization Translating these Mechanisms to Humans C- fos

83. Peripheral Sensitization Glu, Sp, cGRP, NA, NGF BK, PGs, HA, 5-HT, H + Adenosine, NO Central Sensitization Glu Sp C-fiber/A delta A  fiber Impulses BTX/A PNS CNS Increase WDR Spinal Cord or Nucleus Trigeminal Caudalis DRG or TGG BTX/A inhibits release of mediators at the peripheral pain fibres, resulting in an indirect effect on the CNS Blocking Headaches with Botox