TIC DOULOUREUX AND BILL SWEET, TOO.

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TIC DOULOUREUXANDBILL SWEET, TOO.
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WITH THANKS TO

• John C. Liebeskind History of Pain Collection
  at Louise M. Darling Biomedical Library, UCLA
• Robert G. Ojemann
• Washington State Historical Society
• Many physicians

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WILLIAM HERBERT SWEET

• Born January 13, 1910 in Kerriston, WA
• Lived in Rochester, MN 1917-1920
• Seattle, WA 1920-1924 Graduated from Broadway
  High School at age 14
• Played piano for a year, worked in a saw mill for
  a year, entered University of Washington

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KERRISTON
Kerriston, WA c.1910
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KERRISTON
Kerriston, WA c.1910
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BROADWAY HIGH SCHOOL
Broadway High School c. 1924
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WILLAIM HERBERT SWEET

• B.S. University of Washington 1930, summa cum
  laude, first in class of 1000
• Rhodes Scholar 1932-34
• B.Sc. Oxford University 1934
• A.T. Cabot Fellow, Harvard Medical School
  1935-36
• M.D. Harvard University 1936, cum laude

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UW
Denny Hall
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WILLIAM HERBERT SWEET

• Neurosurgical House Officer, MGH 1936
• General Surgical House Officer 1936-37
• Neurological Resident Billings Hospital, Chicago
  1937-38
• Neurosurgical Resident Billings Hospital,
  Chicago 1938-39

(Bucy, Bailey, and Walker)
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WILLIAM HERBERT SWEET

• Neurosurgical Service, Radcliffe Infirmary,
  Oxford, and Rhodes Research Fellow National
  Hospital for Nervous Diseases 1939
• Instructor in Neurosurgery, Billings Hospital
  Chicago 1939-40
• Commonwealth Fund Fellow 1940-41
• Assistant in Neurosurgery, MGH 1940-41

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WILLIAM HERBERT SWEET

• Acting Chief, Neurosurgical Service, Birmingham
  United Hospital, U.K. 1941-45
• Assistant in Neurosurgery, MGH 1945-47
• Instructor in Surgery, Harvard Medical School
  1946-47
• Chief, Neurosurgical Service, MGH 1961-77
• Professor of Surgery, Harvard Medical School,
  1965-1976

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Barringer title
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Birmingham
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WILLIAM HERBERT SWEET

• Emeritus Professor of Surgery, Harvard Medical
  School 1976-2001
• D.H.C. Universite Scientifique et Medicale de
  Grenoble 1979
• F.R.C.S.Ed. (Hon) 1986
• D.Sc. Ohio State University 1993

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Rogue River Neurosurgical Society
SWEET
RANEY
RAY
RAFF
MACK
Courtesy of Dr. William Buchheit
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WILLIAM HERBERT SWEET

• King George VI Medal for Service in the Cause of
  Freedom 1945
• Emperor of Japans Order of the Rising Sun 1983
• Diplomate ABPN 1946
• Diplomate ABNS 1946
• Phi Beta Kappa, Sigma Xi, Alpha Omega Alpha

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WILLIAM HERBERT SWEET

• Honored Guest of the Congress of Neurological
  Surgeons
• Cushing Medal of the American Association of
  Neurological Surgeons
• Distinguished Service Award of the Society of
  Neurological Surgeons

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CLINICAL INTERESTS

• Boron Neutron Capture Theory
• Treatment of Syndromes of Facial Pain
• Treatment of Persistent Pain in General
• Diagnosis and Treatment of Craniopharyngiomas
• Diagnosis and Treatment of Optic Gliomas

MGH Website
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Pain by White and Sweet
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THE FOUR CS OF GYBELS

• Competence
• Creativity
• Confidence
• Courage

All unostentatiously personified.
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An inspiring role model, he was the most
articulate educator with whom I ever had the
privilege of working.

• Gerald M. Aronoff

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Neurosurgery for him was a form of applied
neuroscience rather than a branch of surgery. No
other neurosurgeon has contributed so much to the
advancement of our specialtyit was a privilege
to have known him so well.
B. Meyerson
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Some people look like scholars but are not, some
are scholars but fall short in their
presentation Sweet was a scholar, sounded like a
scholar and was a scholar in the classic sense.
He was an unforgettable person. I knew him only
in his later years, but memories of him will be
an inspiration for anyone looking into the abyss
of aging.
J. Campbell
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Hi, my name is William Sweet as in Sweet
William. gentle, kindly and very supportive.
In his leadership of APS he was professional,
rational, and, well, sweet.
D. Chen
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He was a stalwart of the scholarly approach.
Everything about the pain business interested
him. He was known for a phenomenal memory.
K. Burchiel
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WILLIAM H. SWEET
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TIC DOULOUREUX
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SWEET ON TIC DOULOUREUX
White and Sweet 1969
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CHARACTERISTICS OF TIC DOULOUREUX

• Intermittent, with pain-free intervals
• Abrupt on and off
• Lancinating, shock-like, stereotyped
• Unilateral, trigeminal, rarely VII or IX
• Minimal, if any sensory loss
• Triggered by ipsilateral non-noxious stimulation

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TRIGGERING

• Response latency suggests large, myelinated
  afferents are involved.
• Often manifests refractory period if
  repetitively activated.
• Triggering site may be in a different
  division from pain site.

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Anticonvulsants are the only class of medications
that control the pain of tic douloureux.
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MEDICATIONS
Generic drug Pill Size Dosing Range

• Phenytoin 100mg 300-600mg
• Carbamazepine 100, 200mg 600-1800mg
• Oxcarbamzepine 150, 300mg 800-1200mg
• Baclofen 5, 10, 20mg 20-100mg
• Gabapentin 100-800mg 900-4800mg

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SURGICAL TREATMENTS

• Neurectomy
• Gangliolysis
• Stereotaxic Radiosurgery
• SOC with MVD
• Trigeminal Rhizotomy
• Trigeminal Tractotomy

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GAMMA KNIFE TARGETTING
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PAIN RELIEF SURGERY FOR TIC
SOC MVD
GANGLIOLYSIS
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Tronnier results
MVD
Tronnier et al. 2001
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This study, and many others demonstrate that MVD
does not eliminate the pain of tic douloureux by
damaging the nerve.
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TIC DOULOUREUXANATOMIC FINDINGS

• Demyelinization of trigeminal root and
  nerve
• Compression of trigeminal root
• Neoplasm of trigeminal nerve or root

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MS Plaques
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TIC DOULOUREUXPATHOPHYSIOLOGY

• Circus excitation in nerve and root
• Ectopic impulse generation
• Ephaptic connections in nerve
• Epileptiform disorder in trigeminal nucleus

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CIRCUS EXCITATION

• Impedance mis-match at branch points or regions
  of demyelination can result in reflected
  depolarization of the rapidly recovering segment.
• Could also occur if membrane channels were
  expressed that had different time constants.

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Tigeminal anatomy White and Sweet
White and Sweet 1969
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ECTOPIC IMPULSE GENERATION

• Known to occur in damaged axons.
• Can originate in neuroma.
• Can occur in skin and ganglia adjacent to
  axon injury
• Can originate in dorsal root ganglion cells,
  perhaps in Gasserian Ganglion as well.

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Ectopic impulse sitesKoltzenburg
Koltzenburg and Scadding 2001
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EPHAPTIC CONNECTIONS

• Found in ventral roots of dystrophic rats.
• Never shown in a sensory system of any
  species.
• Since trigeminal nerve is somatotopically
  organized, should produce pain adjacent to
  triggering area, but this is often not the case.

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EPILEPTIFORM FOCUS IN TRIGEMINAL NUCLEUS

• Epileptiform agents injected into trigeminal
  nucleus or dorsal horn of experimental
  animals produce a severe, constant pain
  state.
• Such pain is not obviously triggered, but it
• is eliminated by local anesthetic in
  peripheral nerves.

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DISCOVERING MECHANISMS THE PROBLEM

• There is no animal model that has the
  characteristics of tic douloureux.

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Why is this type of pain syndrome seen only in
cranial nerves? Tabes dorsalis does produce a
similar lancinating pain in spinal segments.
Spinal nerve root compression certainly does not.
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CRITICAL QUESTION

• Is triggering a form of mechanical allodynia?

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ALLODYNIA IN NEUROPATHIC PAIN

• Thought to indicate altered dorsal horn function.
• Covers a wide area in a dermatome or nerve
  territory.
• Reported as burning.
• May exhibit windup.
• Alleviated by blocking involved nerve.
• Not associated with a radicular mechanical lesion.

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TRIGGERING IN TIC DOULOUREUX

• Not a diffuse dermatomal pattern.
• Pain is not where stimulus is applied.
• Often manifests refractory period, not wind-up.
• Pain reported as lancinating, not burning.
• Is associated with possible axonal injury.

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MOLECULAR GENETICS
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Genetic factors can be shown to play a
significant role in the response to nerve injury
in experimental animals. Thus far, no genetic
factors have been discovered in humans that are
important in tic douloureux.
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Genetic factors may also be the determinants of
drug efficacy and side effects in addition to
their influence on susceptibility to the disease.
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Is the variability in response to drug due to
genetic differences of drug metabolism in those
with tic, or, alternatively, are there different
mechanisms in patients with a very similar
clinical presentation?
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GROWTH FACTORS
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Axon damage may influence transport of growth
factors to trigeminal nucleus, thereby changing
phenotype of sensory neurons.
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DEVELOPMENT AND PLASTICITY
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CYTOKINES

• Proinflammatory cytokines (IL-1B, TNF) are
  liberated at sites of nerve injury.
• Cytokines induce or increase pain behaviors
  that are associated with nerve injury.
• Relevance to tic is unknown.

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Sprouting as a cause of neuropathic pain
Woolf 99
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PLASTICITY

• The processes that initiate neuropathic pain may
  be different from those that maintain it.
  Reduction of afferent input may change descending
  facilitation and lead to chronic pain. Other
  forms of CNS reorganization may also occur.

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Trigeminal tractotomy will stop the pain of tic
douloureux therefore, the outflow of the
trigeminal system to thalamus and higher regions
behaves as predicted and is like other pain
syndromes.
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RECEPTORS
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Absence of response to opioids suggests no role
of c-fiber input onto lamina II neurons in the
genesis of tic pain mu receptors have no
influence on this pain syndrome. This supports
the concept of dorsal horn plasticity.
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CHANNELS
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Responsiveness to anticonvulsants suggests that
changes in sodium channels play a role in tic
douloureux. Stereotypy of pain implies damage to
sub-set of axons in trigeminal system.
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Up-regulation of a specific subset (Nav1.3/type
III) of Na channels secondary to axonal injury
may explain abnormal firing patterns generated in
mid-axon in response to an afferent volley.
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Are there membrane channels in cranial sensory
nerves that are not found in other nerves
elsewhere in the body?
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Moving an artery away from the trigeminal root or
damaging the trigeminal nerve from its peripheral
branches to the pons will stop the pain of tic
douloureux.

• Do they share a mechanism? Is it the same reason
  why anticonvulsants are often effective?

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Physiological studies of the trigeminal nerve in
humans are difficult.

• The mechanisms of tic douloureux will be
  discovered only through animal experimentation.

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TIC DOULOUREUX

• An adequate standard of care does not include
  unrelieved tic pain. When medicines fail, surgery
  should be promptly recommended.

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TIC DOULOUREUX

• THE MOST READILY CURED CHRONIC PAIN SYNDROME

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BERTRAND RUSSELL VISITED THE DENTIST WITHA
TOOTHACHE

• Where does it hurt? the dentist asked.
• In my mind, thephilosopher replied. Does
  anybody believe that a tooth is capable of
  hurting?

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