Management of Facial Palsy following Head and Neck Cancer Therapy

Transcript

• 00:00Hi, good morning, everyone.
• 00:02Thank you and welcome to Yale
• 00:05Cancer Center Grand Rounds.
• 00:07My name is Sarah Omar.
• 00:08I'm the Chief of Head
• 00:09Neck Surgery at at Yale.
• 00:10And it's my distinct pleasure to
• 00:13introduce our speaker for today,
• 00:16one of my colleagues in ENT head
• 00:18neck surgery, Doctor Suresh Mohan.
• 00:21So Doctor Mohan is assistant professor in
• 00:24surgery in otolaryngology here at Yale.
• 00:27He earned his medical degree
• 00:29from Brown University.
• 00:30He did a one year research fellowship
• 00:32at the NIH and then he actually did
• 00:35A7 year research track residency
• 00:37at the Massachusetts Eye and Ear
• 00:39Infirmary and Harvard Medical School.
• 00:41Normally ENT is a five year residency
• 00:44program and so he did an extra 2 years
• 00:47dedicated to research while in training.
• 00:51Then not only that,
• 00:52he went on to do a fellowship in
• 00:54facial plastics and micro vascular
• 00:57reconstructive surgery at UCSF,
• 01:00a very renowned program in
• 01:02this field here at Yale.
• 01:04Dr.
• 01:05Mohan's clinical expertise is
• 01:06focused on a lot and everything
• 01:09to do with facial reanimation.
• 01:12For patients with facial paralysis,
• 01:14that includes dynamic and static reanimation.
• 01:17He also is a force in microvascular
• 01:20reconstruction for patients with head
• 01:23and neck cancer as part of our team.
• 01:25And he's also expert in MO's reconstruction
• 01:28for patients with skin cancers.
• 01:30He also another part of his practice has to
• 01:33do with functional aesthetic rhinoplasty,
• 01:35facial trauma,
• 01:36gender affirmation surgery,
• 01:38and the cosmetic treatment of the aging face.
• 01:41In terms of research,
• 01:42which she's going to talk to
• 01:44us a lot about today,
• 01:45it's all related to clinical
• 01:47outcomes in facial policy and nerve
• 01:50repair through the understanding
• 01:52of molecular foundations of
• 01:54peripheral nerve regenerations.
• 01:56He has won numerous awards for his
• 01:58research and teaching and has over 30
• 02:01peer reviewed publications to date.
• 02:03And he just joined the faculty
• 02:04less than a year ago.
• 02:07It's rare that we bring in a
• 02:09new recruit to the Yale Cancer
• 02:10Center and Department of Surgery,
• 02:12where we're actually bringing something new.
• 02:15And that's what Doctor Mohan's
• 02:18recruitment was all about.
• 02:19He is bringing advanced facial nerve,
• 02:23facial paralysis reconstruction,
• 02:25functional rehabilitation
• 02:27to patients here at Yale.
• 02:29And it's, it's he's
• 02:31just getting started, but he's
• 02:32already very busy and we're very,
• 02:34very happy to have him here.
• 02:35And he's going to tell
• 02:36us all about the management of facial policy
• 02:38and head neck cancer therapy. Doctor Mohan,
• 02:45good morning. Thanks so much,
• 02:47Cyril, for the kind words.
• 02:48It's truly an honor and privilege
• 02:50to be invited to speak here.
• 02:52So thank you all for being here.
• 02:54I wanted to start into with
• 02:56talking a little bit how I got
• 02:59interested in facial palsy.
• 03:00I had the privilege of training
• 03:02with Tessa Hadlock at Mass Sioneer,
• 03:05who's one of The Pioneers and
• 03:08I would say gurus of facial
• 03:11nerve reanimation in the world.
• 03:13And I fell in love with this patient
• 03:16population because not only is it a
• 03:18condition that affects form and function,
• 03:20but truly psychosocial well-being overall.
• 03:24And especially in the context of
• 03:26dealing with a cancer diagnosis,
• 03:28having this life changing sequelae
• 03:31of treatment,
• 03:32I think really affected patients
• 03:33in a deep way.
• 03:34And being able to help with that seemed
• 03:37like a really special opportunity.
• 03:41So I wanted to start with what I hope to
• 03:46leave you with at the end of this hour.
• 03:48Facial palsy is not just a
• 03:51physical visible appearance change.
• 03:53It's a functional problem.
• 03:54It's a psychological problem
• 03:56for these patients.
• 03:58For the longest time,
• 03:59patients have been told there's
• 04:01nothing to do, I'm sorry,
• 04:02go to Boston or go to New York and no
• 04:05longer is that true in Connecticut?
• 04:06And I've heard many patients
• 04:07say that and over and over.
• 04:09And it's, it's a privilege to be able to,
• 04:11to bring this care here.
• 04:14And finally,
• 04:16facial reanimation surgery
• 04:18re establishes smile blink,
• 04:20symmetry of the face and self-confidence
• 04:24psychologically for patients.
• 04:26So all the sequela have head and
• 04:28neck cancer and its treatment.
• 04:30I would say facial palsy is one
• 04:31of the most devastating because
• 04:32of its broad reaching effects.
• 04:36I could describe to you in words or I
• 04:39could show you what facial palsy does
• 04:41to the cancer patient. This is Carol.
• 04:45She was diagnosed with a aggressive
• 04:48DLBCL of the neck that invaded the skull
• 04:51base and left her with facial palsy.
• 04:53You can see she can't raise her eyebrows,
• 04:55she can't close her eye,
• 04:56she can't breathe through her left nostril,
• 04:58she can't smile, she can't speak
• 05:00and she can't eat without drooling.
• 05:04The facial nerves has such broad
• 05:06functions in terms of expression,
• 05:08corneal protection,
• 05:09hair cell protection in the ear,
• 05:11breathing through the nose,
• 05:13chewing and speaking,
• 05:14and it's injury leaves patients with
• 05:17functional psychosocial impacts.
• 05:23This picture is special to me
• 05:24because I think in this expression
• 05:27Carol really depicts what this
• 05:29patient population goes through.
• 05:31Not only is she suffering from a cancer
• 05:33diagnosis, but the stigma of having
• 05:36facial palsy and trying to face the
• 05:39world with with this altered condition.
• 05:42So let's take a step back and talk
• 05:44about the facial nerve anatomy.
• 05:46Cortical projections from the motor cortex
• 05:48synapse on the facial nucleus in the ponds,
• 05:51and the facial nerve loops around
• 05:53the abducense nucleus and exits
• 05:55at the pontomedullary junction,
• 05:57enters the internal acoustic mediatus,
• 05:59traverses the temporal bone and exits
• 06:01the skull base at the Stalin masted
• 06:04foramen where it divides into several
• 06:07branches of muscles that supply
• 06:09different branches and nerves that
• 06:11supply different muscles of the face.
• 06:13Not only does it provide motor
• 06:16movement to these muscles,
• 06:18there are also branches to the greater.
• 06:21The greater superficial petrosal nerve
• 06:24provides preganglionic parasympathetic
• 06:26innervation to the lacrimal glands,
• 06:29and also then stupedius nerve provides
• 06:31protection of hair cells in the middle ear.
• 06:37When we look deeper at the
• 06:38facial nucleus in the brain stem,
• 06:40it's divided into several subnuclei.
• 06:42Each of these nuclei are correlated
• 06:45with a specific function,
• 06:48so the medial submuculus, for example,
• 06:50correlates to the auricular muscles,
• 06:51so on and so forth.
• 06:53And even along the course of the nerve,
• 06:55there's variable topography,
• 06:56and so different axons are found
• 06:59at different places in the nerve
• 07:01as it travels into the face.
• 07:03This has significant implications
• 07:06for what happens after injury to
• 07:08the nerve and how important the
• 07:11location of the nerve injury is.
• 07:13What causes facial palsy?
• 07:15There are many causes.
• 07:17Probably the most common that
• 07:19you've heard of is Bell's palsy.
• 07:20I will say,
• 07:21I'll take this moment to emphasize
• 07:23the importance of distinguishing
• 07:25between Bell's palsy and facial palsy.
• 07:29Facial palsy is the final diagnosis.
• 07:31Bell's palsy is a type of facial palsy.
• 07:33I think very commonly we hear
• 07:35people use them interchangeably.
• 07:36In fact,
• 07:37they're very different because the
• 07:39etiology determines the treatment.
• 07:42Of course,
• 07:42today we will focus on facial
• 07:44palsy associated with benign or
• 07:46malignant tumors and their treatment.
• 07:50What happens after the
• 07:51facial nerve is injured?
• 07:53The face is in normal condition,
• 07:55it suffers an insult which results
• 07:57in valerian degeneration of the
• 07:59nerve and the face goes flaccid.
• 08:03If the nerve remains intact,
• 08:05eventually regenerating axons traverse
• 08:07the nerve and the face recovers.
• 08:1130% of patients will go on to
• 08:13develop aberrant regeneration or
• 08:15overzealous regeneration that
• 08:16results in post paralytic facial
• 08:19palsy or what we call synkinesis.
• 08:21If the nerve was cut or if there's
• 08:23an ongoing insult such as a tumor,
• 08:25then the state of the face
• 08:27remains in the flaccid state.
• 08:31On the left you see one of our
• 08:34patients with flaccid facial palsy
• 08:36for several years nearly 20 and
• 08:38a patient on the right with post
• 08:40paralytic or synkinetic facial palsy.
• 08:41You can see these are very different
• 08:43conditions, both categorized as facial palsy.
• 08:47In the cancer patient,
• 08:48the flaccid state is much more common cause.
• 08:50Typically the tumor or the treatment
• 08:53for the tumor results in transection
• 08:56or complete destruction of the nerve.
• 08:58We define synkinesis here as
• 09:00abnormal involuntary movements
• 09:01associated with a voluntary movement.
• 09:04And this begins usually six
• 09:05months after an insult.
• 09:09Muscle has a lifespan, denervated
• 09:11muscle has a much shorter lifespan.
• 09:15And so when you injure the nerve to a muscle,
• 09:18you get 18 to 24 months to
• 09:20reinnervate that muscle before the
• 09:22muscle is no longer receptive,
• 09:24the neuromuscular junctions fade away
• 09:26and there's no ability to reinnervate.
• 09:29So when we have a a facial nerve injury,
• 09:32the sooner reconstruction happens
• 09:33the better the long term outcome.
• 09:39The way we think about the face is
• 09:42by dividing it into sub sub areas
• 09:44and each zone of the face has a
• 09:46specific treatment associated with
• 09:47it for both the flaccid state here,
• 09:50I know this is a busy slide,
• 09:51but we'll walk through it in detail
• 09:53for the flaccid state as well As for
• 09:56the paralytic post paralytic state.
• 10:02What are the most common head and neck
• 10:04neoplasms associated with facial palsy?
• 10:05From a benign perspective,
• 10:07we have vestibular swanomas, facial swanomas,
• 10:09geniculate hemangiomas and of course
• 10:11from a malignancy perspective,
• 10:13high grade parotid tumors
• 10:14such as mucadermoid, adenoid,
• 10:16cystic or aggressive cutaneous glamosyl
• 10:19carcinomas are the most common.
• 10:21And as we know,
• 10:22the most common treatment for
• 10:24parotid tumors is surgical resection,
• 10:26and therefore the most common 'cause a
• 10:30facial palsy of with treatment of parotid
• 10:34tumors is requires surgical repair.
• 10:37So what is our algorithm?
• 10:38How do we repair the facial nerve after
• 10:41resection of a parotid malignancy?
• 10:45If the parotid tumor can be removed,
• 10:47for example with benign tumors
• 10:48with no damage to the nerve,
• 10:49then of course no treatment is necessary.
• 10:52Sometimes there can be temporary neuropraxia
• 10:54of the nerve from from dissection and
• 10:57that will typically recover as long
• 10:59as there's not a a deep nerve injury.
• 11:03If the nerve is transected in the
• 11:05process of removing the tumor,
• 11:07then we have multiple options for treatment.
• 11:11Depending on which branches transected.
• 11:15Periocular work may be done,
• 11:17may be necessary for corneal protection.
• 11:19A primary repair of the nerve
• 11:20can be performed,
• 11:21or an interposition graft can be can be
• 11:25inserted if more distal branches need
• 11:27to be resected but the proximal stump
• 11:30of the facial nerve is still preserved.
• 11:33In that case,
• 11:34a static suspension is typically
• 11:37performed based on the age of the patient.
• 11:40Older patients need more support in the face.
• 11:44A nerve transfer can be performed
• 11:46if there's insufficient donor
• 11:49axons from the native nerve.
• 11:51And finally interposition grafts again,
• 11:54if if, if there is a distal stump to sew too.
• 11:57In the most radical of resections of of
• 12:01parotid tumors where the lateral temporal
• 12:04bone must be resected into the middle ear,
• 12:07the proximal stump may be absent.
• 12:09And in those cases we depend completely
• 12:11on nerve transfer procedures to
• 12:13reanimate the face and sometimes
• 12:15requiring free muscle.
• 12:16So
• 12:19I'm going to walk through
• 12:20each of these strategies and,
• 12:21and some of the surgical details
• 12:24and then I will go into some of my
• 12:26research at the at the end of the talk.
• 12:30So we'll begin with eye care,
• 12:31protecting the eye,
• 12:33the cornea is the single most biggest
• 12:36priority in in treating facial palsy.
• 12:38And so when we do these
• 12:41radical parotid resections,
• 12:42staging the periocular work is
• 12:45helpful because we don't necessarily
• 12:47know the amount of of tightening
• 12:50of the upper eyelid or the lower
• 12:51eyelid that needs to be done.
• 12:52And so I'd like to stage this
• 12:54work until one to two weeks after
• 12:56the initial ablation so that the
• 12:58correct lid weight can be placed or
• 13:00the correct amount of tightening
• 13:01of the lower lid can be done.
• 13:03From a static perspective perspective,
• 13:05we can we teach patients to do
• 13:09lid stretching and eye patches.
• 13:10So this is the the lowest option
• 13:14on the totem pole.
• 13:15When patients develop paralytic lag of
• 13:18thalamus from injury to the facial nerve,
• 13:20they can't close their eye usually
• 13:22because the upper eyelid is unable to
• 13:24come down low enough to cover the cornea.
• 13:26By stretching the upper eyelid
• 13:28on a consistent basis,
• 13:311 to 2mm of improvement can be
• 13:35obtained and moisture chambers are
• 13:36used to keep the cornea moist.
• 13:41Next step up from this is performing
• 13:43a lateral tarsoraphy and so this
• 13:45is basically a procedure to close
• 13:48the lateral aspect of the eye and
• 13:50this helps with corneal protection.
• 13:52The downside to this is it's very temporary,
• 13:55doesn't last very long and and
• 13:58patients can have irritation
• 13:59from the suture being there.
• 14:01There's also decreased palpable
• 14:03fissure with and so vision can be
• 14:06occluded and also the cosmetic
• 14:08appearance of half your eye being
• 14:10closed is is problematic for patients.
• 14:15The next option we have to close the
• 14:17eye is by adding weight to the upper
• 14:19lid so that it descends further.
• 14:21The way we do this is by using a
• 14:23test weight before the surgery to
• 14:26determine the exact amount of weight.
• 14:28It's usually around 1.2 to 1.4g and
• 14:31we used to do this with gold weights.
• 14:34You may have heard of that,
• 14:36but the problem with gold is
• 14:37that it's very reactive,
• 14:39can trigger inflammatory reactions.
• 14:42Also, it has a high density.
• 14:44And so nowadays we use platinum
• 14:46because it's lower density.
• 14:48So you can produce a thinner profile
• 14:50weight that's less likely to extrude
• 14:52and achieves the same effect.
• 14:54And this comes in both a chain or
• 14:57format or just a regular profile.
• 15:00And so here you create a pretarsal
• 15:02or supertarsal pocket,
• 15:03insert the weight and secure it.
• 15:07What about for the lower eyelid?
• 15:09The other way we can tighten the
• 15:10lower eyelid of something called
• 15:12a lateral tarsal strip.
• 15:13So here there's a lateral canthotomy being
• 15:16performed with an inferior cantholysis.
• 15:18And so the inferior tarsus is
• 15:21released away from the canthus
• 15:23and the edges are stripped,
• 15:25as the procedure name indicates.
• 15:29And then this is sutured to the Whitnalls
• 15:33tubercle or the prominence on the medial
• 15:36aspect of the lateral orbital wall.
• 15:38And by doing this,
• 15:39we're able to tighten the lid.
• 15:40And you can see here a patient
• 15:42who's had the procedure,
• 15:43he had Atropian before and
• 15:45able to achieve much better eye
• 15:48closure with with the tightening.
• 15:50And in some cases,
• 15:52the lateral tarsal strip is insufficient
• 15:54because they have medial lag athalmos
• 15:55in addition to the lag lateral portion.
• 15:58So in those cases,
• 15:59we'll take,
• 16:00we'll perform what's called
• 16:01a lower lid tarsal sling.
• 16:02And so you can take fascia
• 16:04from the leg and thread it,
• 16:05think of it as a belt for the lower lid.
• 16:08And so you secure it to the
• 16:11lacrimal bone medially.
• 16:12Here you can see it's being tacked
• 16:14to the bone medially and brought
• 16:17through between the anterior posterior
• 16:19Lomella across to the orbital
• 16:21rim laterally and secured there.
• 16:22And this improves the medial lag of thalamus.
• 16:28Everything we've talked
• 16:29about so far is static.
• 16:30Is there a way for the upper eyelid
• 16:33to blink again? Indeed there is.
• 16:35So dynamic blink reanimation has been
• 16:38growing in popularity in the last few
• 16:40years due to some novel techniques.
• 16:43So here what's done is a
• 16:44cross faced nerve graft.
• 16:46So a nerve graft is harvested from the leg,
• 16:47it's A and you find a suitable
• 16:50eye closure branch on the
• 16:52other side that has redundancy.
• 16:53You connect it to that nerve
• 16:55and then you tunnel across the
• 16:58forehead and bring it into the
• 17:00upper eyelid on the other side.
• 17:02In the second stage of the surgery,
• 17:03six months later,
• 17:04you come in with a free muscle graft and
• 17:07allow the nerves to grow into the muscle.
• 17:09And as this happens,
• 17:10the eye is able to blink once again.
• 17:14So this is a patient that came to me
• 17:16with flaccid facial palsy after a
• 17:18cerebellar hemangioblastoma resection.
• 17:20And so I performed the first stage.
• 17:23Here you can see the nerve is brought
• 17:25through into the upper eyelid.
• 17:26And she also had a a graft for
• 17:28a future smile or animation and
• 17:30the fascicles are splayed here.
• 17:32And so though in the second,
• 17:33her second stage is coming up
• 17:34in in six months.
• 17:39Free muscle transfer for blank re
• 17:40animation has also been described.
• 17:42A cross faced nerve graft can be placed
• 17:45and a free platysma flap can be taken
• 17:47and muscle strips placed in the upper and
• 17:50lower eyelids to reestablish blank as well.
• 17:52The problem with this technique is it's,
• 17:54it's very laborious and and the outcomes are
• 17:58not nearly as good as the dynamic blink.
• 18:00We just, we just saw, OK,
• 18:03so we talked about the eye.
• 18:05What about the nerves that have been
• 18:07cut after the tumor was resected?
• 18:10So we can repair those nerves with
• 18:12either either primarily if they're
• 18:13close enough together or with a graft if
• 18:16there's too much space in between them.
• 18:19One of the fundamental tenets of nerve
• 18:22repair is attention free coaptation.
• 18:25This was a case from residency where
• 18:29a parotid cancer was resected and
• 18:33the superior division of the facial
• 18:35nerve was transected and the surgeon
• 18:37brought them together,
• 18:38brought the ends together and and sewed
• 18:40them as you can see in the top right.
• 18:43Unfortunately,
• 18:43it was under significant tension and
• 18:46it was eye opening to me because we
• 18:48actually took the patient,
• 18:49even though the nerve was repaired,
• 18:50we took the patient back to put in an
• 18:53interposition graft because of the tension.
• 18:55And so I looked more into why,
• 18:58why, you know,
• 18:59where did this tension concept come from?
• 19:02So it began very early canine
• 19:04studies in the 40s.
• 19:05This was a study where they used
• 19:09primary repair or interposition
• 19:10grafting and then they used
• 19:12inter arterial lead injection.
• 19:14So you can see on the right side here
• 19:18where they perform a tension high
• 19:21tension repair versus interposition
• 19:23graft and you just have much better
• 19:26vascularization of your distal
• 19:28segment inferiorly here with using
• 19:31the interposition graft.
• 19:32So this is kind of where the concept
• 19:35of avoiding tension in nerve repair
• 19:37began and and why it's so important
• 19:40in in in the face as well.
• 19:43There have since been other strategies
• 19:45I've been developed using nerve
• 19:47wraps or other ways to mechanically
• 19:50distribute the tension.
• 19:51As you can see,
• 19:52these wraps can be sutured at other
• 19:54parts of the nerve to minimize
• 19:56tension at the actual interface.
• 19:58Nerve lengthening procedures.
• 20:00While this sounds counterintuitive
• 20:02because we know neuropraxia is is
• 20:04damaging to nerves when stretching
• 20:06of the nerve is.
• 20:08Performed in a slow fashion over 20 minutes,
• 20:12you can actually take advantage
• 20:14of the elasticity of the nerve
• 20:17to to improve tension.
• 20:19And finally,
• 20:19this was a a product that came out
• 20:21recently where there are micro
• 20:23hooks in the in the wrap that can
• 20:25actually hold the nerve together
• 20:26to reduce tension as well.
• 20:30OK, so if we have nerves to repair,
• 20:33we've done that.
• 20:34What about for the facility of the face?
• 20:37So let's move on to the static suspension.
• 20:42So this was a gentleman who came
• 20:44in with a who who needed a radical
• 20:49temporal bone resection and protectomy
• 20:51with facial nerve sacrifice.
• 20:53And so for him we performed a,
• 20:56amongst other things, static suspension here.
• 20:57And so the way we do this is we take
• 20:59fascia from the thigh, the fascia lata,
• 21:01and then we cut it into strips and attach
• 21:04it to different points in the face.
• 21:06Here you can see to the nasal base,
• 21:08to the nasolabial fold and
• 21:10to the oral commissure here.
• 21:12And while it's not a dynamic movement,
• 21:15it does help with resting position.
• 21:18And here he is three weeks after.
• 21:22And functionally this improves drooling,
• 21:24that's probably one of the main things,
• 21:26and also breathing.
• 21:28So the nasal,
• 21:29the nose here collapse and collapses.
• 21:31And so being able to pull that valve
• 21:33laterally improves air flow through the nose,
• 21:35improves drooling and appearance.
• 21:39This is another gentleman who you can
• 21:42see on the left side here had a static
• 21:45suspension along with a direct brow lift.
• 21:48And you can see also how the the brow
• 21:50can really descend and cause dramatic
• 21:53Oasis and and vision occlusion as well.
• 21:55So both of these are improved
• 21:58important techniques.
• 22:01OK, so we've addressed the mid face,
• 22:02what about dynamic movement
• 22:05of the mouth and upper lip?
• 22:07So this is what takes us
• 22:09into our nerve transfers.
• 22:11And so when you don't have the native facial
• 22:13nerve driving the muscles of the face,
• 22:15you need alternate nerve sources.
• 22:17And so that's where nerve transfers come in.
• 22:20So we can use the contralateral facial nerve,
• 22:22which is great because
• 22:25it provides spontaneity.
• 22:26And then we can also use the trigeminal
• 22:28nerve on the same side or the opposite side,
• 22:3012th nerve,
• 22:31the ANSA or even the the
• 22:34spinal accessory nerve.
• 22:35So the crossface nerve graft,
• 22:37the way this works is so on.
• 22:38In this scenario,
• 22:39the patient has weakness on
• 22:41the left side of her face.
• 22:42And So what we do is we harvest
• 22:44a nerve graft again and open the
• 22:46face and find a branch that's
• 22:49redundant and connect it to here.
• 22:50So when the graft is connected and
• 22:52brought across the other side of the face,
• 22:55whatever this is connected to
• 22:56will have the same function.
• 22:58So it'll mirror the function
• 23:00of the healthy side.
• 23:01And so this is a very powerful
• 23:03technique that we, we,
• 23:05we will revisit here shortly.
• 23:07This can be done for the smile or,
• 23:09or the eye as we talked about earlier.
• 23:12The next is the mesoteric nerve.
• 23:14The mesoteric nerve is the branch that
• 23:17that control of V3 that controls the
• 23:20masculatory function of the master muscle.
• 23:22And you can see here that the
• 23:25nerve is basically because there's
• 23:27redundancy of the muscle.
• 23:28The patients don't have any
• 23:30donor site morbidity in terms
• 23:32of not being able to chew.
• 23:34The nerve is then connected to a
• 23:37distal branch of the facial nerve.
• 23:38And so when they bite down,
• 23:40instead of chewing, they can smile.
• 23:43What does that look like?
• 23:50And relax. And now give me a
• 23:53gentle smile, biting down.
• 23:56And relax, give me a big smile biting down
• 24:02and relax. So you can see here
• 24:06when the patient, one second
• 24:14the patient bites down,
• 24:15he's able to smile.
• 24:17And so the the reason is because the
• 24:21mesoteric nerve has excellent exonal load,
• 24:25nearly 1500 axons in the mesoteric nerve
• 24:28compared to the facial buccal branch,
• 24:30which only has about 800.
• 24:32And by the time we connect that
• 24:33branch to a cross faced nerve graft,
• 24:34there's only about 200 axons or 100
• 24:36axons that make it across the face.
• 24:43So this is him. He had a salivary
• 24:46ductal carcinoma and had a radical
• 24:47pyridectomy that left him with this
• 24:49appearance in the left side of the face.
• 24:51And again with the five seven transfer,
• 24:53he's able to re establish smile.
• 24:57This was a young child
• 24:59with an AV malformation.
• 25:02You can see she has weakness on the right
• 25:04side. After the five seven transfer,
• 25:11she bites down with teeth
• 25:17and she bites down close smile.
• 25:24So very powerful technique.
• 25:26Downside is it's voluntary,
• 25:28it's not spontaneous.
• 25:29You have to remember to bite
• 25:31down to be able to smile.
• 25:32And so an important part of it
• 25:34is the physical therapy that
• 25:36goes along with this in terms
• 25:38of making sure patients remember
• 25:39to use it and to bite down when
• 25:42they when they want to smile.
• 25:44Another example of a patient,
• 25:48OK, what are other nerves?
• 25:49So the hypoglossal nerve,
• 25:50the 12th nerve, is also a donor source.
• 25:53It can be used when the main trunk of
• 25:57the facial nerve has been transected
• 25:59and it's mostly useful for tone,
• 26:02but sometimes for movement.
• 26:04Of course, the risks are tongue weakness,
• 26:06dysarthria, dysphasia.
• 26:09Here was a patient who had a facial
• 26:11spinoma that was resected and outside
• 26:14hospital the facial nerve of course,
• 26:16was injured and there was no proximal stump.
• 26:18I need it to be identified and therefore
• 26:21the 12th nerve was transferred.
• 26:22And so you can see here for her,
• 26:25she has to move her tongue against the
• 26:27side of her mouth to be able to smile.
• 26:33This is her at rest
• 26:37and that's her pushing her
• 26:38tongue against her cheek.
• 26:44Again, voluntary is the downside.
• 26:48So this was a group from Spain who published.
• 26:52So the technique here is actually
• 26:53a side to end. So we don't take
• 26:55the entire hypoglossal nerve.
• 26:56So you maintain function of the nerve by
• 26:59only taking 1/3 of the axons and you're
• 27:02borrowing basically a portion of it.
• 27:04And with the endoside technique,
• 27:07So like we talked about for
• 27:09these voluntary nerve transfers,
• 27:10it's really important that,
• 27:11that we have facial rehabilitation
• 27:13that goes along with it.
• 27:14If they are not taught to use it,
• 27:16it's like anything else, they,
• 27:18it's, it's not functional and
• 27:19not useful to the patient if
• 27:21they're not trained to use it.
• 27:22So we have, we take facial
• 27:24rehabilitation very seriously.
• 27:25We have a strong partnership with
• 27:27here with our physical therapy
• 27:29department and we recently had
• 27:31a visiting lectureship as well.
• 27:32And, and so focusing on,
• 27:34on neuromuscular retraining of,
• 27:36of the muscles is, is a,
• 27:38is a important part of this.
• 27:41You can see here
• 27:44smile out by relaxing the tension in your eye
• 27:48and in your cheek and in your neck muscles.
• 27:51So form a small smile and at the same time
• 27:55you smile, you're gonna relax the tension
• 27:59around your eye and into your cheek,
• 28:03focusing on the cheek muscles
• 28:05forming the smile motion.
• 28:07I think of it like your cheek
• 28:09balls trying to form.
• 28:11There you go, that motion.
• 28:13Excellent.
• 28:16So you can imagine this takes a
• 28:18very cooperative patient and a
• 28:19very understanding therapist to
• 28:20make this that make this work.
• 28:24OK, so we've talked about
• 28:26static options so far.
• 28:27How about dynamic smile
• 28:29reanimation when there's no,
• 28:31when we're outside of the
• 28:32window for nerve transfers.
• 28:33So nerve transfers only work if the native
• 28:35musculature in the face is still alive.
• 28:37Like we talked about earlier,
• 28:38the native musculature only survives
• 28:40for 18 to 24 months after the injury.
• 28:42So if you're five years out,
• 28:45nerve transfers are not an option for you.
• 28:46So in that case, we need to bring in
• 28:49fresh muscle that can be innervated.
• 28:51And so that's what we do in this scenario.
• 28:53And so here there's multiple
• 28:54options of muscles that can be
• 28:56transferred for dynamic reanimation.
• 28:58The temporalis tendon can be brought
• 29:01down to connect to the oral commissure.
• 29:03Even the masseter muscle has been
• 29:05described to be transferred over.
• 29:06And from a functional muscle
• 29:09free flat perspective,
• 29:11many muscles have been used but the
• 29:14most common remains the gracilis muscle.
• 29:18So how does the temporalis
• 29:19transfer work here?
• 29:20Remember the temporalis muscle assists
• 29:22in in chewing and so when we flip
• 29:26the muscle down when it contracts
• 29:28and can pull on the oral commissure.
• 29:31Another way to do it was is with
• 29:33a orthodontic tendon transfer.
• 29:34In here the coronoid process is actually
• 29:40osteotomized and brought forth to
• 29:42connect to the oral commissure and this
• 29:45is accessed through a nasally beautiful
• 29:47incision or intraorally and this can
• 29:49cause smiling with biting down just
• 29:50like we would expect with the five 7.
• 29:54When we have to brew free muscle transfer,
• 29:56we go to the leg and we harvest a
• 29:59muscle flap with a nerve supply,
• 30:02the interruptory nerve as well as the
• 30:05blood vessels to the to the muscle.
• 30:08And previously they've already
• 30:10had a first stage crossface nerve
• 30:12graft placed for spontaneity.
• 30:14And so when you bring the muscle
• 30:16in and connect the blood vessels
• 30:18and connect the 5th nerve,
• 30:20you can get a nice smile.
• 30:22Again in a patient who's more than
• 30:24two years out from nerve injury.
• 30:31And in children,
• 30:32they have such remarkable nerve
• 30:33regeneration that you don't even
• 30:35need to go to the mesoteric nerve.
• 30:37Just across face nerve graft,
• 30:39despite the lower Axon load is
• 30:40sufficient to produce a smile.
• 30:42You can see here,
• 30:44this is her spontaneously smiling.
• 30:46And of course this is our gold
• 30:48standard outcome to be able to smile,
• 30:50not have to think about
• 30:51it and it just works.
• 30:55There are variations of the gracilis,
• 30:58not just using one nerve,
• 31:00but using both nerves using the mesoteric
• 31:02nerve and the crossface nerve graft,
• 31:04as you can see here, as well as
• 31:06the mesoteric nerve as an insurance
• 31:08policy if the crossface nerve graft.
• 31:10One of the downsides of this procedure
• 31:12is that while the spontaneous
• 31:14smile is our gold standard,
• 31:15the procedure fails nearly
• 31:1730 to 40% of the time.
• 31:19That is an unacceptably high
• 31:21rate in adults at least.
• 31:26There are also variations here where
• 31:28you can do intramuscular dissection
• 31:29and do different vectors of muscle.
• 31:32Of course the the facial,
• 31:33the smile mechanism takes nearly ten
• 31:36different muscles to engage a smile
• 31:39and so only one vector is is only.
• 31:42It's a small piece of the pie in
• 31:45terms of what allows natural smile.
• 31:48And so variations here,
• 31:49putting in a muscle graft to the lower
• 31:52lip can allow lower lip depression,
• 31:54which is normal when we smile.
• 31:59So of course with our cancer patients,
• 32:00what, what about after surgery?
• 32:03What about adjuvant radiation?
• 32:04How does that impact our, our repairs?
• 32:08There's not great data,
• 32:10mostly because facial reanimation still
• 32:13remains fairly uncommon at at the time of,
• 32:16of radical resection,
• 32:17though it's improving.
• 32:19This was a a small study that looked
• 32:22at 3039 patients and they found
• 32:25no significant difference in house
• 32:27Brackman outcomes between patients
• 32:29who had radiation and didn't.
• 32:32So it supports a theory that
• 32:36getting radiation should not
• 32:39preclude upfront nerve repair.
• 32:43Timing of facial nerve repair has
• 32:44also been brought up as an issue,
• 32:46but we know that time is muscle.
• 32:48So it's very clear now that the
• 32:51sooner you repair the nerve,
• 32:52the better outcome.
• 32:54But a recent study looked at almost
• 32:5811,000 cases of of parotidectomy
• 33:00and found that only 24 percent,
• 33:0325% are undergoing reanimation at
• 33:05the time of facial nerve sacrifice.
• 33:08So I think that is an indication of
• 33:11of how much room we have in terms
• 33:13of improving outcomes for patients.
• 33:19So as I mentioned earlier,
• 33:22the failure rate in this procedure
• 33:24is 30 to 40% and many theories
• 33:27have been proposed as to why.
• 33:29But one of the prevailing theories
• 33:31is that as these axons start from the
• 33:34contralarial side and are growing across,
• 33:37Schwann cells in the distal nerve graft
• 33:40lose their ability to support regeneration.
• 33:43And so by the time axons make it across,
• 33:46very few Schwann cells are alive to
• 33:49support and get the Axon into the muscle
• 33:52into the neuromuscular ejection junction.
• 33:54And because of that the failure
• 33:56and the the procedure fails.
• 33:58So this got me interested in thinking
• 34:01about what are these repair swan
• 34:02cells doing at a molecular level?
• 34:04What is the state that gets turned
• 34:07off and how do we keep that state
• 34:10for a longer period of time to
• 34:12maybe allow better regeneration?
• 34:14So when a nerve is cut,
• 34:15the distal nerve undergoes valerian
• 34:17degeneration and the Schwan cells
• 34:20that were myelinating Schwan cells
• 34:22take on a repair repair phenotype.
• 34:24And we know this is a transient state.
• 34:26So the repair swan cells come from either
• 34:29the myelinating differentiated cells
• 34:30or the non myelinating Schwan cells
• 34:33and they become repair Schwan cells.
• 34:35After injury,
• 34:35macrophages are brought in for
• 34:38breaking down the myelin debris.
• 34:40There's an inflammatory response.
• 34:45So this led to the question,
• 34:47can we exploit the repair Schwan
• 34:50cell response to injury to
• 34:52improve regeneration outcomes.
• 34:56So our objectives were first,
• 34:57what cells are in the facial nerve,
• 35:00Can we characterize this repair Schwan
• 35:02cell phenotype at a transcriptional
• 35:04level and can we potentially
• 35:07identify any therapeutic targets?
• 35:09So what do we do?
• 35:11So I used a mirroring facial
• 35:13nerve transection model.
• 35:14So as you see here in Figure 1,
• 35:18the right side of the face
• 35:19of the mouse is shown here.
• 35:21Of course the mouse facial
• 35:23nerves are sub millimeter,
• 35:25but we harvested.
• 35:26So first we opened the face and
• 35:29performed an injury and closed
• 35:31up on one side of the face.
• 35:33Five days later we came back,
• 35:35harvested the nerve from this
• 35:37the the distal nerve from the
• 35:39site of transection to the
• 35:41to the distal buckle branch.
• 35:43And then we harvested contralateral facial
• 35:45nerves that are healthy for controls.
• 35:48We took those nerves,
• 35:49dissociated them down and
• 35:50ran them through the single
• 35:53cell sequencing platform 10X.
• 35:56And then what did we find?
• 35:59So here we're looking at
• 36:00something called a fate plot.
• 36:02Each dot on here represents
• 36:04a cell and as you can see,
• 36:07the difference in each color
• 36:08represents a different cell type.
• 36:09As shown on the right.
• 36:11When you compare between the
• 36:12wild type or healthy condition
• 36:14and the injured condition,
• 36:15there's obviously a new
• 36:16cluster that has shown up.
• 36:18And this correlates with the repair
• 36:19Schwann cells that we'd expect
• 36:24when you do an ontology analysis.
• 36:26They have expected gene functions,
• 36:28isonagenesis guidance,
• 36:29and restructuring of the
• 36:32extracellular matrix as Schwann
• 36:34cells undergo conformational
• 36:36changes to allow for reinnervation.
• 36:39We do Ade analysis and we found
• 36:41several genes that were correlated
• 36:44with the repair phenotype.
• 36:48Some of these upregulated genes were
• 36:52established and some of them were novel.
• 36:57So to understand this better,
• 36:58we used a technique called RNA velocity.
• 37:02I wanted to be able to ideally would
• 37:03look at several different time points,
• 37:05but for anyone who's done
• 37:06single cell or any sequencing,
• 37:08you know, it's very expensive.
• 37:09And so there are bioinformatic ways of
• 37:12trying to understand gene trajectories
• 37:14without doing every time point that you have.
• 37:17I explain it this way,
• 37:20you see a picture,
• 37:21but what was happening before and after?
• 37:25Can you use what's in the picture to
• 37:28give you a sense of the trajectory?
• 37:31So that's what we did.
• 37:32And the way RNA velocity works is
• 37:35it basically takes the ratio of
• 37:37unspliced to splice transcripts and
• 37:40can predict the number of genes that
• 37:43are moving at that point in time.
• 37:45It's it's kind of like taking the
• 37:47time derivative of gene expression
• 37:49to get a sense of of trajectory.
• 37:51So when we look at this map,
• 37:53we see that in in teal are the
• 37:56myelining Schwan cells in in all of
• 37:58are the non myelin Schwan cells.
• 38:00And we see vectors of differentiation towards
• 38:03the repair swan cell phenotype in blue.
• 38:06In pink,
• 38:07we see the macrophage cluster also
• 38:09showing a differentiation as we'd
• 38:11expect because they have similar
• 38:13functions in in breaking down myelin.
• 38:17And when we zoom in here again,
• 38:19we see that five days post injury,
• 38:21there's a significant increase in
• 38:23the repair swan cell phenotype.
• 38:25So what are the genes that are
• 38:28driving this this transformation?
• 38:30We performed a driver gene analysis
• 38:32and identified a few different genes
• 38:34that that had the greatest impact.
• 38:38But we so far had been looking at
• 38:41individual genes. But we know that
• 38:42genes don't work in isolation.
• 38:44So we did a regulon analysis
• 38:46and a regulon is basically a
• 38:48regulatory network of genes.
• 38:50And that way we can understand
• 38:52what is impacting what in terms of
• 38:54downstream to upstream effects.
• 38:57And so with the regulon,
• 38:58we found regulon analysis,
• 38:59we found that the ATF 3 regulon
• 39:02had the highest specificity.
• 39:03So when we look at the cluster,
• 39:04we see here in the bottom right that this
• 39:08correlates with with our Schwann cell,
• 39:10a repair Schwann cell phenotype.
• 39:12So we realized that the ATF 3 regulon
• 39:14was very specific for this cluster.
• 39:20What are the genes in the ATF 3 regulon?
• 39:22It came up we were able to narrow down
• 39:25from thousands of genes that were involved
• 39:28in nerve injury to a couple to 16.
• 39:31And of these, Gal three was
• 39:33was the most expressed.
• 39:34But how do we know that these in silico
• 39:36findings are truly reflected in biology?
• 39:38So we went back and did validation
• 39:41with in situ hybridization and
• 39:44found that indeed Gal three's
• 39:46upregulated after injury in in our
• 39:51in our cell population as well.
• 39:53And our positive control was C
• 39:54June which we is a well established
• 39:56marker of injury in nerves.
• 40:00So in conclusion, we've performed
• 40:02profiling of the facial nerve cellulum.
• 40:04We've identified driver genes and
• 40:06found that the ATF 3 regulon and
• 40:08GAL three may be a targetable
• 40:10factor of the program and.
• 40:12Next steps would be trying to
• 40:14assess this in a more realistic
• 40:17cross faced nerve graft model.
• 40:19We have models with fluorescent
• 40:21reporter mice where we're able
• 40:24to harvest the nerves and look at
• 40:27specific transcriptional changes
• 40:29and then potentially create a
• 40:31knockout of the gall 3 gene and
• 40:33see impacts on nerve regeneration.
• 40:39I'd like to thank my collaborators
• 40:42and mentors and specifically
• 40:44my Yale order oncology family,
• 40:47Ben Judson, Sarah Mara,
• 40:49Zephyr Syed and Sarah Pay.
• 40:51Thank you all for for being here.
• 40:52And those who are not here,
• 40:54thank you as well.
• 40:55It's been a wonderful year so far and
• 40:58I'm excited to help grow this program.
• 41:01We have over 75 patients already in a year.
• 41:04We're rapidly growing as word gets out.
• 41:06We're getting a lot of referrals
• 41:07from people who were going to Boston,
• 41:09NY and want to bring their
• 41:11care back to Connecticut.
• 41:12We have several reanimation procedures going.
• 41:14We got multiple clinics,
• 41:16established workflows.
• 41:17We had AI mentioned the the physical
• 41:21therapy visiting lectureship.
• 41:23So it's a very exciting time at
• 41:25the facial nerve center and I'm
• 41:27very grateful for all the support.
• 41:29And I leave you again that facial palsy
• 41:33results in not just visual appearance,
• 41:35but functional and psychological
• 41:37quality for these patients.
• 41:39They have nearly every patient
• 41:41has an option for for improvement
• 41:43in their condition.
• 41:45And we have a bit ways to re establish,
• 41:47smile and blink.
• 41:50And I think that's all I have.
• 41:51I can take questions.
• 41:51Thank you so much,
• 42:00Doctor Sayed. Sorry. So, yeah,
• 42:02I want to really applaud you for all
• 42:04the amazing work you're doing and the
• 42:05fact that you're in The Apprentice here
• 42:07in Yale and to Connecticut at large.
• 42:10With regards to the gene expression,
• 42:12the GAL 3, for example,
• 42:14are you able to tell if there's differential
• 42:16expression across the nerve that you took,
• 42:19like proximal versus distal?
• 42:21Is that something that needs to be looked at?
• 42:23Yeah, absolutely. Yeah.
• 42:25That's so the question was,
• 42:28is the repair SWAN cell gene expression
• 42:31variable across the length of the
• 42:34nerve from distal to proximal segment
• 42:36and that's a very good question.
• 42:39We know that there are, you know,
• 42:41by definition the proximal segment
• 42:43is not injured.
• 42:44And so although there are changes
• 42:46at the level of the facial nucleus
• 42:48as soon as exotomy occurs.
• 42:49So short answer is no, I haven't done it yet.
• 42:53But yes, there are expected changes and
• 42:57I think it would be very easy to do.
• 42:59It's just multiple time points.
• 43:01And at the time I didn't have
• 43:02the resources to do that.
• 43:04But great question, Sarah.
• 43:05Great talk.
• 43:05Thanks so much.
• 43:06Yeah.
• 43:07I was wondering if you guys
• 43:09were going to look at the
• 43:12potential interacting ligand.
• 43:20Absolutely, Yeah, I think the next
• 43:22step would be trying to yes, sorry.
• 43:24So the question is have we done a lagging
• 43:28analysis for Gal three and looked at
• 43:31what's interacting And absolutely
• 43:33we've found several chemokines and
• 43:37I think there are some GPC Rs that
• 43:39are also involved with with Gal 3.
• 43:42And so it, it, I think our sample size
• 43:44was not high enough to be able to to get
• 43:47a significant data on the lag analysis.
• 43:49So we did, we kind of ditched it,
• 43:50but that is definitely on the table by Ray.
• 43:55Yeah, so amazing work for the patient
• 44:00who let's say has product tumor,
• 44:02you know that you're going to
• 44:04be doing chemo radiation are
• 44:08are there any particular considerations in
• 44:11our, let's say antivant treatment planning,
• 44:14are there particular nerve branches
• 44:15is the person who's contralateral neck
• 44:18that we should be paying attention
• 44:20to so you have the optimal nerve to.
• 44:24Yeah, that's a great question.
• 44:26Question was in the patient with a
• 44:29parotid tumor who needs is expected
• 44:31to need chemo radiation afterwards.
• 44:33Are there any considerations about what
• 44:35nerves to preserve or protect? You know,
• 44:38if we're doing upfront facial reanimation,
• 44:41then it doesn't really change. I think.
• 44:44I think the prevailing opinion has been like,
• 44:48do your rename management early and then
• 44:50whatever treatment has to they need to get,
• 44:52they need to get anyway.
• 44:54And so I don't think anyone has thought
• 44:58of a way to alter their management.
• 45:01The only thing that might be different is,
• 45:03sorry, you're saying do the
• 45:05reanimation and then radiate that.
• 45:08Yeah.
• 45:09So those transplanted nerves and yeah.
• 45:11And so it turns out,
• 45:12turns out that the the data on radiation of,
• 45:16of the nerves is not,
• 45:17is not as bad as initially thought.
• 45:20You know that for a long time,
• 45:21people are like, oh,
• 45:21if you're going to get radiation,
• 45:22don't bother with facial reanimation.
• 45:25And the outcomes are not that different
• 45:27between.
• 45:27And so that's why now there's a
• 45:29push to just do it up front because
• 45:31then patients end up not getting
• 45:33it or for whatever reason.
• 45:35So I think that's that's
• 45:39my strategy currently.
• 45:46OK, thanks so much. All right,
• 45:48thank you. Doctor Mohan,
• 45:48I have one more question for you.
• 45:50And as I as I moderate and end this.
• 45:54So it sounds like you have some great
• 45:58opportunities here at Yale for research,
• 45:59not not only basic science,
• 46:02but also in clinical outcomes
• 46:03like the question that was
• 46:04just asked by Doctor Burtness,
• 46:05you know, what are the outcomes?
• 46:07You know, we, I think there's
• 46:08great opportunity here with the high
• 46:10volume head neck cancer we have.
• 46:11Have you found any collaborators at
• 46:14Yale Cancer Center or at Yale in nerve
• 46:16regeneration or you looking for some?
• 46:19And how can people contact you if there
• 46:20are some people listening who might
• 46:22be interested in working with you?
• 46:25Thank you. Yeah, I,
• 46:26I promise I didn't plant him for that.
• 46:28But absolutely, I am very
• 46:30eager to continue this work.
• 46:32And I've been trying to find the
• 46:35right collaborators and just haven't
• 46:37exactly found found them yet.
• 46:39So please do reach out e-mail.
• 46:41I would be would be great.
• 46:42And I think there's an opportunity
• 46:44to be able to bring tissue from from
• 46:46the operating room and and really do
• 46:48this because so far all the work has
• 46:50been in my sense of being able to
• 46:51bring human tissue into the end and play.
• 46:53It would be great. Thank you.
• 46:56All right. Thank you, everybody.