Long COVID: Q&A with Dr. Lindsay McAlpine of Yale School of Medicine

February 28, 2024

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Dr. Lindsay McAlpine, a neuroimmunologist and an Instructor in the Division of Neurological Infections and Global Neurology at the Yale University School of Medicine, answers follow-up questions for the LISTEN community.

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00:10Hello everyone.
00:11Today we are welcoming back
00:13Doctor Lindsay McAlpine.
00:14Lindsay was here for the
00:16Kindred Cafe in July,
00:17and she has kindly offered to
00:19come back and answer a few more
00:21of the questions that were in the
00:23chat when Doctor Lindsay McAlpine
00:25is a neuro neuroimmunologist and
00:27an instructor in the Division
00:29of Neurological Infections and
00:30Global Neurology at the Yale
00:32University School of Medicine.
00:34She started the Neuro COVID Clinic
00:35at Yale in October 2020 and
00:37sees patients with neurological
00:39issues related to long COVID.
00:41She is an investigator in the
00:42COVID MIND study at Yale and her
00:44research interests are related to
00:45the pathophysiology of cognitive
00:47impairment after COVID-19 using
00:49several modalities including MRI.
00:53A question for Doctor McAlpine if
00:55there is time, can small fiber
00:57neuropathy resolve over time or
00:58is it permanent for Progressive?
01:00What are some of the theories behind this?
01:02The 'cause, this common long
01:03COVID long back symptom?
01:08Yeah, so I think that's a important question
01:12because so many patients with long COVID
01:15are found to have small fiber neuropathy.
01:18So the first does it resolve over time?
01:22In a lot of cases it does resolve
01:26and in other cases it doesn't.
01:29Usually there's a complicating factor
01:31when it's not resolving like diabetes
01:34or pre diabetes can be another reason
01:37to have small fiber neuropathy,
01:39another disease that's damaging
01:43and affecting the nerves.
01:46Is it permanent or progressive?
01:48After COVID, in my experience
01:53it is worst at onset,
01:56so it's the worst right after the infection.
02:00Usually comes on within one to
02:03six weeks after the infection
02:04and that's the worst it gets.
02:07It doesn't usually progress unless
02:09you have another inflammatory
02:11influence causing progression.
02:13And what are the theories behind this?
02:16So one of the theories is that
02:21there is during the acute infection
02:24there's such significant inflammation
02:26that's triggered that it damages
02:29the small fiber nerves.
02:30The exact mechanism of the damage,
02:33we're not sure is that molecular mimicry.
02:36So do the small nerve fibers to
02:39the immune system look like the
02:41virus and therefore cross react?
02:44That's one of the thoughts.
02:46But what we think it is given the
02:49time of onset post viral autoimmune
02:52conditions almost always happen
02:55within the first one to 12 weeks
02:58after a viral infection.
03:00And so because it comes on in that
03:03window and is maximal at onset,
03:05it makes sense that it's an autoimmune
03:08condition that's triggered.
03:10And often we see that there are also
03:13auto antibodies that are developed
03:16Like I mentioned during the panel
03:19last time that the University of
03:23Saint Louis or Universe Washington
03:26University in Saint Louis has an
03:28excellent panel that tests for some
03:30auto antibodies that are linked
03:32with small fibro neuropathy.
03:36And you know that addresses one of
03:38the other questions that when when
03:42you have an autoimmune disease,
03:44every time you get a viral
03:47infection or any infection really,
03:50you can have worsening of your
03:52autoimmune symptoms because you're
03:54turning on and turning up and revving
03:56up the immune system and that's going
03:58to Rev up your autoimmune disease.
04:00So one of the other questions was that
04:03they got worse during viral infections
04:04after this that that makes a lot of sense.
04:09Thank you so much.
04:10Next question is related to migraine
04:12and face a recent appointment
04:14with an MECFS practitioner.
04:15It was proposed that the initial
04:17long COVID symptoms were atypical
04:19migraine that after persisting
04:21caused POTS a month later and all
04:23the other symptoms my husband has
04:25been bedridden since the fall and
04:27extremely severe at this point.
04:28Does the explanation of untreated
04:31persistent migraine track? So
04:34I think that in some individuals
04:37that untreated migraine is definitely
04:40considering contributing to long COVID.
04:45We've seen an increase in new migraines
04:49after COVID and also an increase in
04:52severity of migraines after COVID in
04:54people who have already had migraines.
04:57So as a neurologist we call almost all
05:00headache migraine because it is mediated
05:03through the same trigeminal ganglion
05:06which mediates pain in the brain.
05:09So I don't think that migraine is an
05:15explanation for all of long COVID.
05:18It's certainly
05:22is common in some of is commonly
05:26comorbid with some of the conditions
05:28that come on after COVID like pots,
05:31pots and migraine can be linked
05:33same with you know elderstand lows
05:36or chronic fatigue or mast cell
05:38and migraine are closely linked.
05:39So there's a connection but I
05:42don't think it's the entire,
05:45you know explanation.
05:47And so treating each of those
05:50individual conditions is what
05:52is going to kind of remove the
05:55roadblocks to recovery and making
05:57sure that each migraine is treated
06:00effectively is very important.
06:02You want to treat a migraine at the
06:04very onset of the headache before it
06:07ramps up into a a major painful attack.
06:13Some of the other questions include head
06:16pressure and pain at the back of the head.
06:20So we've seen quite a bit
06:22of occipital neuralgia.
06:23So the occipital nerves comes out
06:28of the neck and it comes through the
06:31neck muscles and tight neck muscles
06:33pinch the occipital nerve and then it
06:37causes this numbness, tingling pain
06:39in this distribution on each side.
06:42So we've seen that quite frequently as well.
06:46And then there's a question here about what,
06:47what's headache and what's migraine.
06:49So I think we call almost
06:51everything migraine.
06:52Typically a migraine can be associated
06:54with a bunch of other symptoms.
06:56So migraine can be associated
06:58with sensitivity to light,
07:00sensitivity to sound and smell.
07:03You become sensitized to everything.
07:05It's associated with nausea because migraine
07:09involves the vagus nerve which slows down,
07:12causes some gastroparesis as well and it
07:15also can be associated with neck discomfort,
07:18neck pain, irritability,
07:21word finding difficulty,
07:24what else specifically?
07:25Aura as well.
07:27So visual aura, sensory aura can all be
07:31involved and so migraine is is a syndrome.
07:33It's just not head,
07:35it's not just head pain.
07:36Next question.
07:42Next question is,
07:43any suggestions for screen sensitivity?
07:45Since COVID, I have developed
07:48atypical treadmill neuralgia and
07:50feel like I am in a sci-fi film.
07:53Looking at any screen through my right eye,
07:55sets the entire left side of my face on fire,
07:58even with my left eye closed.
08:00Incredibly debilitating.
08:00Can't work hard to function.
08:03Yeah. So I think when, when I was
08:06looking through a lot of the questions,
08:07I think this is really important
08:09because not everything that comes
08:12on after COVID is long COVID.
08:15So a lot of patients have other
08:18conditions that come on after long COVID.
08:21So I would call new trigeminal neuralgia,
08:24that's trigeminal neuralgia.
08:25We're not going to treat it any
08:27differently because it came on after
08:29COVID and I wouldn't put it in
08:31that bucket of long COVID either.
08:33And I think that's important
08:35because you want your physicians,
08:37your care team to treat that
08:39condition like that condition,
08:41no different because of COVID.
08:43And so trigeminal neuralgia is really
08:46painful, uncomfortable, awful condition.
08:48I'm sorry that happened.
08:50And there's a lot of different
08:52therapies you can try,
08:53making sure you get a full work up with
08:55imaging and everything is really important.
08:57And then going through, you know,
08:59just like any condition,
09:01it's important to try each thing and
09:04and see what works for you 'cause
09:06it's going to be different for each patient.
09:10One of the other things is that,
09:12you know,
09:12seeing patients with Yon Bray syndrome,
09:15which is a distal progressive numbness,
09:19tingling and weakness that develops,
09:23that is going to come on.
09:25We do see it after COVID,
09:26we do see it after the vaccines.
09:28We see it after any viral
09:30infection or vaccine.
09:31It has reports and it's an autoimmune attack
09:34of the myelin on the peripheral nerves.
09:38And so it it's triggered by the
09:41infection and then it comes on within
09:43a couple few weeks after the infection.
09:46And so if you're kind of falling into that
09:49long COVID bucket of after three months,
09:52then it's not going to be related
09:54to Guillain Barre.
09:55And it has a very classic symptoms
10:00and timeline too.
10:02So one of the other questions is
10:04a patient wrote in about being
10:07diagnosed with transverse myelitis.
10:10And again,
10:11I would say transverse myelitis can be
10:15triggered after COVID or after a vaccine,
10:19but I would not call it long COVID.
10:21It's transverse myelitis,
10:22it has its own set of work up,
10:26has its own set of treatments,
10:29and it's I wouldn't consider that long COVID.
10:33Let's see
10:36and same with the GAD 65 S GAD 65
10:42is an auto antibody that develops
10:45and it causes stiff person syndrome.
10:48So one of the patients said that
10:50was positive in both both their
10:52blood and their spinal fluid.
10:54And so I would say to that that's
10:57you know probably early stiff
10:59person syndrome and that warrants
11:01a full work up and treatment,
11:04so disease modifying therapy and close
11:09monitoring with a neuroimmunologist.
11:11And so I would take that approach.
11:15You know, when I see a patient,
11:17I'm always making sure that
11:19we're not missing something else,
11:21we're not missing another disease
11:23and just lumping the symptoms
11:26in with a bucket of long COVID,
11:28things that aren't long COVID.
11:31Yeah, next question.
11:32Thank
11:33you. That's a really important distinction.
11:37Next question, can you briefly
11:38mention the theories of what causes
11:40persistent neurological COVID
11:41symptoms and what traction each has,
11:44EG autoimmune reaction,
11:45persistent virus viral remnants, etcetera?
11:49Yeah. So I have a slide.
11:56So here is a figure from the
12:00publication Science by my mentor
12:04Doctor Sweeness Footage and one of our
12:08colleagues at the NIH, Doctor Avinath.
12:12You can see here that it kind of reviews
12:17the mechanisms of effect and so starting
12:23generalized neuro inflammation with
12:25track of trafficking of immune cells,
12:28cytokines and auto antibodies into the
12:31brain and activation of the microglia.
12:33We know this happens during
12:36the acute infection,
12:37but once the immune system
12:39is kind of turned down,
12:42to what extent is this persisting?
12:44We're not seeing ongoing cytokine
12:47elevations in the spinal fluid.
12:50And so it's unknown the extent of the
12:53persistent neural inflammation particular
12:56particularly in the absence of objective
13:00clear inflammatory lesions on MRI.
13:05We're not seeing that.
13:06So we're not see most,
13:08the vast majority of people with long COVID
13:12have completely normal clinical Mris.
13:16So
13:19antibody production within the spinal
13:22fluid in response to the virus and auto
13:26antibodies we've published on this.
13:29We found unique auto antibody
13:31signatures in the spinal fluid.
13:33We've also found auto antibodies
13:36to COVID in the spinal fluid.
13:39Extended portion of that is probably
13:42leaking over from the bloodstream
13:44into the spinal fluid and may or may
13:47not have a clinical effect because
13:50we see elevated antibodies in both
13:53our control subjects with no long
13:55COVID and in our long COVID subjects.
13:59So it's unclear.
14:01So there's limited, you know,
14:03evidence for the presidents of actual
14:06viral particles or proteins in the brain,
14:10very, very limited.
14:11So I think this is an unlikely scenario.
14:14Here the blood vessels is my
14:18main focus of interest.
14:20They may be damaged or dysfunctioned
14:23dysfunctioning due to endothelial
14:25activation which is the lining of
14:28the blood vessel and this cascade
14:32of Coagulopathy and in some cases
14:35leading to micro bleeds or stroke
14:38particularly in the acute infection.
14:40This is not seen as frequently in long COVID.
14:43So after three months after
14:45the acute infection,
14:46we're not seeing strokes
14:48or bleeds in the brain.
14:50But when we talked about before the
14:57dysfunction of blood vessels and
15:00withdrawal of oxygen from the tissues,
15:03that occurs in chronic fatigue syndrome where
15:06the blood that's going through the tissues,
15:08you're,
15:09you know,
15:10a chronic fatigue patient
15:11is only extracting half,
15:1250% of the oxygen and an individual
15:17without that would extract 80%.
15:20So that dysfunction of the
15:22diameter of the blood vessels and
15:24shunting at the tissue level may
15:27also be happening at the brain.
15:29So that would explain why
15:31there's such exquisite
15:35sensitivity. So the brain is a very
15:38sensitive organ to any dysregulation
15:40or disruption and function.
15:42So even if there's a little bit
15:44of disruption in the function of
15:46the blood vessels in the brain,
15:48I would expect there to
15:49be symptoms from that.
15:50And so that's my theory,
15:52but I have no proof for this.
15:55There is some preliminary evidence out of
15:59Harvard that there is cerebral hypoperfusion.
16:04And I think this all goes
16:06on the same spectrum.
16:08And what we're not seeing
16:11is objective frank strokes.
16:13So that is the good news.
16:15So there's subtle dysfunction but no
16:19severe lack of oxygen to the brain.
16:24Thank you so much. Yeah, next question,
16:28are there reliable tests available here
16:30in the US to diagnose micro clotting?
16:35We addressed this a little
16:37bit that at the last meeting,
16:38but we haven't found clear evidence
16:43of micro clots, actual clots in
16:46the tissue in the blood vessels.
16:48It's more the activation of the
16:52endothelial lining and subtle
16:54persistent vascular inflammation.
16:56There's a number of clinical blood
17:00tests that can tease this out.
17:03One of them I'm trying to think of
17:06a lot of them are research tests.
17:11C reactive protein can be a very general
17:15marker of inflammation of the blood.
17:18Elevated Von Willebrand factor has
17:21been shown to be elevated in acute
17:24COVID linked to endotheliopathy.
17:27There's there's a number of different
17:30markers that can be used both in research
17:32and clinically to tease this out.
17:35How are you diagnosing the vascular
17:37inflammation you described?
17:39Right, so it's in the in the blood
17:42we're we're using research tests and
17:45in the brain we're using also research
17:48tests sequences to look at subtle
17:51perfusion differences in the brain. Yeah.
17:58Next question. Do
18:01you have an experience opinion about
18:04HBOT following up on the theory
18:05of poor oxygen at the micro level?
18:11Yeah, So there have been some small
18:16promising studies that show that H Bot
18:20can improve fatigue and some of the
18:23neuropsychiatric symptoms of long COVID.
18:26I do think it's related to this
18:30chronic fatigue pathology.
18:31So the dysautonomia pathology,
18:34the one issue is that in patients
18:39who undergo H bot therapy,
18:41it improves while they're on it,
18:43which is, you know,
18:45and it time intensive therapy.
18:48But once it finishes,
18:50it doesn't seem to have a lasting
18:55recovery effect like like the DIS
18:58Autonomia PT exercise protocols do.
19:02Yeah. And then you know,
19:03one of the other thoughts
19:05is with severe fatigue,
19:06it's also important to look
19:08for those other things.
19:10So we'll talk about sleep next,
19:12but making sure that everybody
19:14has a cortisol test,
19:16making sure that there's
19:18no adrenal insufficiency,
19:20that's really important.
19:21And then there was another question here.
19:29I think it's important to a lot of
19:32patients come to me really wanting to
19:34know was it COVID that caused my post
19:38viral syndrome or was it something else?
19:40And I know that an A definitive
19:44answer would be helpful,
19:45would make patients feel better,
19:47but from my perspective it doesn't
19:51matter because this condition post viral
19:54syndrome can happen after anything, right.
19:58So it can happen after Mono CMV.
20:03You know, GYN infections any the
20:07flu parafluenza you know can happen
20:10after any inflammatory viral illness.
20:13And so I would say take what you
20:18have and what symptoms you have and
20:21focus on how to heal and get better.
20:24And that that answer is like something
20:26we can't always provide and doesn't
20:29won't necessarily change your treatment,
20:31if that makes sense.
20:32Have there been patients post
20:34COVID who you have sent for
20:36further evaluation for narcolepsy
20:38or autoimmune eccentral latest?
20:41Yes, sorry. Yeah,
20:43yeah. So we've seen and there were
20:45quite a few questions about sleep.
20:47We've seen a lot of sleep
20:49disorders after COVID.
20:50People seem to be much more
20:53sensitive to sleep deprivation
20:55and interruption after COVID.
20:58One of the first things that I do for
21:00anyone with sleep issues and cognitive
21:03issues is to send them for a Sleep
21:06Medicine evaluation with a sleep study.
21:08That's really important.
21:10We are finding a lot of new
21:13sleep apnea after COVID.
21:15I don't think COVID necessarily caused that,
21:18but it's just now you're
21:20going to have much more,
21:21many more symptoms from it.
21:23You're not going to be
21:24able to tolerate it well.
21:25And so sleep apnea is treated,
21:28whether it's central or obstructive,
21:30it's treated very similarly with a CPAP.
21:33So the continuous positive
21:36pressure machine overnight,
21:37a lot of patients balk at that,
21:40understandably so.
21:43But it improves the quality of sleep
21:47and the quality of life so much that
21:50almost everybody who gets it loves it.
21:53They take it everywhere, vacation,
21:55they have to come to the hospital,
21:56people bring their own machine,
21:58they love it.
22:00So I really encourage all my patients to
22:04give it a try to pursue the full work up,
22:07get treatment for sleep apnea.
22:09And then I've had patients
22:11convert their entire family,
22:13get their entire family diagnosed and
22:16treated and everybody feels a lot,
22:18a lot better.
22:19So I think that's a really important thing,
22:21getting treatment for insomnia,
22:23really important to treating the
22:26underlying anxiety or depression that
22:28might be contributing to insomnia.
22:30The gold standard therapy is
22:32cognitive behavioral therapy,
22:34a type of you know, psychology approach.
22:37It's wonderful.
22:38We have a wonderful team here that does
22:42CBT for insomnia and my patients love it.
22:45It's a really healthy approach to
22:48sleep and it gives you the coping
22:51tool tools to manage insomnia.
22:54Some of the medicines that
22:56I'll use one second
23:00or insomnia, one of the ones I use
23:03the most is probably Trazodone.
23:05It's well tolerated, lower doses,
23:08not habit forming and generates sleepiness.
23:12In addition to that,
23:15all of the sleep, hygiene things,
23:17so no blue light, no screens,
23:21cool bedroom wine down before bed.
23:24It's all of the lifestyle
23:27factors are so important.
23:29We can put medicine band aids on top of them,
23:33but if we don't change the
23:35underlying health, you know,
23:36create a healthy lifestyle,
23:37it's really hard to to medicate over
23:40that. Hi, I got the COVID shots.
23:42I have stomach issues since I got the shots.
23:44Now I have ticks going on.
23:46Plus this month alone I I was plus stutter.
23:51I was in the ER on July 9th.
23:55Yeah. Plus I stutter.
23:58So stutter and ticks. Yeah, it
24:02it's COVID itself can cause
24:06new psychiatric issues.
24:09Anxiety, depression, panic attacks.
24:11I've had patients who during
24:14their acute illness were,
24:17you know, suicidal and never
24:18been suicidal in their life.
24:19Like, there is objective evidence that
24:21it does alter the function of the brain.
24:25And then the experience of long
24:28COVID is so difficult that it's
24:31not surprising that people,
24:33in reaction to the difficult experience,
24:37develop anxiety,
24:38depression and other psychological disorders.
24:42I've seen it a lot, you know,
24:45new ticks and stutters.
24:47Sometimes people with stutter
24:48will have had it as a kid and
24:51then it comes back after COVID.
24:54Sometimes it's it's as a stress response to,
24:59you know, I think one of the other
25:03participants mentioned developing
25:05somatic symptom disorder,
25:08which is basically excessive anxiety about,
25:12you know,
25:13physical symptoms in their body,
25:15which again is an understandable
25:17response to having so many symptoms.
25:20Developing long COVID,
25:22you know,
25:23there's such an interplay between mood,
25:26cognition, sleep,
25:27function all well-being that you
25:30really can't tease those things apart.
25:34And so I really encourage all of
25:37my patients to address all of the
25:40psychological issues because they can
25:42be a big roadblock to healing and
25:44to feeling better because no one,
25:47well,
25:47I'm not and and certainly no one
25:50in our clinics is saying that
25:53any of this is in someone's head,
25:55but the suffering in your head
25:57can make your symptoms and make
26:00you feel a lot worse.
26:01And so I really encourage all of my
26:04patients who are struggling to get
26:07the help they need with therapists,
26:10psychiatrists,
26:10sometimes going on a medicine for
26:12six months to a year while you're
26:15going through this really struggling,
26:17you know this difficult time while
26:19you recover, it's not forever.
26:20You know, I I think it's really,
26:23really important.
26:24And and on on the same vein,
26:27I have seen quite a few patients with
26:30functional neurologic disorders,
26:32which is where neurology and psychology
26:35really kind of overlap and come together.
26:38Functional neurologic disorders are
26:41basically they're not volitional.
26:43Patients are not doing these
26:45things on purpose.
26:47There's no like awareness that this
26:50is on purpose, it's not on purpose,
26:52but it can come in many different ways.
26:55So it can be new tremors of a certain
26:59they're very distinct characteristics.
27:01So it's hard to describe,
27:02but tremors, seizure like events,
27:07lower extremity, weakness,
27:10trouble walking,
27:11these are all common ways that
27:14functional neurologic disorders develop
27:15and these things develop in response,
27:18typically to stress.
27:20The way that we describe it is it's
27:23a it's a dissociative disorder where
27:26your your mind and your body's
27:28experiencing stress, depression,
27:29anxiety, and it's difficult to cope with.
27:33Your subconscious doesn't know how
27:35to deal with it.
27:36And so this is how it comes out.
27:38It comes out as a new tremor,
27:39comes out as kind of complete dissociation,
27:42seizure like events.
27:43It comes out as difficulty walking.
27:46And so,
27:46you know,
27:47the number one thing for
27:49getting better from a functional
27:51neurologic disorder is
27:53insight, really insight into Oh yes,
27:56I have been, this has been really hard.
27:59I have not been feeling well.
28:00I've been dealing with so many
28:03other symptoms and issues.
28:04I it makes sense that, you know,
28:06I'm having a hard time and and
28:08one of the treatments is also
28:10cognitive behavioral therapy,
28:11so using relaxation and coping methods to
28:17address address the psychological issues.
28:19So we've seen that a lot in
28:22conjunction with long COVID too. Yeah.
28:27Thank you. I
28:28do think you know another question when
28:32it comes to like the somatic symptoms is,
28:36you know a lot of people have said
28:38they've had so much work up, they've had
28:41so many tests and they're all normal.
28:43You know in in this condition
28:45we expect them to be all normal.
28:47We, you know, you may have a
28:49positive tilt table test from POTS
28:51if you're lucky enough to get an
28:53invasive CPAP that would be abnormal.
28:55But we expect the MRI,
28:57the lab test to be normal and if
29:00you've had a thorough work up for
29:04all of the symptoms that you have,
29:06then usually I say to my patients we
29:10can stop looking and focus on recovery.
29:13So I think that's like a really hard
29:17balance is when to know when to stop
29:20going down the diagnostic pathway and
29:23turning into the healing recovery pathway.
29:27So you know working closely with your
29:30doctor to kind of figure out where
29:33that line is and then moving ahead
29:35with the with the therapies and the
29:38treatments that that work, yeah.