"I Can't Believe It Both Is and Is Not Encephalitis!" Or: What do you do when the evidence is crazy?

post by Erhannis · 2024-03-19T22:08:00.724Z · LW · GW · 3 comments

This is a question post.

Contents

  The short version
  The gritty details
  Evidence and theories
    Anxiety?
    Hypothyroidism, low-t?
    Re: acyclovir efficacy, placebo effect?
    HSV-1 encephalitis?
    A different encephalitis?
  Possible explanations why some indicators don't apply
  Some plans
None
3 comments

The short version

Three weeks ago, starting on a Sunday, my brother stood up to turn off the light and felt a wave of disorientation, which passed after a minute or two. Periods of cognitive impairment increased in frequency over the following week, along with mild photophobia, until they became continuous, and continued increasing in severity. He also experienced severe fatigue while driving and had to pull over. Doing some research of possible causes, and considering a suspicious rash he'd noticed for a few months, he hypothesized a small possibility of HSV encephalitis, a rare but deadly illness, and obtained an internet prescription for acyclovir and began to take it that Saturday night, as a low-risk precaution. He also went to Urgent Care and the Emergency Room several times, but all tests came back negative, including a CT scan of his brain on Sunday night. As the CT scan should theoretically have shown something in the case of encephalitis, he stopped taking the acyclovir. The symptoms continued to increase until Monday night, now including unusual neck tension, and he described it as being unable to perceive the present, only things half a second in the past, and had to struggle to keep his actions coherent. He believes that were the trend to continue, he would have lost coherency entirely in a matter of days. However, Monday night, he suddenly felt better - about 48 hours after starting acyclovir. The next morning started fine, but then he began to feel the symptoms gradually returning. He started an internet prescription of valacyclovir, which converts to acyclovir in the body, with greater bioavailability. However, his symptoms continued to worsen. After three days of worsening symptoms, he switched back to acyclovir. One more day of bad symptoms, and then he suddenly felt better in the evening. He has continued taking acyclovir, and over the subsequent third week, he has felt...acceptable, for now, with some stressful ups and downs. The symptoms haven't gone away entirely, but for now it seems they are held at bay.

And this is nonsense. The evidence we have is nonsense.

1. Against: HSV Encephalitis cases are about 1 in 500,000 people per year. (Treated cases have ~20% mortality, and ~50% have severe brain damage.)
2. Against: He was missing a number of the usual symptoms, such as fever and headache, or anything notable on a CT and MRI.
3. For: He did have several other indicative symptoms, such as cognitive decline, photophobia, and neck tension (at the height of symptoms, at least), and, less unusual, had moderate headaches several times towards the end of week three.
4. Strongly for: Encephalitis is commonly caused by HSV-1 (the cold sore virus most people have), or HSV-2 (genital herpes), both part of the HHV family. Acyclovir, an antiviral targeted at the HHV family, appears effective.
5. Strongly against: Valacyclovir, which should end up chemically identical to acyclovir, and more bioavailable, appeared not to be effective.
6. For: The placebo effect doesn't make sense, because he didn't feel better until after he'd decided the acyclovir didn't work, and the valacyclovir (which he got because he believed it would be more effective) DIDN'T work. This suggests acyclovir's effect is indeed physiological rather than psychological.

It's 4 and 5 that are the most baffling to me. Acyclovir should have an effect on cognitive symptoms if and only if the disease is an HHV family virus affecting the brain. It does have an effect, so it must be an HHV virus affecting the brain, surely. But the same should hold true of valacyclovir, and it doesn't.

What do you do when the evidence you have strongly conflicts like this? We've read dozens of articles about encephalitis, HSV, looked at lists and descriptions of other diseases, talked to several doctors, petitioned for and received dozens of emails suggesting other possibilities, and so forth, but our primary theory, the one that fits most cleanly, is still bad.

I welcome suggestions on how to approach such scenarios, in general. I also welcome more specific advice on what to do in my brother's case - whether this sounds familiar, what this could be, tests to try, likely-useful doctors in the central Arizona area or tele-available that would have availability within a week or so, and so forth.

I omitted a lot of details from the short version above - there are more factors on both sides of the argument, many of which you can read in the subsequent expanded version and discussion, if you would like more info.

The gritty details

Again: three weeks ago, on a Sunday, my brother stood up to turn off the light and felt a wave of disorientation, which passed after a minute or two. These increased in frequency over the following week, and on Friday he felt fatigue strong enough to cause him to pull over the car. He has also reported mild photophobia since that first sunday, initially ignored. Later that night, and the next two nights, he tried going to Urgent Care and/or the Emergency Room, where they did some tests (heart monitors, etc.) that turned up nothing. Saturday the symptoms felt more-or-less constant, and continued to gradually worsen. Doing some research of possible causes, and considering a suspicious rash he'd noticed off and on for a few months, he hypothesized a small possibility of HSV encephalitis, a rare but deadly illness, and obtained an internet prescription for acyclovir and began to take it that Saturday night, as a low-risk precaution.  On Sunday he got a CT scan of his brain, and when that revealed nothing weird, he stopped taking the acyclovir, because surely encephalitis would have shown up on the scan. Somewhere in all this a doctor prescribed him Ativan, an anti-anxiety medication, which he has since periodically taken to help him not panic, but which (he reports) does not affect the symptoms of cognitive impairment. On Monday, the symptoms were the worst: I will refer to this period as the peak of symptoms. (A secondary symptom at this time was significant neck tension.) For the cognitive symptoms, he has described some of the specific manifestation as though he is unable to perceive the present, instead remembering things half a second after they happen, and is continually struggling to keep his actions on the rails. He has said that he would observe words to have come out of his mouth, and think "now why did I say that?...though I guess the words make sense in context." He reports a feeling of detachment and distance, tentatively explained as it being difficult to feel his body. He has characterized the overall experience with phrases such as "intolerable, disoriented, memory loss, odd feeling, trouble remembering words", and so forth. He believes if his condition continued to decline, within days he would no longer have been able to keep things together. However, Monday night, he abruptly felt better, almost entirely.

The following morning he felt alright, but began to feel weird again an hour or two after waking up. He then took a dose of acyclovir, but switched to the new prescription of valacyclovir he'd managed to get - valacyclovir having a purported greater bioavailability, it should work better. He was also able to get some blood tests, the results of which we learned about a week later - which, to our then-surprise, indicated no blood antibodies to HSV-1 or 2. However, despite the valacyclovir, over the next four days (Tuesday, Wednesday, Thursday, Friday), his symptoms worsened again. In addition, the rash that he'd had off-and-on for months reappeared, which he suspected of being an HHV family virus, and thus suspected relevant to his cognitive issues. The later-returned blood test results were particularly confusing in light of this. Friday, his symptoms nearly as bad as the peak, in the middle of the day after researching dosages he re-added acyclovir on top of the valacyclovir. (Meanwhile, he'd been trying to schedule doctor appointments, but it's hard to get a doctor on short notice, especially if you don't have measurable symptoms.) On Saturday, he took one last valacyclovir, then switched back to acyclovir alone, at an increased dose (again consulting literature on what could be done with reasonable safety). (In keeping with literature warning of acyclovir potentially crystallizing in your kidneys, he has been drinking lots of water and monitoring e.g. urine creatinine. Aside from a few false alarms, it seems to be working.) Most of the day he felt almost as bad as on Friday, but in the evening he suddenly felt better. He notes that the rash also seemed to improve after switching to the acyclovir, and its improvement or worsening seems to predict the same for his cognitive symptoms on a scale of hours, perhaps. (I'm not sure the correlation has persisted or been consistent; our notes haven't been sufficiently detailed.)

I talked with him, going over a list of symptoms for a few diseases with other overlapping symptoms, and discovered a few symptoms he hadn't thought to mention - namely, the mild photophobia for most of the time since the symptoms began, the notable neck tension the night of peak symptoms, and possible susceptibility to cold or chills. (However, no fever or headache, at least up to then.) Photophobia and neck tension are both symptoms of encephalitis and/or meningitis, and aren't symptoms of a lot else that seemed plausible. Susceptibility to cold was a symptom of hypothyroidism, which I noted but didn't pursue. With the continued efficacy of the acyclovir, and the two additional symptoms discovered pointing to encephalitis, I advocated for him to receive a lumbar puncture and associated tests of cerebrospinal fluid. However, as he is somewhat stable, and you need a doctor's say-so to get an LP, we've been trying to schedule doctors appointments and so forth for several days. Since then, a scheduling item got bumped up and he has had an MRI with contrast - which showed nothing beyond a small cyst that the evaluating technician/physician found unremarkable. (My brother was feeling normal on the day the MRI was taken, and we wonder if e.g. inflammation had gone down.) We ALSO received the results of those blood tests from Tuesday, wherein antibody tests came back negative for both HSV-1 and 2. This argues against our leading (admittedly bad) theory of HSV-1 encephalitis. Problem is, we don't HAVE a good theory. My brother's brain threatened to give out and we don't know why.

Further miscellaneous items:

1. He has in the past few days (end of week three) commented about feeling pressure in his head or something, and also minor headaches the past day or two - contrasted with a notable absence of headache the first two weeks.
2. A thyroid specialist says my brother's numbers nearly reach the hypothyroidism levels, and that he has extremely low testosterone. He started taking a medicine for that this Friday, but it may take several weeks to take effect, and we're not convinced that almost-hypothyroidism and low-t explains all the evidence, anyway.
3. It seems like lying down and/or sleeping trigger cognitive symptoms; for several nights he's said he'll wake up during the night feeling very weird, and wake up in the morning feeling wavy and disoriented, but after a minute of walking around it goes away. He tried sleeping more upright, and didn't notice as much of a problem. On the other hand, he fell asleep sitting up in the car the other day, and still woke up feeling weird again. Perhaps related, he noted a few times it seemed like exertion had an (inconsistent) effect.
4. He experiences notable fatigue maybe every few days.
5. We've seen a couple doctors, but only like, whatever ER doctors were there, a general practitioner, a thyroid specialist, and one time a neurologist. They have proposed no strong theories, yet, and the closest we've gotten to agreement on encephalitis is basically "yeah, something weird does seem to be happening, but that's not my area of expertise." We're trying to visit the neurologist again, with the data we've collected since last visit, but he took a vacation, and also is booked. We tried contacting an encephalitis specialist, but they were booked for a month.
6. He wore a pulse oximeter last night while asleep, and it indicated no particularly notable changes in blood oxygenation. Lowest was 89%, and we believe that was an instance of him adjusting the sensor while awake.

Evidence and theories

Anxiety?

1. Against: The cognitive symptoms my brother describe sound fairly specific and unusual.
2. Against: The anti-anxiety med makes him calmer, but does not appear to affect the symptoms.
3. Against: Acyclovir shouldn't affect anxiety.
4. For: Anxiety can explain confusion and so forth.
5. Against: Anxiety seems to be a possible explanation for almost ANY head-oriented symptom, and then some.
6. Anxiety is also a low-consequence outcome, so we're currently trying to confirm the absence of the worse possibilities.

Hypothyroidism, low-t?

1. For: I'd consider this the best non-encephalitis guess we have so far...
2. Against: but it doesn't explain the acyclovir efficacy
3. Against: and it only explains the primary symptoms in the sense that, according to the thyroid doctor, it can explain almost ANY symptom - same as anxiety.

Re: acyclovir efficacy, placebo effect?

1. For: This would be plausible...
2. Against: except that it seemed to take effect after my brother no longer believed it would help
3. Against: and the valacyclovir did not help, when my brother believed it would.

HSV-1 encephalitis?

1. Against: This is a very rare condition, about 1 in 500,000 people get this per year.
2. Against: It's usually accompanied by fever and headache, which my brother has not displayed.
   1. (He has begun to have minor headaches the past few days.)
3. For: photophobia, neck tension, cognitive decline. Recent reports of feeling head pressure, and of headaches.
4. Against: whatever other symptoms he doesn't have. (nausea, seizures, aphasia, coma....)
5. For: Acyclovir, an HHV-family-specific antiviral, appears to be effective against my brother's symptoms. I regard this as strong evidence.
6. Against: My brother's PCP says acyclovir takes longer than a few days to work, though we didn't see this reflected in the literature, and we're not sure how often he actually prescribes the stuff.
7. Against: Valacyclovir does NOT appear effective against my brother's symptoms, and may in fact be counterproductive. This...should also be strong evidence.
8. Against: A CT scan and MRI both showed nothing notably abnormal.
9. Against: His blood tests came back negative for HSV-1 and 2 antibodies. If the rash were the same thing as is affecting his brain, and he has HSV-1 or 2 encephalitis (the most common encephalitis types), he should have antibodies.

A different encephalitis?

1. Against: HSV-1 encephalitis is among the common encephalitis types.^[1]
2. For: Negative blood tests.  See the following section, "Possible explanations why some indicators don't apply"

Possible explanations why some indicators don't apply

We have some theories why some of these may be false negatives - though we acknowledge that it is dangerous to start questioning the efficacy of your tests, and can lead to tinfoil hat territory. However, consider the following.

1. Encephalitis is difficult to diagnose. "No clinical features are pathognomonic of herpes simplex encephalitis."^[2]
2. It is also rare, 1 in 500,000 per year.
3. Therefore, I posit, it usually isn't caught until the disease has already progressed substantially and caused significant damage to the brain, enough to cause measurable outward symptoms such as ataxia or aphasia.
4. See, for instance: "A 16-year-old girl presented to the emergency department with a 10-day history of aphasia and a one-day history of convulsion.... She was confused and did respond to verbal stimuli. Intravenous (IV) acyclovir 1500 mg/m2/day in 3 divided doses was started for probable encephalitis."^[3]
5. Note further: "A large retrospective study showed a delay in initiating acyclovir for more than 48 hours as one of the factors associated with poor outcomes"^[2]
6. In contrast to these, my brother started acyclovir on his own, while symptoms were still comparatively mild, perhaps the earliest of all such patients. If he managed to stall the disease at this stage, it seems plausible he would not yet have visible damage to the brain, and as he was feeling quite well on the day the MRI was taken, inflammation may have been reduced or absent.

As for the lack of blood antibodies - we're not sure, and this is worrying.

1. Perhaps his body simply isn't producing antibodies for HSV-1 (or 2, if we suppose that possibility). Is that even possible?  He otherwise appears immunocompetent.
   1. Our sister was immunocompromised with respect to a specific pathogen, which suggests a potential genetic factor, but she still produced antibodies to it.
2. My brother notes that contrary to descriptions of HSV rashes, his rashes never went away on their own, only after application of a steroid cream, or (recently) while on acyclovir.
3. Perhaps it was a simple false negative? There ARE reports of e.g. ~20% false negatives on HSV tests.
4. Perhaps the rash was actually unrelated, and so the encephalitis is a primary infection rather than a recurrence, and so his body hasn't yet formed antibodies? (Even though the rash responds to acyclovir, suggesting an HHV family virus?)
5. Perhaps it's somehow an even rarer HHV encephalitis, like VZV, so we tested the wrong antibodies.

We're concerned that if we get a lumbar puncture and any of the above are true, the LP could be a false negative. If it truly isn't any form of encephalitis, good, but we want to make sure we don't incorrectly rule it out, because it's such a rapidly devastating illness.

Some plans

In case anyone has constructive feedback, there are two plans of action my brother and I have debated.

First: my brother has suggested trying other HHV antivirals, particularly if acyclovir stops working, but one of my brother's prior concerns had been that perhaps the illness is gaining a resistance to acyclovir. (This seems unsupported by the literature.) I therefore argue that we don't want to give it resistance to everything else ourselves, before the doctors even acknowledge that anything serious is wrong. However, I concede that I would not have tried acyclovir in the first place, instead relying on the doctors' judgement, yet it appears that acyclovir was a good decision, suggesting that my brother's instincts here are better than mine.

Second: given the difficulty so far of scheduling doctors and of getting them to consider this a serious, urgent illness, I'm concerned that a negative lumbar puncture would delay additional testing should the acyclovir stop working and my brother's condition deteriorate. One train of thought is: if we're only going to get one shot at a conclusive test, we should make it count. Given that our primary theory regarding the negative test results is that the acyclovir is too effectively suppressing the infection, we could schedule an LP, and whatever other tests we can, for a single specific day, then stop the acyclovir perhaps three days beforehand. Expect the symptoms to return, and cross our fingers that if there IS something to be caught this way, it'll get caught. The primary danger here is that the infection could do additional, avoidable damage, and the reprieve could give the infection a chance to regroup, as it were. We're going to talk to the neurologist first and see if this line of thinking is even necessary.

We appreciate any feedback or insight you can offer, about any aspect of this situation.

1. ^{^}

   https://www.hopkinsmedicine.org/health/conditions-and-diseases/encephalitis

2. ^{^}

   https://www.ncbi.nlm.nih.gov/books/NBK557643/

3. ^{^}

   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411519/

Answers

3 comments

Comments sorted by top scores.