Hi, I ran this by Claude Opus, in hopes it would have better advice/ideas than me in this circumstance. So for quick feedback until someone with expertise can chime in:
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This is a complex and concerning medical situation. A few key points and suggestions based on the information provided:
1. The inconsistent efficacy of acyclovir vs. valacyclovir is indeed very puzzling if this is an HHV encephalitis. Normally they should have equivalent effects once metabolized. I'd recommend closely documenting the timing and dosage of each medication along with detailed symptom progression to see if any patterns emerge that could explain this discrepancy.
2. While the CT and MRI not showing abnormalities seems to argue against encephalitis, as you note, it's possible they were done early enough in disease progression, or at a time when inflammation was reduced, to not yet show changes. Serial imaging over time may be more informative.
3. The lack of HSV antibodies is concerning for the leading HSV encephalitis theory. As you mention, possibilities include immunodeficiency, false negatives, or a rarer non-HSV HHV encephalitis. Repeating the HSV antibody tests as well as testing for antibodies to other HHVs like VZV may be worthwhile.
4. I would be very cautious about stopping acyclovir for the purpose of "unmasking" the illness prior to a lumbar puncture. HSV encephalitis can progress extremely rapidly and cause permanent damage. It's crucial to continue presumptive treatment until the diagnosis is certain.
5. Regarding other antivirals - using multiple agents empirically runs risks of unnecessary side effects and drug interactions. I would reserve additional antivirals for cases of confirmed acyclovir resistance or failure of clinical improvement.
6. Continued close follow-up with the neurologist is essential. Push for repeat imaging, LP, and any other indicated testing ASAP. Consider seeking a second opinion from another neurologist or infectious disease specialist if your current providers do not share your sense of urgency.
7. Aside from infectious causes, autoimmune encephalitis is another possibility that can present similarly and is worth evaluating for via LP and antibody tests if infectious work-up is unrevealing.
8. Maintain detailed records of all symptoms, medications, test results etc. to help providers see the full picture.
9. Ensure your brother receives adequate supportive care in the meantime - hydration, rest, safety precautions if mentation is compromised, and management of any comorbidities like hypothyroidism that could complicate his condition.
I commend you for being such a thorough advocate for your brother during this scary time. Keep pushing for answers and comprehensive care. I hope he recovers quickly and completely. Let me know if you have any other questions!
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My own thoughts are that the (other) antiviral might not be being metabolized in the expected fashion, so it's not working the same as if it were metabolized in the expected fashion. Not sure what this is evidence for or against aside from that sticking with the one that works makes sense.
Thanks. In case this additional detail helps anybody: my brother says he'd take valacyclovir two times a day, and it seemed like his rash (and possibly cognitive symptoms, hard to tell) would get worse a couple hours after, then subside.
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.
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.
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:
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.
As for the lack of blood antibodies - we're not sure, and this is worrying.
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.
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.