In one of my favorite lines from Full Metal Jacket a solider notes, “Anyone that runs, is a VC. Anyone that stands still, is a well-disciplined VC!” Or if you prefer, from The Simpsons, Chief Wiggum observes about the ghost cars that he believes haunts the highway near Springfield, “They always come out at night, except during the day.”

These lines are funny because we immediately recognize the flawed logic. They are blatant examples of, “Heads I win, tails you lose.” In scientific terms, no matter what the outcome it is evidence that supports the original hypothesis, rendering the hypothesis unfalsifiable. And yet, as obvious and funny as these examples are, it is easy to make the same mistake ourselves in perhaps less obvious fashion.

Let us take, for example, the Jarisch-Herxheimer reaction (JHR) and its relation to alleged chronic Lyme disease. For background, the JHR was first described by Austrian dermatologist Adolf Jarisch (1895) and German dermatologist Karl Herxheimer (1902). They described a reaction to mercury in treating syphilis, in which the patients would have an exacerbation of their symptoms beginning 1-3 hours after treatment, lasting for about a day. Jarisch hypothesized that the mercury was killing off the syphilis spirochetes in large numbers, and the lysed bacteria were releasing endotoxins which were causing the symptoms.

This is almost exactly right. The reaction, it has recently be discovered, is caused more by nonendotoxin pyrogen and spirochetal lipoproteins which stimulate the immune system, including inflammatory cytokines and tumor necrosis factor. The reaction has also been observed in Lyme disease, which is also caused by a spirochete, and in several other bacterial infections.

Symptoms of JHR include fever, chills (often to the point of rigors), worsening skin rash, and may include hypotension, tachycardia, hyperventilation, flushing, and myalgia (muscle pain). In rare severe cases reactions can include meningitis, alterations in consciousness, seizures, and strokes. Death is very rare, except in young children or those who are already in compromised health.

How does all this relate to unfalsifiable hypotheses and the discipline of possible VC? The issue involves how to interpret symptoms occurring during treatment for alleged chronic Lyme disease. But some further background is necessary. I have already reviewed the issue of Chronic Lyme, so see that article for details, but here is the very quick overview: Lyme disease is a real thing, and infection with a spirochete bacteria that causes a primary, secondary, and possibly tertiary infection if left untreated. Patient with tertiary Lyme can have neurological involvement, including symptoms of meningitis, nerve or spinal cord inflammation, in addition to systemic symptoms. The bacteria is killed off by standard antibiotic treatment, but may require IV antibiotics for tertiary Lyme.

All of this is non-controversial and well-established. However, there is a dubious claim that some patients can have chronic Lyme disease which can survive even IV antibiotic treatment. Treatment reduces the symptoms, but the infection remains chronic and cannot easily be eradicated. The problem with this hypothesis is that proponents have rendered it unfalsifiable by explaining away negative evidence. Patients with alleged chronic Lyme may have negative blood tests for Lyme, but that’s OK because the antibody titers and Western blot tests are not 100%. They may also not have all the classic symptoms of Lyme, but a long list of non-specific symptoms that do not point specifically at an infection or Lyme. They also are not cured by a single round of antibiotics, but that is because, it is argued, they have treatment-resistant strains of the Lyme spirochete.

In essence the argument is that chronic Lyme disease represents an atypical presentation of seronegative treatment-resistant Lyme. That is what we call special pleading – inventing a specific explanation for each instance of evidence (or lack of evidence) that would seem to falsify a hypothesis.

None of this means that patients who are diagnosed with chronic Lyme are not sick. The probably just don’t have a chronic Lyme infection. This is critical because if they are being wrongly diagnosed with a dubious entity then their real diagnosis is being missed, and they may be subjected to multiple rounds of long term IV antibiotics, which is not without risks, to say the least.

Finally we get to the connection to the flawed logic referred to at the top of this article. When patients diagnosed with chronic Lyme are treated, no matter what happens as a response to the treatment is considered by believers to be evidence in support of the diagnosis. If they get better, then that is evidence that the treatment is working. If they get worse, then that is evidence that the treatment is working and they are experiencing the JHR (or “herxing” as the community calls it). If nothing happens, they just need more treatment. No matter what happens or doesn’t happen, it’s chronic Lyme.

Further, just as the symptoms that are used as evidence for chronic Lyme don’t match the actual symptoms of documented Lyme disease, “herxing” after treatment for alleged chronic Lyme can also be highly variable. Here is one chronic Lyme disease site’s description of the JHR:

A Herxheimer Reaction usually causes near-immediate physical symptoms such brain fog, pain, fatigue, and just an overall lack of motivation or passion for anything, but one that lasts for days on end can begin to influence the mentality of a person enduring that Herxheimer Reaction.

You will notice that this does not resemble, except very superficially, the classic description of the JHR. There is no mention of fever, chills, rigor, or hypotension. Instead we get a list of typical non-specific symptoms – similar to the symptoms that lead to the diagnosis of chronic Lyme in the first place. The symptoms can also last for weeks, and fluctuate with good days and bad days. This also does not fit the known pathophysiology of the JHR, which results from starting treatment when there are large numbers of spirochetes that all die and lyse over a short period of time.

Further, I have to note the inherent contradiction here. The JHR results from killing large numbers of spirochetes, and yet chronic Lyme is premised on the existence of treatment-resistant Borrelia burgdorferi (the spirochete that causes Lyme) that can survive antibiotic treatment. You would think that a treatment-resistant strain wouldn’t die off so effectively as to cause a JHR. You can invent an explanation for this as well (a hidden reservoir of the bacteria survives to spread again), but this amounts to more special pleading as there is no evidence for any such explanation nor a reason why it would differ from all our current research into the life cycle of Borrelia burgdorferi.

In science, and in medicine specifically, we have to be careful about the criteria we use to validate or falsify our hypotheses. This is not just in research, but in treating patients as well. We need to decide ahead of time what objective criteria we will use to determine outcomes. It is easy to fall into the trap of ad hoc or post hoc reasoning – interpreting outcomes after the fact. We are great at making everything appear to make sense – just as astrologers are very creative in explaining how behavior, personality, and events are consistent with astrological charts, but only after the fact. They are abysmal at actually making predictions.

Medicine becomes astrology unless we use evidence to decide how we will interpret future data, such as a response to treatment. Related to this is the need to think of signs and symptoms in terms of how predictive they are, not just how typical they are. The predictive value of specific signs relates to how specific they are to one or a category of diagnostic entities. For example, fever may be typical of a specific infection, but it is not very predictive by itself of that one infection because fever can occur in hundreds of entities. This is precisely why we frequently criticize the reliance on non-specific symptoms to allegedly establish the existence of scientifically dubious conditions.

Finally, I want to emphasize that Lyme disease is real, and the JHR is also real and may occur in response to antibiotic treatment for Lyme disease. However, it is a fairly specific reaction in terms of time frame and symptoms, varying mostly in severity. Proponents of chronic Lyme disease, however, rely on a broadening of the possible symptoms, natural history, response to treatment, and reaction to laboratory tests to maintain belief in this entity. They also have to deny the various studies which show a lack of response to treatment for alleged chronic Lyme. Similarly they have taken the concept of the JHR and then applied it to any worsening of symptoms that happens after any treatment for alleged chronic Lyme. This is used to further validate a dubious diagnosis, and to keep patients invested in getting a treatment which the evidence shows not only doesn’t work but may be giving them side effects.


Posted by Steven Novella

Founder and currently Executive Editor of Science-Based Medicine Steven Novella, MD is an academic clinical neurologist at the Yale University School of Medicine. He is also the host and producer of the popular weekly science podcast, The Skeptics’ Guide to the Universe, and the author of the NeuroLogicaBlog, a daily blog that covers news and issues in neuroscience, but also general science, scientific skepticism, philosophy of science, critical thinking, and the intersection of science with the media and society. Dr. Novella also has produced two courses with The Great Courses, and published a book on critical thinking - also called The Skeptics Guide to the Universe.