Post Treatment Lyme Disease Syndrome (PTLDS)

Some Lyme patients continue to have symptoms after they have been treated with antibiotics. 10-20% of the patients in the early and disseminated stage of the infection and 30% or even more of the patients in the late stage of Lyme disease will continue to have lingering symptoms. These ongoing symptoms include severe fatigue, pain, depression, headaches and concentration problems. It can be very debilitating and prolonged.

Risk factors for Post Treatment Lyme Disease Syndrome (PTLDS) include delayed diagnosis, increased severity of initial illness and the presence of neurologic symptoms.

The cause of PTLDS is unknown but scientists believe there could be four reasons for these ongoing symptoms that can overlap:

  1. persistence of Borrelia spirochetes
  2. auto-immune and immune response to antigenic debris
  3. co-infection with other tick borne organisms such as Babesia and Bartonella
  4. residual tissue damage

Immunologic mechanisms of persistent symptoms

Earlier I have written an article based on the hypothesis that the Lyme bacteria survive the antibiotic treatment and that these ongoing symptoms might be caused by persisting infection.

However, some patients that have been given antibiotics (even for years on end by some ILADS doctors) don’t recover and keep having these chronic symptoms. Patients don’t like to hear that their condition is currently not treatable and they demand long-term antibiotics because having to accept that your condition is not treatable doesn’t offer hope.

Antibiotics can’t only harm the individual patient, there is also a responsibility towards the community at large: by prescribing antibiotics we also promote the development of super-bugs and antibiotic resistant infections will become a serious threat to public health within the next 10-20 years.

Experts on Lyme disease have done many studies towards the immunological mechanisms that could be involved in the persistence of these symptoms.

1. Anti-neural antibodies

In patients with persistent symptoms after antibiotic therapy there seems to be an abnormal immune response to neural antigens. This response is not seen in the post-treatment healthy patients. The immune response to neural antigens was not dependent on seropositivity or seronegativity. Patients can be treated timely with antibiotics aborting the development of antibodies but this doesn’t prevent the development of PTLDS.

The reason  for this abnormal immune response could be due to neural injury as a result of Borrelia infection which could explain why patients who develop neurologic Lyme disease are more at risk of developing PTLDS. Borrelia is known to be a potent polyclonal B cell activator and it might be that Borrelia is capable of inducing non specific B-cell proliferation in genetically predisposed individuals which will result in the development of anti-neural antibodies.

Re-treatment with antibiotics did not have an effect on the amount of these anti-neural antibodies in PTLDS patients which makes it less likely that these antibodies are caused by ongoing infection.

PTLDS and Chronic Fatigue Syndrome are different conditions

Because patients with chronic fatigue syndrome (ME/CFS) have similar clinical symptoms to PTLDS patients with fatigue, pain, depression, headaches and concentration problems some doctors think that Lyme disease could be the cause of their chronic fatigue syndrome.

Scientists looked at the levels of anti-neural antibodies in ME/CFS patients because this condition is suspected to have an immunological basis too. Researchers however did not see any reactivity in ME/CFS patients above the healthy controls. This further proofs that PTLDS and chronic fatigue syndrome are different conditions.

2. Cytokine abnormalities

Interferon alpha (IFN-α) has been associated with cognitive impairment both in humans and in animal models. Serum from PTLDS patients with objective cognitive deficits shows increased IFN-α activity but the serum from healthy post-Lyme patients and healthy controls didn’t show increased IFN-α activity.

The IFN-α activity did not change significantly in response to antibiotics. The increase in IFN-α activity is suggestive of a mechanism contributing to the ongoing neuropsychiatric symptoms.

Transgenic mice that overexpress IFN-α from astrocytes display severe encephalitis and cognitive abnormalities and intraventricular infusion of IFN-α into the brain provokes behavioral alterations and concomitant changes in expression of serotonin and pro-inflammatory cytokines.

The authors of the study looking at IFN-α hope that treatments that aim to inhibit IFN-α activity will be effective in improving the cognitive functioning of PTLDS patients.

3. Immune response to Borrelia burgdorferi proteins/epitopes

The antibody response to Borrelia burgdorferi antigens in PTLDS patients is different from post-Lyme healthy patients. Most strikingly is the antibody response to Osp-A which is a lot higher in patients who have post treatment symptoms in comparison with patients who do not have post treatment symptoms. The antibody response to Osp-B, P30 and P38 also show differences in comparison with post-Lyme healthy patients.

Osp-A and Osp-B antibody responses are associated with late stages of Lyme disease which could explain why delayed diagnoses poses a significant risk to developing PTLDS. But also the patients that develop PTLDS in the early phase have a stronger antibody response to Osp-A.

This observed antibody response may indicate persisting attenuated forms of the Lyme bacteria or antigenic debris in certain tissues after antibiotic treatment in some PTLDS patients. This could be the reason for a continuing significant antibody response. Or they might have been infected with a different strain of Borrelia burgdorferi.

Late neurologic Lyme disease

The later stages of neurologic Lyme disease are associated with a stronger antibody response to two specific epitopes of the VlsE antigen. Immune response to the C6 region of VlsE develops early on in Lyme disease, but the immune response towards the membrane proximal domain of VlsE develops much later and is associated with late manifestations of Lyme disease.

A good question would be if patients with antibodies to membrane-proximal domain of VlsE are more likely to develop PTLDS.

The observed elevated antibody response to specific borrelial proteins adds to the evidence for the existence of a differential immune response in PTLDS patients.

Summing up

This article might be beyond what many patients are capable of understanding but it is important to write for the individuals who are able to follow these findings. This further points into the direction that the symptoms that 10-20% of the patients continue to experience after antibiotic therapy could be caused by an auto-immune and immune response to antigenic debris. At the same time it doesn’t dismiss the possibility of persistence of the spirochete in some form.

The experts that have put tremendous work into this have been accused of horrible things and have been threatened by patient groups. They have been called everything from criminals to scientists with tunnel vision. However, these scientists are on the front of solving the mystery of PTLDS since many patients still suffer from these symptoms even if their doctor liberally prescribes antibiotics for their Lyme infection in the first place.

This is so cool! Based on these findings scientists can continue their search for answers and some day design new treatments that can address these causes and help patients lead normal lives again. Science is so exciting!

References