Alison W. Rebman, Kathleen T. Bechtold, Ting Yang, Erica A. Mihm, Mark J. Soloski, Cheryl B. Novak and John N. Aucott. The Clinical, Symptom, and Quality-of-Life Characterization of a Well-Defined Group of Patients with Posttreatment Lyme Disease Syndrome. Front. Med., 14 December 2017 | https://doi.org/10.3389/fmed.2017.00224
Background: The increased incidence and geographic expansion of Lyme disease has made it the most common vector-borne infection in North America. Posttreatment Lyme disease syndrome (PTLDS) represents a subset of patients who remain ill following standard antibiotic therapy for Lyme disease. The spectrum of symptoms and their impact on quality of life remain largely unexplored among patients with well-documented PTLDS.
Objective: To characterize a case series of patients with well-documented PTLDS compared to a sample of healthy controls.
Methods: Sixty-one participants met the proposed case definition for PTLDS. Twenty-six healthy controls had neither a clinical history of Lyme disease nor current antibodies to Borrelia burgdorferi. Participants with PTLDS and controls were evaluated by physical exam, clinical laboratory testing, standardized questionnaires, and a 36-item current symptom list.
Results: Compared to controls, participants with PTLDS reported significantly greater fatigue, pain, sleep disturbance, and depression (Fatigue Severity Scale: 50.0 ± 10.6 vs. 19.8 ± 8.6; Short-Form McGill Pain Questionnaire: 13.7 ± 8.3 vs. 0.8 ± 1.9; Pittsburgh Sleep Quality Index: 10.1 ± 4.7 vs. 4.1 ± 2.1; Beck Depression Inventory-II: 15.1 ± 7.7 vs. 2.2 ± 3.2; p < 0.001 for each), and significantly lower quality of life (SF-36 Physical Component Score: 33.9 ± 9.7 vs. 55.1 ± 6.2; Mental Component Score: 42.9 ± 10.1 vs. 54.2 ± 5.4; p < 0.001 for each). Nineteen non-PTLDS-defining symptoms were found to be significantly more severe among participants with PTLDS than controls, including sleep difficultly and visual complaints. Initial delayed or misdiagnosis was characterized in 59.0% of participants with PTLDS, and 32.2% had abnormal vibratory sense.
Conclusion: Although physical exam and clinical laboratory tests showed few objective abnormalities, standardized symptom questionnaires revealed that patients with PTLDS are highly and clinically significantly symptomatic, with poor health-related quality of life. PTLDS patients exhibited levels of fatigue, musculoskeletal pain, sleep disturbance, and depression which were both clinically relevant and statistically significantly higher than controls. Our study shows that PTLDS can be successfully identified using a systematic approach to diagnosis and symptom measurement. As the prevalence of PTLDS continues to rise, there will be an increased need for physician education to more effectively identify and manage PTLDS as part of integrated patient care.
From the article
Results from the physical exam and laboratory testing in our sample of patients with PTLDS did not show a pattern of significant objective abnormalities. The most notable exception was the higher rate of diminished vibratory sensation on physical exam among participants with PTLDS (32.2%), compared to the 5% expected to fall below the age-adjusted cutoffs used in this analysis. This abnormality were not only present among those with a prior diagnosis of neurologic Lyme disease or a later diagnosis of neuropathy but also among those without a specific prior neurologic diagnosis. This finding was also observed in a previous population-based study, in which decreased vibratory sense was noted in 29% of a sample of individuals with prior Lyme disease, and was one of the sole physical exam findings to differ significantly from controls. Additionally, although only found in a small subset of our sample (3.4%), two participants met criteria for postural orthostatic tachycardia syndrome, an autonomic condition that has been previously reported following Lyme disease. Laboratory tests, including complete blood count, complete metabolic count, and C-reactive protein, showed no significant difference between participants with PTLDS and controls. The rates of current two-tier IgG-WB positivity among those with confirmed early (7/36, 19.4%) and late (4/6, 66.7%) Lyme disease were similar to those found in a 10- to 20-year follow-up study of treated patients assessed to have good overall health (22), further emphasizing that current serology cannot be used as a diagnostic marker for PTLDS.
By contrast, participants with PTLDS reported prominent symptoms that are often diverse and can be moderate to severe in nature. We expected that current symptom severity of fatigue, pain, and cognitive complaints would be higher among PTLDS participants than controls, given that presence of at least one of these symptoms was included in both the IDSA proposed case definition and our enrollment criteria. Indeed, severe levels of each of these were reported by 50.0 (30/6), 28.3 (17/60), and 23.3% (14/60) of participants with PTLDS, respectively, compared to none of the controls for each. Standardized questionnaire scores on fatigue and pain for these participants were also considerably worse than clinically relevant cutoffs (FSS: 55.9 ± 5.9; SF-MPQ: 15.9 ± 6.9; p < 0.001 for both). Previous studies have suggested that fatigue and cognitive symptoms are common, and may be particularly important contributors to decreased functioning in this syndrome (38, 39). As Lyme disease incidence continues to increase in endemic regions and spread to new geographic areas (2), PTLDS is likely to be increasingly relevant in the differential diagnosis of patient-reported symptoms commonly encountered by the general internist.
Participants with PTLDS also reported significantly higher severity of an additional 19 diverse symptoms that were not part of the IDSA criteria but which could be diagnostically and clinically relevant. Among these, sleep difficulty was the most frequently reported current symptom, and the symptom with the highest difference in proportion reporting “moderate” or above between cases and controls, suggesting that it may be a clinically important component of this syndrome. Sleep difficulty has been previously identified in the context of Lyme disease, and was found to correlate highly with fatigue in one study. In our sample, severe sleep difficulty was reported by 31.7% (19/60) of participants with PTLDS and none of the controls, and their PSQI scores were significantly worse than the clinically relevant cutoff for poor sleep quality (PSQI: 14.0 ± 3.5, p < 0.001). Additionally, severe visual clarity issues and photophobia were reported by 5.0 (3/60) and 8.3% (3/60) of our sample of participants with PTLDS respectively, compared to none of the controls. Although ophthalmologic signs can occur in untreated disease, persistent subjective symptoms have not been described extensively in PTLDS. Finally, those symptoms not statistically significantly different between participants with PTLDS and controls notably included objective signs of rheumatologic, neurologic, or ocular involvement (such as joint swelling, drooping facial muscle, and double vision) that traditionally distinguish untreated Lyme disease from the posttreatment phase …
Our study is limited by the fact that no definitive biomarker exists either for B. burgdorferi infection or PTLDS. As such, we cannot be completely certain that our participants with PTLDS had initial signs and symptoms that were correctly attributed to Lyme disease at illness onset. To minimize this risk, we required medical record documentation to establish the initial signs and symptoms, diagnosis, and treatment for Lyme disease that adhered to the IDSA proposed case definition, which few prior studies have done. We also cannot be completely certain that these symptoms are attributable to PTLDS and not other co-morbidities, as was suggested by a recent publication. To address this potential confounding effect, our study compared participants with PTLDS to a healthy control group recruited following the same exclusionary criteria, which included a range of conditions independently associated with fatigue, pain, and cognitive dysfunction. Furthermore, while the inclusion of LD-probable patients could also presumably lower specificity of our findings, our analysis did not find a prominent pattern of difference between LD-probable and LD-confirmed groups. Lastly, our study is limited by an inability to address the possibility of recall bias for those variables which were based on self-report and not medical record review.