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The goal of this activity is to better appreciate the controversies surrounding Lyme disease as well as methods to treat the neuropsychiatric sequela.
• Understand the controversies surrounding Lyme disease diagnosis and treatment, including perspectives of different medical communities and patient communities
• Describe common neuropsychiatric presentations of and treatment options for Lyme disease and of posttreatment Lyme disease (PTLD)
This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals seeking to improve the care of patients with mental health disorders.
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Since its first appearance in a group of children in Old Lyme, Connecticut in the late 1970s, Lyme disease has proliferated throughout the United States and abroad. Only 30,000 to 40,000 cases are reported to the Centers for Disease Control and Prevention (CDC) per year, although recent studies looking at the time period between 2010 and 2018 estimate the actual number to be more than 10 times higher at approximately 476,000.1 Lyme disease is transmitted when an infected tick bites a human and injects the causative bacteria, Borrelia burgdorferi, into the skin. The majority of transmission in the United States occurs in the Northeast, mid-Atlantic, and upper Midwest, as shown in Figure 1.1 While 70% to 80% of patients develop an erythema migrans rash,2 the majority of these rashes do not have the classic “bull’s-eye” appearance. Other patients may not recall seeing a rash and may have a flu-like illness with such mild symptoms that they do not seek medical attention. Left untreated, Lyme disease can cause wide-ranging effects, including arthritis, cranial nerve palsy, meningitis, depression, and cognitive impairment.
Even after appropriate diagnosis and antibiotic treatment, some patients continue to experience longer-term symptoms, including fatigue, cognitive problems, or musculoskeletal pain in a condition known as posttreatment Lyme disease syndrome (PTLDS), sometimes also called posttreatment Lyme disease (PTLD). Studies suggest that approximately 10% to 20% of patients who are treated for Lyme disease with the recommended 2- to 4-week course of antibiotics continue to have nonspecific symptoms afterwards.2,3
The Infectious Disease Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR) published joint “2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease”4 that included commentary on the terminology chronic Lyme disease, commonly used in the patient community, expressing concern that it lacks an accepted definition and is applied to a highly heterogeneous population who may have weak clinical or laboratory evidence to confirm prior infection with B burgdorferi. Although the IDSA had previously developed provisional criteria for the more specific subgroup of PTLD, a term preferred by some researchers as it suggests a well-documented prior diagnosis of Lyme disease, they do not mention this term in their latest guidelines and instead refer to “persistent or recurring nonspecific symptoms such as fatigue, pain, or cognitive impairment following recommended treatment for Lyme disease.”4 There continues to be debate and conflict among patients, providers, and researchers about appropriate terminology for patients with chronic symptoms.
The Scope of the Problem and the “Lyme Wars”
There has been conflict and controversy surrounding Lyme disease since its earliest days. In 1970s Connecticut, mothers of children with unusual arthritis symptoms were angered due to feeling dismissed or ignored by public health officials after little was initially done when they told the officials of this unusual clustering of children with arthritis. In the decades following, intense disagreement continued among professional organizations, community doctors, and patients about what is required for a diagnosis of Lyme disease and what constitutes adequate treatment. The most pressing debates today involve how to treat PTLDS.
The recent joint IDSA/AAN/ACR guidelines recommend against repeat antibiotic treatment for patients with persistent or recurring nonspecific symptoms (eg, fatigue) who do not have objective evidence of reinfection with B burgdorferi or treatment failure (Table 1).4 The guidelines define objective evidence of persistent infection or treatment failure as signs of disease activity such as arthritis, meningitis, or neuropathy.
The International Lyme and Associated Diseases Society (ILADS) guidelines (Table 1) recommend “patients with persistent symptoms and signs of Lyme disease be evaluated for other potential causes before instituting additional antibiotic therapy”; however they advocate for “… antibiotic retreatment when a chronic Lyme infection is judged to be a possible cause of the ongoing manifestations and the patient has an impaired quality of life.”5 Some providers adhere to the more rigid IDSA/AAN/ACR guidelines and others follow the more flexible ILADS guidelines, sometimes leading to heated debate. Such debates have also involved patients and their advocates who can feel dismissed or disbelieved. Amid this charged climate that the media have referred to as the “Lyme wars,” physicians and patients alike can feel frightened, alienated, and overwhelmed.
Given the substantial overlap in symptomatology between Lyme disease and common psychiatric disorders, as well as the psychological effects that can result from a stigmatized illness, many psychiatrists will see patients with documented or suspected Lyme disease. It is important for psychiatrists to keep Lyme disease on their list of differential diagnoses, to be familiar with diagnostic and treatment strategies, and to understand the challenges patients and providers face due to this complex illness. The following case and text will highlight signs and symptoms to look for, as well as diagnostic strategies and management approaches for such patients.
“Christina,” aged 45 years, is a mother of 2 children who presented reporting several months of low mood, fatigue, subjective memory problems, and headaches. She tearfully explained that she could barely function and reported feeling dismissed by her primary doctor. Christina briefly saw a therapist in college for stress related to a relationship breakup, but she otherwise has had no history of psychiatric treatment. She had a recent unremarkable exam, including vitals and basic blood work, by her primary doctor, who referred her to the psychiatry department for depression.
Christina was started on sertraline 50 mg with some mild improvement in low mood, but had ongoing fatigue, memory issues, and headaches. On further discussion, you learned that 3 months prior, Christina visited family in Massachusetts for the July 4th holiday. She remembered returning from the party with a flu-like illness, but she tested negative for COVID-19 infection and on a Lyme enzyme-linked immunosorbent assay (ELISA) antibody test the following week. She did not recall having any tick bites or rashes. After you discussed the case with Christina’s primary doctor, he ordered a repeat Lyme ELISA antibody test, which yielded positive results. She was then given a confirmatory immunoglobulin (Ig) -G Western blot test, which also yielded positive results.
Christina received treatment with a course of doxycycline and experienced improvement in her fatigue, headaches, and mood. Two months later, she returned with worsening fatigue and headaches. Looking to the IDSA/AAN/ACR guidelines, Christina’s primary doctor recommended against retreatment with antibiotics, as he felt there was no clear evidence of reinfection or persistent infection. Christina sought a second opinion from another community physician, who did additional lab testing—including cerebrospinal fluid (CSF) studies—to evaluate for tick-borne coinfections and autoimmune disease. Workup was unremarkable, but given her severe symptoms, he treated her with courses of doxycycline and amoxicillin, and her fatigue and headaches improved. However, she continued to struggle with low mood, leading to conflict with her family. She ultimately improved with increasing sertraline to 150 mg and a course of individual therapy with several family meetings.
Beyond the Rash: Signs and Symptoms
Lyme disease can develop after an infected Ixodes scapularis tick bites human skin. Usually, at least 36 hours, and sometimes up to 72 hours of attachment is required to transmit the infection. Notably, Ixodes scapularis ticks may also transmit other infections, including Babesia microti, Anaplasma phagocytophilum, Borrelia miyamotoi, and others. In 70% to 80% of Lyme cases, an erythema migrans rash will develop at the site of the bite, often within 3 to 32 days.2 The rash typically starts as a red patch, that measures approximately 2 or more inches in diameter. This rash is not painful, but it expands over time and may have satellite rashes. As it grows, the initial patch may develop a central clearing, giving it a classic bullseye appearance (Figure 2). Most often, Lyme disease rashes do not have the bull’s-eye appearance and a significant percentage of patients do not recall having a rash at all.
Dissemination of infection beyond the initial localized area can result in a multitude of other symptoms in the following weeks to months. Because the initial immunologic response to Lyme disease involves the release of cytokines, many patients will experience moderate to severe flu-like symptoms during the early disseminated phase of infection (Table 2). A flu-like illness during the summer months in a Lyme disease–endemic area should always raise suspicion for possible B burgdorferi infection. Patients may also experience arthralgias and myalgias; these typically affect large joints and often migrate from 1 joint or muscle to another. When acute Lyme infection targets the nervous system, the patient could develop a myriad of conditions (Table 3). Less commonly, Lyme disease can also affect the liver to cause a mild hepatitis, the eyes to cause conjunctivitis, and the heart to cause myocarditis or atrioventricular conduction block.
Months to years later, if Lyme disease goes untreated, patients may experience late disseminated–stage symptoms, many of which can overlap with symptoms of primary psychiatric illness. Such patients may develop neurological problems that include encephalopathy, encephalomyelitis, and neuropsychiatric symptoms that are less common in the earlier phases of the disease. Lyme encephalopathy involves cognitive problems, specifically impacting short-term memory, verbal fluency, and processing speed, as well as a subjective feeling of brain fog or feeling mentally slowed down. Rarely, it may involve moderate to severe memory loss and personality changes. Lyme encephalomyelitis may result in confusion, hallucinations, paranoia, mania, abnormal movements, lack of coordination, or seizures. Less dramatic, but more common, are the neuropsychiatric symptoms, such as depression and anxiety, that occur in 40% of individuals with disseminated Lyme disease either before or after initial antibiotic treatment (Table 4).6 Paranoia, hallucinations, mania, anger outbursts, and symptoms of obsessive-compulsive disorder are uncommon, although they have been reported. A recent nationwide retrospective cohort study in Denmark by Fallon et al demonstrated that individuals with Lyme borreliosis after a hospital-based diagnosis had increased rates of any mental disorder, of affective disorders, of suicide attempts, and of death by suicide compared to those without Lyme borreliosis.7
Although psychiatric problems can arise during the illness course, it is important to communicate to patients that most psychiatric symptoms in the general population are unrelated to Lyme disease. Treatment of such potentially disabling psychiatric disorders should not be delayed while trying to determine whether or not a patient has Lyme disease. Patients with preexisting anxiety may catastrophize and hyper-focus on information from the media that presents the most frightening consequences of their possible Lyme disease. It may be helpful to explain that whether or not a patient has Lyme disease, treatment of any cooccurring psychiatric disorder, such as major depression or panic disorder, is an essential part of the path to health.
It is also important to note that anchoring to Lyme disease early on, to the exclusion of consideration of other possibilities, can delay diagnosis of other serious medical conditions. The differential diagnosis for neuropsychiatric Lyme disease and PTLDS is wide and includes other tick-borne diseases, psychiatric disorders, autoimmune disease, multiple sclerosis, sleep disorders, fibromyalgia, and others. A 2015 case series published in JAMA Internal Medicine described patients who were misdiagnosed as having persistent symptoms after Lyme disease, but actually had different malignancies, including pituitary adenoma and Hodgkin’s lymphoma.8 Thus, ensuring that patients have had a thorough medical evaluation and follow-up is critical.
The Types and Limitations of Testing
The ideal diagnostic test for Lyme disease would clearly indicate the presence of B burgdorferi and activity or resolution of infection. Unfortunately, available tests fall short of this ideal, leading to conflict over diagnosis and treatment.
Two commonly available blood tests for Lyme disease are the ELISA and Western blot assay. The ELISA is an inexpensive, widely available, quantitative assay that reflects the magnitude of the antibody response (IgM and IgG) to spirochetal proteins. The Western blot assay (IgM and IgG) is an antibody-based test that detects binding of serum antibodies to an array of Borrelia antigens; it previously required interpretation by a skilled laboratory technician, but more recent developments have allowed interpretation by optical scanners. The IgG Western blot is considered highly specific for confirmation of current or past infection with B burgdorferi, while the IgM Western blot is less specific and may result in false positives.
In the 1990s, the CDC recommended a 2-tier testing approach to enhance diagnostic standards (Figure 3). The first step involves ordering an ELISA or immunofluorescence assay (an older test that now is less commonly used). If negative results are obtained, no further testing is recommended. If positive or equivocal results are obtained, then the Western blot assay is ordered. A positive result of the Western blot assay supports diagnosis of Lyme disease. A negative result does not necessarily rule it out, as early antibiotic treatment can abrogate the immune response or the assay may have been conducted too early, before the 2 to 3-week interval required for antibody development.
A central problem, therefore, in the 2-tiered method is that sensitivity varies considerably depending upon on how early in the course of infection a patient is tested and on the specific manifestations of Lyme disease. Studies suggest that sensitivity of the 2-tier approach in early Lyme disease is poor, and only 29% to 45% of patients with Lyme disease will test positive; many may have false-negative assay results, such as early on in Christina’s case.9 Although sensitivity is excellent for Lyme arthritis, it is lower in disseminated neurologic conditions related to Lyme disease. Equally problematic is that a patient may test positive on an antibody test due to past exposure, and a positive test does not indicate treatment failure. The newer C6 ELISA and VlsE/pepC10 ELISA have improved sensitivity, although they are still far from ideal. In 2019, the CDC updated its recommendation to allow a second enzyme immunoassay, such as the C6 ELISA or VlsE/pepC10 ELISA, to be a reasonable substitute for the Western blot assay.10
For suspected neurologic Lyme disease, lumbar puncture is indicated. In central neurologic Lyme disease, CSF analysis typically shows elevated lymphocyte and protein levels with normal glucose levels. Comparing the ratio of antibody levels in the CSF to blood collected on the same day allows determination of the intrathecal index which can provide strong evidence in support of the diagnosis of neurologic Lyme disease. The presence of B burgdorferi DNA on polymerase chain reaction testing is also strong evidence for Lyme disease; however, this test has substantial rates of false negatives among patients with neurologic Lyme disease and thus should not be used to disqualify a patient for antibiotic treatment. Structural and functional MRI as well as single-photon emission computed tomography and positron emission tomography scans have been used adjunctively to aid in diagnosis, but they are not sensitive or specific and may be costly or impractical in some clinical settings.
Neuropsychological testing may be helpful in supporting a diagnosis or measuring response to treatment, with studies showing the most consistently identified deficits in adults with Lyme disease to be problems with verbal memory, information processing speed, and memory-related tasks.11 However, this too can be costly and it yields nonspecific results.
Given the limitations of available tests, diagnosis for Lyme disease must be made considering factors such as the patient’s history of tick exposure, time spent in Lyme disease–endemic areas, clinical symptoms, and laboratory findings. Exciting developments are underway in Lyme disease testing, such as urine-based proteomic assays, blood-based metagenomic assays, and point of care tests, that hopefully will improve diagnostic accuracy and reduce delays in the provision of treatment.9
Treatment of Lyme Disease and PTLDS
Because the diagnosis of Lyme disease is easy to confirm when the erythema migrans rash is present, the research community previously focused its efforts on studying the treatment of early Lyme disease; there have been fewer controlled studies of the later manifestations. Treatment of erythema migrans in adults includes a 10-day course of doxycycline or a 14-day course of cefuroxime or amoxicillin. This results in remission and apparent cure in most cases. Adults with Lyme arthritis can be treated with 28 days of oral doxycycline or amoxicillin. If joint swelling and pain persist, additional antibiotic therapy is recommended with 2 to 4 weeks of IV ceftriaxone. Acute neurologic Lyme disease (including Lyme-disease associated meningitis, cranial neuropathy, radiculoneuropathy, or other peripheral nervous system manifestations) and Lyme-related heart disease requires 14 to 21 days of IV ceftriaxone, cefotaxime, penicillin G, or oral doxycycline.2,4 IV antibiotic therapy is preferred for patients hospitalized with Lyme carditis. IV antibiotic therapy is also recommended over oral antibiotics when parenchyma of the brain or spinal cord is involved. The above treatment recommendations are based on the 2020 guidelines created by the IDSA, AAN, and ACR.4 The ILADS treatment guidelines for Lyme disease differ in general by recommending somewhat longer initial courses of antibiotic treatment.5
When Lyme-triggered symptoms return or persist despite the standard antibiotic recommendations, considerable controversy arises over how to treat these patients. Approximately 10% to 20% of patients treated for Lyme disease have symptoms that can last for more than 6 months and even years after treatment.2,3 Common symptoms include muscle and joint pains, brain fog, fatigue, and sleep disturbance. Such symptoms cause significant distress and functional disability.9
There have been 4 controlled studies of repeated antibiotic therapy for patients with PTLDS in the United States. In 2001, Klempner et al conducted 2 studies (1 for Lyme seropositive patients and 1 for seronegative individuals) randomizing patients to either 1 month of IV ceftriaxone followed by 2 months of oral doxycycline or IV placebo followed by oral placebo.12 Ultimately, no difference was found on the self-reported functional disability outcome measure between the antibiotic and placebo groups. The authors also noted that the treatment itself can cause significant risk, such as blood clotting. In 2003, Krupp et al randomized patients with persistent fatigue after treatment of well-documented Lyme disease to either 1 month of IV ceftriaxone or IV placebo, each followed by 5 months of no treatment.13 Those who received ceftriaxone were significantly more likely than those given placebo to be judged as responders on the fatigue measure at 6 months (69% vs 23%, respectively; P < .01). However, somewhat surprisingly, the authors recommended against retreatment, likely due to the risk of serious adverse events associated with IV antibiotics.
In 2008, Fallon et al randomized patients with Lyme encephalopathy to 10 weeks of IV ceftriaxone or placebo.14 There was overall greater cognitive improvement in the drug-treated group that was apparent at 3 months compared with the placebo group (P = .053), but this improvement was not sustained to 6 months. The authors argued that better treatments resulting in sustained cognitive improvement are needed. When the study was reanalyzed using the methods employed by Krupp et al in their fatigue study, very similar significant findings were found—nearly two thirds showed clinically meaningful reduction in fatigue after IV ceftriaxone compared to only 25% on IV placebo. Interpretation of these 4 studies has varied significantly from the IDSA/AAN/ACR guidelines, which largely recommend against retreatment with antibiotics for patients with PTLDS, to ILADS and others who argue retreatment should be considered for debilitating fatigue, as the only randomized controlled trial designed to assess fatigue found significant and clinically meaningful improvement on the primary fatigue outcome measure.15
Several hypotheses exist to explain persistent symptoms after treatment for Lyme disease. One hypothesis is that such symptoms may represent an immune response to persistent infection with B burgdorferi. To date, multiple studies in animals have shown that B burgdorferi spirochetes can persist following standard recommended antibiotic treatment of a disseminated infection. Less often, case studies in humans have documented persistent bacteria, though it remains unclear whether these spirochetes are metabolically active or causing clinical disease.16 Other hypotheses include postinfectious processes that result in ongoing immune dysregulation, neural network dysregulation such as central sensitization, and preexisting vulnerability to anxiety and somatization.9 However, the exact cause of persistent symptoms is still not well understood, may be complex and multifactorial, and likely differs depending on the patient. A thorough medical evaluation to rule out tick-borne coinfections such as Babesia microti or Borrelia miyamotoi and other unrecognized comorbid medical or psychiatric problems is essential.
Patients with persistent symptoms after Lyme disease treatment may find that their family, friends, and doctors start to question why they still have symptoms, sometimes leading them to feel hurt, disbelieved, and defensive. Ironically, some of the problems typical of PTLDS may well be “in the head” as a result of neural changes induced by the Lyme disease infection or due to the stress and trauma associated with having a relapsing remitting illness. It is, therefore, important to guide patients in considering a trial of therapeutic strategies and to recognize brain- and symptom-focused treatments (eg, use of a serotonin-norepinephrine reuptake inhibitor for depression and pain, psychotherapy for interpersonal and other issues, graded exercise to address deconditioning, CBT and/or medications to improve sleep) that may have direct healing effects on the body.
There is no specific proven treatment for PTLDS at this time, but many patients find that typical treatments offered by psychiatrists can result in decreased pain, increased energy, better cognition, and enhanced quality of life. Additional research is underway internationally to better understand this complex illness, enhance diagnostic accuracy, and improve treatment outcomes.9
Lyme disease is a growing public health problem in the United States. If a sensitive and reliable test of active infection were available, much of the conflict around diagnosis and treatment would be diminished. This is the holy grail that scientists continue to seek. It is important to remember that symptoms of PTLDS (eg, fatigue, head/body aches, sleep difficulties, low mood, irritability, memory problems) can overlap substantially with those of common psychiatric disorders. The treatment approach should be based on the cause—persistent infection, postinfectious factors, or another more likely diagnosis. When psychiatric features are present, the psychiatric care should be optimized to enhance the likelihood of reduced suffering and optimal outcome. As a clinician, you should approach patients with PTLDS or chronic Lyme disease symptoms with humility and compassion, assuming they have been disbelieved by many. Advocate for additional medical workup when appropriate and treat their symptoms with appropriately targeted therapies.
Dr Sotsky is a fellow in consultation-liaison psychiatry at Columbia University Irving Medical Center with a part-time private practice; she formerly was a chief resident at Columbia’s psychiatry residency program. She is co-author of Conquering Lyme Disease: Science Bridges the Great Divide.
1. Kugeler KJ, Schwartz AM, Delorey MJ, et al. Estimating the frequency of Lyme disease diagnoses, United States, 2010-2018. Emerg Infect Dis. 2021;27(2):616-619.
2. Tickborne diseases of the United States: Lyme disease. Centers for Disease Control and Prevention. Reviewed October 1, 2020. Accessed November 15, 2021. https://www.cdc.gov/ticks/tickbornediseases/lyme.html
3. Marques A. Chronic Lyme disease: a review. Infect Dis Clin North Am. 2008;22(2):341-360, vii-viii.
4. Lantos PM, Rumbaugh J, Bockenstedt LK, et al. Clinical practice guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 guidelines for the prevention, diagnosis and treatment of Lyme disease. Clin Infect Dis. 2021;72(1):e1-e48.
5. Cameron DJ, Johnson LB, Maloney EL. Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease. Exp Rev Anti Infect Ther. 2014;12(9):1103-1135.
6. Fallon BA, Nields JA. Lyme disease: a neuropsychiatric illness. Am J Psychiatry. 1994;151(11):1571-1583.
7. Fallon BA, Maden T, Erlangsen A, Benros ME. Lyme Borreliosis and association with mental disorders and suicidal behavior: a nationwide Danish cohort study. Am J Psychiatry. 2021;178(10):921-931.
8. Nelson C, Elmendorf S, Mead P. Neoplasms misdiagnosed as “chronic Lyme disease.” JAMA Intern Med. 2015;175(1):132-133.
9. Fallon B, Sotsky J. Conquering Lyme Disease: Science Bridges the Great Divide. Columbia University Press; 2018.
10. Mead P, Petersen J, Hinckley A. Updated CDC recommendation for serologic diagnosis of Lyme disease. MMWR Morb Mortal Wkly Rep. 2019;68(32):703.
11. Rebman AW, Aucott JA. Post-treatment Lyme disease as model of for persistent symptoms in Lyme disease. Front Med (Lausanne). 2020;7:57.
12. Klempner MS, Hu LT, Evans J, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med. 2001;345(2):85-92.
13. Krupp LB, Hyman LG, Grimson R, et al. Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology. 2003;60(12):1923-1930.
14. Fallon BA, Keilp JG, Corbera KM, et al. A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology. 2008;70(13):992-1003.
15. Fallon BA, Petkova E, Keilp JG, Britton CB. A Reappraisal of the U.S. Clinical Trials of Post-treatment Lyme Disease Syndrome. Open Neurol J. 2012;6:79-87.
16. Bobe JR, Jutras BL, Horn EJ et al. Recent progress in Lyme Disease and remaining challenges. Front Med (Lausanne). 2021;8:1276. ❒