A Clinical Diagnostic System for Late-Stage Neuropsychiatric Lyme Borreliosis Based upon an Analysis of 100 Patients

Many late-stage chronic Lyme disease clinical findings are neuropsychiatric. A total clinical assessment is critical in diagnosis, especially since controversy surrounds the reliability of laboratory testing. The clinical findings of one hundred Lyme disease patients with chronic neuropsychiatric symptoms were entered into a database. The prevalence of each clinical finding pre-infection and post-infection was compared and calculated within the 95% confidence interval. Patients had minimal symptoms pre-infection, but a high post-infection prevalence of a broad spectrum of acquired multisystem symptoms. These findings included impairments of attention span, memory, processing, executive functioning, emotional functioning, behavior, psychiatric syndromes, vegetative functioning, neurological, musculoskeletal, cardiovascular, upper respiratory, dental, pulmonary, gastrointestinal, genitourinary, and other symptoms. The most prevalent symptoms included sustained attention impairments, brain fog, unfocused concentration, joint symptoms, distraction by frustration, depression, working memory impairments, decreased school/job performance, recent memory impairments, difficulty prioritizing multiple tasks, fatigue, non-restorative sleep, multitasking difficulties, sudden mood swings, hypersomnia, mental apathy, decreased social functioning, insomnia, tingling, word finding difficulties, name retrieval, headaches, sound hypersensitivity, paresis, anhedonia, depersonalization, cold intolerance, body temperature fluctuations, light sensitivity and dysfluent speech. The average patient had five symptoms pre-infection and 82 post-infection. Pattern recognition is critical in making a diagnosis. This study was used to develop three clinical assessment forms.


Historical Perspective
Lyme borreliosis, also called Lyme disease, is a tick-borne disease caused by an infection with Borrelia burgdorferi sensu lato complex, a spirochete that is more complex and more difficult to treat than syphilis [1,2]. Other tick-borne diseases and opportunistic infections may accompany the Borrelia infection and contribute to a complex interactive infectious process [3]. It has been called by many different names throughout the past 100 years including acrodermatitis chronicum atrophicans in Europe for a characteristic late-stage rash. Lyme disease was at one time called Lyme arthritis and early clinical diagnostic criteria focused heavily upon the erythema migrans rash, migratory arthralgia, arthritis, and Bell's palsy. A large number of symptoms associated with Lyme disease have been documented, however there is wide variability of specific symptoms present in a given patient. This makes it difficult to establish clearly defined diagnostic criteria, especially for late-stage disease. A number of definitions for the late-stage, chronic, manifestations have been proposed [4][5][6]. Like syphilis, the symptoms that occur later in the course of the illness are different from the early symptoms. It is well recognized that some patients with Lyme disease have persistent, late-stage, chronic neuropsychiatric symptoms [7][8][9]. Recognizing the full spectrum of these symptoms and quantitating the severity of these symptoms are major challenges. It is difficult to measure a disease when laboratory tests have significant limitations and clinical presentations can be highly variable [10][11][12][13]. These limitations compromise the accuracy of both diagnosis and the measurement of response in clinical treatment and vaccine studies.

Assessment, Total Clinical Assessment or Laboratory Assessment?
A tradition in mainstream medicine is to first perform a thorough clinical exam, to then consider lab tests when they might help with the diagnosis, and to use clinical judgment to develop an individualized diagnosis and treatment plan. We treat patients, not diseases [14]. An individualized approach is particularly significant when dealing with complex and poorly understood multisystem diseases. In opposition to this conservative and traditional approach, some have attempted to oversimplify the diagnosis of Lyme disease by reducing the diagnosis to reliance upon the United States Centers for Disease Control and Prevention (CDC) surveillance definition [15]. However, the surveillance definition has never been intended to be a sole diagnostic criterion, particularly in late-stage disease. Although meeting the surveillance definition for Lyme disease may confirm the diagnosis, not meeting the surveillance definition does not rule out the diagnosis of the disease. This has been emphasized by the Centers for Disease Control and Prevention and has been supported by studies performed by them [16,17]. In spite of this warning, many physicians fail to perform adequate clinical examinations when suspecting Lyme disease, and by default place excessive reliance upon laboratory testing that can be highly flawed [10][11][12][13].
The excessive reliance upon laboratory testing, particularly when dealing with the chronic, late-stage manifestations results in considerable controversy. The most commonly used laboratory testing has never been standardized for late-stage disease, and the commonly used antibody detection methods are of questionable value when testing for a microbe that evades and suppresses the immune system [18].
A total clinical assessment is a diagnostic standard of care throughout medicine, and there is no reason why Lyme disease should be an exception. The chronic, late-stage clinical findings are associated with a broad spectrum of neuropsychiatric and other multisystem symptoms. Although some diagnoses can be made with specific signs and symptoms, other conditions instead require a recognition of symptom patterns and disease progression patterns. Since no two patients with late-stage manifestations of Lyme disease show exactly same symptoms, establishing diagnostic clinical criteria is challenging. A structured clinical assessment has previously been described for the diagnosis and assessment of patients when their screening suggests Lyme disease should be considered in the differential diagnosis [9]. Several studies have addressed the prevalence of different symptoms associated with neuropsychiatric Lyme disease [9,[19][20][21][22][23][24][25][26][27][28][29][30][31]. Two prior studies looked at the prevalence of clinical findings pre-infection and post-infection. However, these studies focused on Lyme disease patients who were suicidal and aggressive [32,33]. Although several studies describing clinical findings were performed previously, no prior study looked at the broad spectrum of clinical findings associated with chronic, late-stage, neuropsychiatric Lyme disease and compared these findings to the baseline state of health. Recording the type of clinical findings and documenting the prevalence of these findings may assist in establishing a reference point of pattern recognition when performing an overall clinical assessment when a clinician is suspecting a diagnosis of late-stage neuropsychiatric Lyme disease. Such a clinical assessment system would be useful in diagnosing these patients, establishing an individualized treatment plan, and assessing treatment response.

Clinical Assessment Scales and Treatment Studies
Lyme disease treatment studies that are frequently referenced use clinical assessment scales that were not specifically developed for Lyme disease. For example, both the Berende and the Klempner studies used the Health Status Inventory Short Form to measure treatment effectiveness [34,35]. However, this scale is a general level of functioning scale, highly subjective, and it was not designed or standardized to measure level of functioning for Lyme disease [36]. Other treatment studies only measured specific symptoms. The primary outcome in the Fallon study was neurocognitive performance, specifically, memory [37]. The primary clinical outcomes measured in the Krupp study was fatigue, measured by the Fatigue Severity Scale and cognitive functioning (mental speed) [38]. When an assessment that does not fully measure the symptoms associated with Lyme disease are used in a study, it may result in inaccurate results. A diagnostic system is needed that fits with the full clinical spectrum of symptoms seen in late-stage Lyme disease.

Materials and Methods
The objective of this study is to describe the clinical presentation of Lyme borreliosis patients with chronic, late-stage, psychiatric symptoms from a retrospective review of 100 charts, and to develop a clinical assessment system from these findings.
The first author specializes in working with treatment-resistant psychiatric illnesses. Some of these treatment resistant patients had psychiatric symptoms associated with Lyme disease. The first author initially developed the assessment form used in this study over 20 years ago and has used this assessment to evaluate a few thousand patients when late-stage Lyme disease was part of the differential diagnosis. The same assessment was performed on all patients by the first author. In the process of performing the assessment, the date of infection was first established. The presence of each clinical finding was established during the examination at the baseline before infection (pre-infection), the emergence of the clinical finding since becoming infected, and the presence of the clinical finding at the time of the assessment. All assessments on each clinical finding were personally performed by the first author, who is a board-certified psychiatrist. No information on these patients was obtained from self-reported check lists. Family members and/or significant others were often present during the evaluation and their participation often helped improve the accuracy of the assessment. When a clinical finding was fully present, a (+) was entered in the assessment form. When a clinical finding was partially present, a (+/−) was entered in the assessment form. If a clinical finding was only slightly present, a (sl) was entered on the assessment form. When a clinical finding was absent, a (−) was entered in the assessment form.
Inactive charts were reviewed to search for charts in which the full assessment was performed documenting psychiatric symptoms associated with Lyme disease. All patients in this study resided in the Continental United States and appear to have been infected in the Continental United States. Since Lyme disease impacts all age groups no age exclusionary criteria were used in this study, with the exception that no congenital Lyme disease cases were included in this study. Inclusion criteria for this study were charts documenting psychiatric findings in patients who had met the Centers for Disease Control and Prevention surveillance definition for Lyme disease. These criteria included erythema migrans rash, nervous system criteria, musculoskeletal criteria, cardiovascular criteria and/or laboratory criteria and most patients met more than one criterion. More specifically, 100% met neurological criteria with cranial nerve and other neurological findings, 81% met the musculoskeletal criteria, 52% met the criteria based upon erythema migrans rash, and 11% met cardiac criteria with heart block. In addition, 100% met laboratory criteria with all having positive Lyme Western blots, some on multiple testing, some were also positive with spinal fluid testing and polymerase chain reaction testing for DNA. Only testing from laboratories validated by the Clinical Laboratory Improvement Amendments of the United States Department of Health and Human Services Centers for Medicare and Medicaid Services was considered valid. Charts in which the diagnosis of Lyme disease was unclear or where the diagnosis of Lyme disease was based upon total clinical criteria, but not meeting Centers for Disease Control and Prevention surveillance criteria were excluded from this study.
Names were converted to an identifier before entering the findings into aggregate data. The aggregate data of baseline health status for each clinical finding before infection served as a control for each clinical finding. The aggregate data of pre-infection and post-infection findings was compared. In addition, the clinical findings assessed included age, sex, documented history of whether there was exposure to an area endemic to Lyme disease, a tick bite, the presence of erythema migrans rash, a flu-like illness, and a reoccurrence of an erythema migrans rash and the length of time between infection and initial antibiotic treatment. The clinical findings were organized into the following categories-attention span; memory; processing; executive functioning; imagery; emotional; behavioral; psychiatric syndromes; vegetative functioning (energy, sleep, eating, sex, temperature control); neurological (headaches, cranial nerves, seizures, other); musculoskeletal; cardiovascular; upper respiratory, dental and pulmonary; gastrointestinal; genitourinary; other; and symptom patterns.
The total impairments of all the 100 patients analyzed was recorded pre-infection and post-infection. When a clinical finding was fully present, it was entered into the database as (1). If a clinical finding was partially present (+/−), it was entered as (0.5). If a clinical finding was only slightly present (sl), it was entered into the database as (0.25). If a clinical finding was not present (−), it was entered as (0). When a clinical finding was not relevant or not addressed in 100% of the patients, the percent was calculated accordingly. The number of patients demonstrating each clinical finding was added and the 95% confidence interval was calculated to determine the diagnostic relevance for each clinical finding.
Since the 100 patients studied or their family members present at the evaluation might have difficulty correctly remembering their pre-infection health status, two secondary control groups were established to assess the validity of the primary control group. The two secondary control groups include the United States National Comorbidity Survey Replication of the prevalence of 12 month Diagnostic and Statistical Manual-IV mental disorders, and the same assessment on heathy medical students who do not have Lyme disease [39].
The post-infection clinical findings were then compared to two other groups. One group was an age-matched group of patients who were evaluated with the Lyme disease assessment but were found to have some other condition. The other group was a comparison to post-infection clinical findings that were seen in a review of other studies [9].
Clinical assessment forms were then created that a clinician can download from this article and use when assessing the possibility of chronic, late-stage, neuropsychiatric Lyme borreliosis. Some clinical findings are added to the list for future reference that contains no data in this retrospective study. These are clinical findings the first author has seen in some Lyme disease patients, but the prevalence was not analyzed in this chart review. The forms provided include three forms-a common symptom 61-item form, a 24-item pre-evaluation form and a full assessment. The common symptom 61-item form includes all the clinical findings that are present in ≥50% of the patients. The short form consists of 24 questions that reduces the information collection but is faster and easier for patients to complete in an unsupervised environment, for example prior to the clinician visit. The questions were selected based on the presence of symptoms in ≥50% of more of study patients and it only included question considered to be understandable to the general public. The full assessment is more thorough and includes all the clinical findings found to be statistically significant and clinically significant, as well as some clinical findings that appear to be clinically significant but have no database for comparison.

Ethical Considerations
The Hackensack Meridian Health Institutional Review Board, Neptune, NJ, USA, approved this study (IRB # 201704192J). Patient consent to review their medical records was not required by the Institutional Review Board as there was minimal risk to subjects, no subject identifiers or links to identifiers were used or collected, and it was a retrospective chart review of already existing data.

Results, Overview
Among the 100 charts reviewed, the average age was 38, with the youngest being 6 years old and the oldest being 89 years old. There were 41 males and 59 females. There were 85 between 18 and 65 years old; 5 older than 65, including 3 who were older than 69; and 10 below 18, including 3 who were below age 13. All in this study appear to have been infected in the United States. Ethnicity and race were not recorded. There was a history of exposure to an endemic area in 98%, a history of tick bite(s) in 60%, an erythema migrans rash in 53%, early flu-like symptoms in 68%, and a recurrent erythema migrans rash in 37%. All met United States Centers for Disease and Prevention surveillance definition at some point in the course of their illness. There were 30 who were diagnosed and treated within 6 months of infection but continued to have disease progression and the development of chronic, late-stage clinical findings. The 70 others had a delayed diagnosis and treatment, with the average delay being 9 years. The longest delay between infection and treatment was 40 years. The average age at the time of infection was 30 years old.
The average patient had five (4.59) clinical findings pre-infection and 82 (82.02) clinical findings post-infection. Most clinical findings evaluated showed a statistically significant difference when comparing the prevalence of these clinical findings pre-infection to the prevalence of the same clinical findings post-infection. There were some clinical findings that showed an increase when comparing the prevalence pre-infection to the prevalence post-infection, but not a statically significant increase. These clinical findings include intrusive sexual images, homicidality, posttraumatic stress disorder, papilledema, iritis, uveitis, optic neuritis, grand mal seizures, partial seizures, Tourette's, torticollis, periostitis, pericarditis, murmur, hypertensive crisis, gastroparesis, hepatitis, pancreatitis, gall stones, inflammatory bowel, interstitial cystitis, acrodermatitis chronicum atrophicans, and lymphocytoma. The only clinical findings assessed that showed no increase post-infection were spasticity and erythema of the palms and soles.

Statistically Significant Clinical Findings
Clinical findings comparing pre-infection health to post-infection health with the 95% confidence intervals demonstrated a statistical difference for multiple sign and symptoms and are shown in Table 1.

Sexual functioning
Decreased libido

Temperature control
Intolerance to cold

Headache (neurological and musculoskeletal)
Headache

Cranial nerves
I Olfactory: loss of smell, altered taste 2% (0-5%) 22% (14-30%) II Optic (and ophthalmologic) Photophobia to bright light no data III, IV, VI Double vision or eye drifts when tired, ptosis no data IX, X Episodic loss of speech, choking on food, difficulty swallowing XI. Sternocleidomastoid and trapezius pain and/or paresis

Other neurological
Tingling Upper respiratory, dental, and pulmonary Cyclic vomiting no data
The following are a list of impairments demonstrating a statistically significant difference when comparing pre-infection status to post-infection status within the 95% confidence interval.

•
Cognitive impairments include impairments of attention, memory, processing and executive functioning. Impairments of attention include impaired sustained attention and allocation of attention, distraction by frustration, hypersensitivity to sound, hypersensitivity to light, hypersensitivity to touch and hypersensitivity to smell. Processing impairments include letter reversals, spelling errors, word substitution errors, number reversals, spatial perceptual distortions, optic ataxia, left-right confusion, and impairments of reading comprehension, auditory comprehension, sound localization, transposition of laterality, calculation, fluency of speech, fluency of written language and handwriting. Executive functioning impairments include unfocused concentration, brain fog, racing thoughts, obsessive thoughts, mental apathy and difficulty with multitasking and abstract reasoning.

Validating the Pre-Infection Control Group with Other Control Groups
Two secondary healthy control groups contributed to assessing the validity of the primary pre-infection control group. The results of the United States National Comorbidity Survey Replication of the prevalence of 12 month Diagnostic and Statistical Manual-IV mental disorders was used to contribute to the validation of the prevalence of pre-infection clinical findings, and a survey of healthy medical students was used to contribute to validating the number of pre-infection clinical findings seen in a healthy control group.

Comparison of the Pre-Infection Control Group to the National Comorbidity Survey
The United States National Comorbidity Survey Replication of the prevalence of 12 month Diagnostic and Statistical Manual-IV mental disorders assesses the prevalence of some of the mental disorders that were also calculated in the pre-infection baseline [39]. Disorders included in both the Comorbidity Study and the Lyme assessment include panic disorder, obsessive compulsive disorder, social anxiety disorder, generalized anxiety disorder and posttraumatic disorder. Since dysthymia (1.5%) and major depression (6.7%) were calculated separately in the National Comorbidity Survey and together in the Lyme disease survey, these two statistics were added together. Also, intermittent explosive disorder was in the National Comorbidity Survey, which was comparable to explosive anger in the Lyme disease survey. The close correlation between the two surveys contributes to the validation of the accuracy of the pre-infection control group. The comparison between the Lyme pre-infection control group and the National Comorbidity Survey is shown in Table 2.

Comparison of the Pre-Infection Control Group to a Healthy Control Group
To help validate the baseline of the average subject before infection, records were retrieved where the assessment had been administered anonymously to 23 healthy medical students during an educational program on Lyme disease which discussed the use of this assessment form for the evaluation of Lyme disease. Any record showing a history of Lyme disease was not included in the data. The average age of the participants was 24. There were 16 with no history of tick bites and seven with a history of tick bites. There were 22 with no history of a bull's eye rash and one with a history of a bull's eye rash. The average number of clinical findings in this group was four. The greatest number of clinical findings was 13 and the least was 0.

Comparison of Post-Infection Clinical Findings
In the database, 10 charts, which represented an age-matched control group, were reviewed. These patients were assessed for the possibility of Lyme disease, but were diagnosed with conditions other than Lyme disease. In this group, the average age was 33 years old. The age range was 7 years old to 73 years old. The average age was 33 years old. The average number of clinical findings in this group was 22 (21.7).

Comparison of Post-Infection Clinical Findings to Other Studies
The post-infection findings of this study can be compared to the findings seen in other groups of Lyme disease patients that have previously been published in 20 other studies of Lyme disease that have included a total of 23 different patient groups. The groups with the most severe symptoms were the Lyme disease patients who were homicidal, followed by the patients who were suicidal [9]. Table 4 compares the post-infection clinical findings to the prevalence of the same findings in other studies.

Discussion
It is recognized these patients were seeking treatment by a psychiatrist and therefore there was probably a selection bias of Lyme disease patients who had a greater number of psychiatric manifestations. Therefore, this assessment is particularly useful when evaluating patient who may have neuropsychiatric symptoms and there is the suspicion that these symptoms may have been caused by Lyme disease. This study helps to demonstrate the broad spectrum of neuropsychiatric and other symptoms that are seen as late-stage manifestations of Lyme disease. The results of this study are a database to develop assessment tools that can be used in the assessment of patients when the diagnosis of Lyme disease is part of the differential diagnosis. Have antibiotics ever caused a sudden worsening followed by an improvement of symptoms?" If the screening assessment provides diagnostic suspicion, a more thorough assessment or a full assessment can be performed.
One type of assessment is the common symptom 61-item assessment, which includes clinical findings which were present in ≥50% of the patients in the database of this article and is shown in Table 5.  Another option, which may be used more for pre-evaluation, is the 24-item assessment that is shown in Table 6. A third more comprehensive option is the full clinical assessment that is shown in Table 7. The more thorough assessment includes an assessment for the presence of all the clinical findings evaluated which are more prevalent in these patients, including those which did not reach statistical significance. It adds greater specificity and support to the diagnosis of the late-stage manifestations of Lyme disease.       The only symptoms totally specific to Lyme disease seen in these patients are erythema migrans rash and acrodermatitis chronicum atrophicans. However, a common pattern with these patients may include early erythema migrans rash, flu-like symptoms and cranial nerve symptoms, followed by a combination of musculoskeletal symptoms, fatigue and cognitive impairments and the later appearance of other multisystem symptoms that may be psychiatric, neurological, cardiovascular, gastrointestinal, genitourinary, upper respiratory, dental, pulmonary, genitourinary and other symptoms. These symptoms and clinical findings can progressively expand and increase in severity over time. When a patient develops such a diversity of symptoms with an expanding number and intensity, one explanation can be one condition occurring with multisystem manifestations. Another possible explanation is a few concurrent conditions may have occurred at the same time. Since the pathophysiology and causal association between Lyme disease and many of these symptoms has previously been explained, a causal association between Lyme disease and the symptoms these patients experienced is a likely explanation [9,[40][41][42][43][44][45]. Also, since the onset of the symptoms was associated with a tick bite, a bull's eye rash and positive Lyme serology in these patients, this adds further support that the most likely explanation is the symptoms were caused by Lyme disease. However, a possible contributory role from other tick-borne, other coinfections, or other coexisting conditions can also be considered [46].
The differential diagnosis of Lyme borreliosis vs. other medical conditions is complex. Lyme, like syphilis can appear as many different conditions. For this reason, it has been called the "new great imitator" [28]. Any condition can coexist with Lyme disease. Therefore, the diagnosis of some other condition, alone, does not rule out the diagnosis of Lyme disease, and the diagnosis of Lyme disease does not rule out the diagnosis of some other comorbid condition. The question in diagnosis is what diagnosis can explain the symptoms seen in any given patient? There are other conditions that cause multisystem illnesses, such as toxicities, deficiencies, other systemic infections and immune disorders that should be considered in the differential diagnosis. A comprehensive examination like the one described in this article can also be useful in identifying symptom patterns seen in other illnesses. The common differential diagnosis that is considered for late-stage Lyme disease include myalgic encephalitis/chronic fatigue syndrome, fibromyalgia, and psychosomatic illness. Myalgic encephalitis/chronic fatigue syndrome has a more acute onset and also has dysautonomia and does not include the neurological and arthritic symptoms seen in Lyme disease. It also has different, but some overlapping findings in spinal fluid [47]. Fibromyalgia can occur following Lyme disease, but also occur in the absence of Lyme disease [22,48,49]. Psychosomatic illness is usually not a multisystem illness with such a diversity of symptoms [50]. In the differential diagnosis, pattern recognition is critical. The greater the number of multisystem symptoms that are associated with Lyme, the greater the likelihood that Lyme disease is the diagnosis. A coinfection screen can be performed when considering the presence of coinfections [Supplementary Materials]. It is difficult to explain this unique combination of clinical findings on the basis of some other diagnosis. When the first author performed this assessment on patients who did not have Lyme disease but had some other condition, there was a lesser number and a different pattern of clinical findings that were seen. A more comprehensive exam, such as the one described, improves the likelihood of a more accurate diagnosis, whether it be Lyme disease or some other diagnosis. Laboratory findings may also be considered in making the diagnosis, while being aware of some of the limitations of current laboratory testing when evaluating late-stage disease.
Based upon the findings of this study, clinical assessment forms can be used by clinicians when assessing a possible case of late-stage neuropsychiatric Lyme disease and to document clinical status following treatment (Tables 5-7 and Screening Assessment and Coinfection Screen in Supplementary Materials).
After completing the assessment(s), it is also important to consider any differential diagnosis that would better explain the pattern of symptoms seen in the patient. Lyme disease is the most likely diagnosis if the pattern of clinical findings and course of illness is most compatible with a diagnosis of Lyme disease compared to other conditions in the differential diagnosis.
After the diagnosis is made, the next part of the assessment is to consider which clinical findings are most severe and most significant in contributing to disease perpetuation and progression and to then prioritize these findings in order of significance. When these symptoms are prioritized in this manner, it helps in planning the symptomatic treatment of these patients. The symptom priority may change as symptoms improve from treatment.
This article is a basic introduction to a comprehensive clinical assessment. Further study, field testing, comparing the results of these assessments on patients with other diagnoses, and independent validation by others shall help to confirm these findings and shall be useful to develop objective evaluations to help standardize this assessment. Two other clinical assessment forms currently exist, The Burrascano Checklist of Current Symptoms and the Horowitz Multiple Systemic Infectious Disease Syndrome Assessment [3,51]. Compared to the other two assessment systems, this assessment is more targeted towards neuropsychiatric symptoms, assesses a broader spectrum of multisystem symptoms, and the full assessment requires more time and clinical expertise on the part of the evaluator.
The physician assessment forms can be scored in a quantitative manner by using the Clinical Global Impression Scale (CGI), a scale that is used in many United States Federal Drug Administration studies [52]. The CGI-Severity Scale (CGI-S) is rated as the average severity level in the prior week as 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill patients. Response to treatment can be measured by the CGI-Improvement Scale (CGI-I). The CGI-Improvement Scale (CGI-I) compares the patient's average clinical change in the prior week in the baseline status since the initiation of treatment. It is rated as "1 = very much improved since the initiation of treatment; 2 = much improved; 3 = minimally improved; 4 = no change from baseline (the initiation of treatment); 5 = minimally worse; 6 = much worse; 7 = very much worse since the initiation of treatment" [52].

Conclusions
The prevalence of psychiatric and other symptoms seen in 100 patients with late-stage Lyme neuroborreliosis was compared pre-infection vs. post-infection and the confidence intervals were calculated. The validity of pre-infection health status was partially confirmed by comparing it to two additional groups. Also, the post-infection findings were compared to patients with other systemic illnesses and compared to results from other studies. The patients in this study had minimal symptoms pre-infection (average of five), but a high post-infection prevalence of a broad spectrum of acquired multisystem symptoms, including neuropsychiatric symptoms, after acquiring Lyme borreliosis (average of 82). These findings included impairments of attention span, memory, processing, executive functioning, emotional functioning, behavior, psychiatric syndromes, vegetative functioning, neurological, musculoskeletal, cardiovascular, upper respiratory, dental, pulmonary, gastrointestinal, genitourinary, and other symptoms. The most prevalent symptoms included sustained attention impairments, brain fog, unfocused concentration, joint symptoms, distraction from frustration, depression, working memory impairments, decreased school/job performance, recent memory impairments, difficulty prioritizing multiple tasks, fatigue, non-restorative sleep, multitasking difficulties, sudden mood swings, hypersomnia, mental apathy, decreased social functioning, insomnia, tingling, word finding difficulties, name retrieval, headaches, sound hypersensitivity, paresis, anhedonia, depersonalization, cold intolerance, body temperature fluctuations, light sensitivity and dysfluent speech. Since this study included Continental United States patients, other symptom patterns may be seen in other geographical areas. In this study, there was a large separation between the average number of clinical findings pre-infection (5) and in in healthy controls (4) vs. other diagnoses (22) vs. post-infection (82). All of the patients with Lyme disease had multisystem symptoms. The greater number of multisystem symptoms correlated with a diagnosis of Lyme disease, and a lesser number of multisystem symptoms correlated with not having a diagnosis of Lyme disease. The results of this study were then used to develop three clinical assessment forms that can be used when the diagnosis of Lyme disease is suspected. This includes the 24-item patient pre-evaluation form, the common symptom 61-item assessment, and the full assessment. If the results of this study are then generalized to other patients, it suggests a greater number of multisystem symptoms correlates with the possibility of a diagnosis of Lyme, and a lesser number of multisystem symptoms correlates with a lower possibility of Lyme disease. The number of clinical findings cannot be rigidly implemented as a diagnostic criterion for a number of reasons. These reasons include: (1) some symptoms are more non-specific and prevalent while other symptoms are more specific; (2) some symptoms may be caused by some other condition; (3) Lyme borreliosis can be latent and not currently symptomatic; (4) Lyme borreliosis can sometimes have a unique presentation; and (5) individualized clinical judgment is always needed. The assessment, however, is a tool that clinicians can use to acquire information to look for pattern recognition. When combined with clinical judgment this assessment can help improve clinical diagnostic effectiveness. Since controversy surrounds the commonly used laboratory testing for Lyme disease, the use of clinical diagnostic assessments can be of value in considering a diagnosis of Lyme borreliosis. The assessment systems can also be used to track further disease progression, improvement or response to treatment. The use of this assessment, further interpretation of the data, further validation, and/or refinement by others can help to further develop these clinical assessment systems for the clinical diagnosis of Lyme borreliosis.

Patents
None of the authors report having any patents that are relevant to this article. Author Contributions: R.C.B. initially conceptualized the project, preformed the clinical interviews, created the study design and methodology and wrote the initial and subsequent drafts. D.M.A. created the database, extracted data and performed initial calculations from data. M.J.C. contributed to conceptualization, preformed data analysis, calculated confidence intervals, used the data to develop Table 4 and contributed to the review. S.J. contributed to data analysis, conceptualization and reviews. All authors have read and agreed to the published version of the manuscript.
Funding: At the time of submission, this study was self-funded.

Acknowledgments:
A special acknowledgement is given to the patients who have been able to describe their symptoms which has helped others to gain insight. Thanks to the Wilderness Medicine Interest Group at Rutgers-RWJ Medical School for assistance with this project.
Conflicts of Interest: R.C.B. has been an expert witness in cases involving neuropsychiatric manifestations, alcohol and drug abuse, opioid overdose death, violence and homicides involving Lyme borreliosis patients.