zun/High Level English Writing 5-6 pages

V I E W P O I N T S

Lyme Disease: Neurology, Neurobiology, and Behavior

John J. Halperin1,2

1Department of Neurosciences, Overlook Medical Center, Summit, New Jersey; and 2Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York

The Lyme disease controversy can be largely linked to the misconception that neurobehavioral effects of illness constitute evidence of nervous system infection. Appropriate differentiation between neuroborreliosis (nervous system Borrelia burgdorferi infection) and Lyme encephalopathy (altered nervous system function in individuals with systemic but not nervous system infection)—or encephalopathies of other etiologies—would lessen the con- troversy considerably, as the attribution of nonspecific symptoms to supposed ongoing central nervous system infection is a major factor perpetuating the debate. Epidemiologic considerations suggest that the entities re- ferred to as “posttreatment Lyme disease” and “chronic Lyme disease” may not actually exist but rather reflect anchoring bias, linking common, nonspecific symptoms to an antecedent medical event. On the other hand, there are data suggesting possible mechanisms by which posttreatment Lyme disease could occur.

Keywords. Lyme disease; nervous system; neuroborreliosis; Lyme encephalopathy; posttreatment Lyme disease syndrome.

“What we have here is a failure to communicate.” —Warden in Cool Hand Luke, 1967

Words matter. Profound disagreements may ensue when people use the same words differently, often re- flecting significant differences in underlying but unstat- ed assumptions. Although many factors contribute to the “Lyme disease controversy,” one of the most power- ful, particularly from the patient’s perspective, may well be differing understandings of what constitutes neuro- logic disease. To the public, neurologic disease, partic- ularly loss of cognitive function, is among the most feared of all illnesses [1,2]. The suggestion that a patient might be suffering from a nervous system infection, such as with Borrelia burgdorferi, with the unstated im- plication that this will lead to progressive loss of brain function, is terrifying. Obviously every effort should be

made to avoid inaccurately suggesting this is the cause of a patient’s difficulty.

It can be challenging to differentiate between neuro- logic disease and the broad range of other disorders af- fecting behavior. Whereas all behavior requires a properly functioning nervous system, nervous system function can be affected indirectly by systemic illnesses (eg, hypoglycemia, hepatic insufficiency, sepsis) in the absence of any direct nervous system damage. Similarly, psychiatric disease—although fundamentally neurobio- logical, and presumably attributable to problems with neurotransmission, neural network function, and learned behaviors—is biologically distinct from what is normally considered neurologic disease. Because nei- ther systemic nor psychiatric disease inherently involves structural damage to the nervous system, these disor- ders have quite different implications for patients’ fu- ture neurologic functioning. For this reason, it is helpful to define what is meant by neurologic disease —which generally consists of medical conditions di- rectly and primarily affecting the nervous system, with resulting abnormalities attributable to underlying struc- tural changes in the central nervous system (CNS) or peripheral nervous system (PNS). It is the expectation of potentially progressive, irreversible nervous system

Received 11 November 2013; accepted 6 February 2014; electronically published 25 February 2014.

Correspondence: John J. Halperin, MD, Overlook Medical Center, Summit, NJ 07902 ([email protected]).

Clinical Infectious Diseases 2014;58(9):1267–72 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected]. DOI: 10.1093/cid/ciu106

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destruction that makes these disorders so frightening. Psychiat- ric disorders, metabolic encephalopathies, and other neurobio- logical phenomena can have devastating effects on patients’ well-being—but are not presumed to result in inexorable ner- vous system degeneration.

How does this relate to “nervous system Lyme disease”? These words are actually used to describe at least 4 distinct dis- orders (see Tables 1 and 2) with different mechanisms and prognoses. The most straightforward is true nervous system in- fection, typically including lymphocytic meningitis, cranial neuritis, or various forms of radiculoneuritis (pain, weakness, and sensory changes suggesting damage to 1 or several nerves or nerve roots) [3].Although these conditions are clearly caused by nervous system invasion by B. burgdorferi, microorganisms are remarkably difficult to demonstrate in samples from pa- tients or experimentally infected animals—by culture, polymer- ase chain reaction, or histology. The presence of spirochetes appears to be necessary, as antimicrobial therapy is rapidly and dramatically effective. There appears to be a clear temporal sequence starting with early spirochete entry into the CNS [4], occurring as early as the first 2 weeks of disseminated infection, even in the absence of clinical evidence of CNS involvement.

This rapidly triggers local production of CXCL13 [5], a B- cell–attracting chemokine produced by monocytes in response to B. burgdorferi outer surface proteins. The resultant B-cell proliferation within the CNS leads to a cerebrospinal fluid (CSF) pleocytosis and local production of specific antibody. No aspect of this process is considered controversial, although the mechanism by which such a small number of spirochetes can cause such pathogenically substantial nervous system in- flammation remains unclear. One suggested mechanism relates to a B. burgdorferi surface protease that may both facilitate in- vasion across the blood–brain and blood–nerve barriers, and lead to the release of proinflammatory fibronectin fragments. Inflammatory cytokines released in response to these fragments might underlie this immune amplification [6]. Similarly uncon- troversial is the fact that patients who suffer neurologic damage, such as facial nerve palsy, may have neurologic residua follow- ing successful antimicrobial treatment; just as with synovial damage from Lyme arthritis, Lyme disease–induced nervous system damage may persist despite microbiologic cure.

Rarely, this infection will involve the parenchyma of the spi- nal cord (myelitis) or brain (encephalitis). Spinal cord involve- ment has been described primarily in European patients with

Table 1. Categorization and Characteristic Findings of Illnesses That Can Impact Behavior

Category Neurologic Systemic (Extraneurologic) Psychiatric

Structural change in nervous system

Yes Not required and usually only in extreme cases

None

Mechanism Cell loss, damage Altered physiologic milieu Altered neurotransmission, neural net function, learned behaviors

Reversibility Limited Usually Usually CNS effects of infection

Diagnostic label for nervous system effects

Meningitis: infection in subarachnoid space Encephalitis: parenchymal brain infection Myelitis: spinal cord infection Abscesses: encapsulated infection

Encephalopathy Broad range of psychiatric diagnoses; generally sparing cognition

Effect on CNS function

Meningitis: meningeal irritation (headache); increased intracranial pressure (altered alertness) or spread to underlying parenchyma

Encephalomyelitis: focal changes in brain or spinal cord function

Altered cognition and behavior due to peripherally produced cytokines and other soluble molecules crossing BBB

Unmasking or accentuation of underlying psychiatric disorder by physiologic stress

CNS imaging (CT, MRI)

Meningitis: inflamed thickened meninges Encephalomyelitis: focal changes in affected parenchyma

Generally normal but, if severe, diffuse brain edema

Normal

CSF cells, protein, glucose

Increased inflammatory cells, protein, variable glucose

Generally normal Normal

Antimicrobial therapy

Must cross BBB BBB irrelevant BBB irrelevant

PNS effects of infection

Effect on PNS function

Focal or multifocal Altered biochemical milieu Not applicable

Diagnostic aid Neurophysiology Neurophysiology Not applicable

Abbreviations: BBB, blood–brain barrier; CNS, central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; MRI, magnetic resonance imaging; PNS, peripheral nervous system.

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radiculoneuritis, in whom there may be segmental inflamma- tion at the same level as the symptomatic nerve roots. Enceph- alitis is extremely uncommon, but is manifest by focal clinical (spasticity, ataxia, sensory loss, or other objective findings) and magnetic resonance imaging (MRI) abnormalities reflecting the site(s) of involvement. Encephalomyelitis is presumed to be due to infection and inflammation within the CNS parenchyma and is similarly responsive to antimicrobial therapy.

NEUROBEHAVIORAL CHANGES WITHOUT CNS INFECTION

The controversy about “nervous system Lyme disease” actually relates to 3 other disorders often included under the same ru- bric—disorders that are actually neurobiological but not neuro- logic (ie, they do not involve active nervous system infection, inflammation, or damage). Unfortunately, the inappropriate at- tribution of these symptoms to nervous system infection imme- diately terrifies patients, who often become convinced they are suffering from an irreversible and devastating brain disorder.

Lyme Encephalopathy The first of these 3, and the one that probably has led to all sub- sequent confusion, is the disorder originally described as “Lyme encephalopathy” [7–9].This impairment of memory and cogni- tive function was described in patients with active, ongoing sys- temic but not parenchymal CNS Lyme disease. The term was introduced to distinguish this disorder from actual brain B. burgdorferi infection, the latter more correctly termed “enceph- alitis” [10]. Lyme encephalopathy, analogous to toxic-metabolic encephalopathies in myriad other inflammatory states, reflects altered CNS function but not CNS infection. It is probably me- diated by peripherally produced soluble neuroimmunomodula- tors that cross the blood–brain barrier, causing neurobehavioral changes [10, 11]. Like true nervous system Lyme disease, this disorder usually clears rapidly with antimicrobial therapy, dem- onstrating the necessary role of active infection.

The other 2 entities, referred to as “posttreatment Lyme dis- ease syndrome” (PTLDS) and “chronic Lyme disease,” are

unresponsive to antimicrobial therapy and are the principal source of debate.

Posttreatment Lyme Disease Syndrome Posttreatment Lyme disease syndrome has been defined as “the presence of any of: widespread musculoskeletal pain, cognitive complaints, radicular pain, paresthesias, or dysesthesias . . . in- terfering with . . . function . . . within 6 months after . . . initial diagnosis and treatment . . . and . . . persist[ing] for at least 6 months” [12, 13]. The symptoms overlap extensively with those of Lyme encephalopathy, differing primarily by the re- quirement that encephalopathy occur in patients with active ex- traneurologic infection, whereas PTLDS patients have already been appropriately diagnosed with and treated for Lyme disease. Such symptoms are often present immediately after treatment— as they may be following treatment of other infections—and usually resolve over time. PTLDS is diagnosed when symptoms persist for 6 or more months.

Chronic Lyme Disease Chronic Lyme disease has not been formally defined, but is op- erationally described as including “persistent symptomatologies including fatigue, cognitive dysfunction, headaches, sleep dis- turbance and other neurologic features . . . ” [14]. Notwith- standing that the listed symptoms are not necessarily neurologic, many of them overlap with those of PTLDS. How- ever, diagnosing chronic Lyme disease requires neither objective manifestations of Lyme disease, nor laboratory evidence of B. burgdorferi infection. Despite compelling evidence that anti- microbial therapy is ineffective in this disorder [13, 15, 16] many individuals given this diagnosis receive long, complex, and sometimes harmful courses of antimicrobial, anti-inflam- matory, and other therapy.

RELATIONSHIP OF PTLDS AND CHRONIC LYME DISEASE TO B. BURGDORFERI INFECTION

The key questions concerning these 2 entities are (1) whether they truly exist, and (2) if they do, what might the underlying

Table 2. Neurobehavioral Syndromes in Lyme Borreliosis

Syndrome

Objective Evidence of Lyme Disease

(Clinical/Laboratory)

Objective Evidence of Active Borrelia

burgdorferi Infection Neurobehavioral Abnormalities

Response to Antimicrobial

Therapy

Encephalitis Required/required Required Focal Yes

Encephalopathy Required/required Required Cognitive Yes Posttreatment Lyme disease syndrome

Required/required No Cognitive No

Chronic Lyme disease

No No Variable No

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mechanism be? With regard to the existence of PTLDS, 30% or more of patients treated for Lyme disease may report persisting, subjective posttreatment symptoms. However, several con- trolled trials have shown that identical symptoms are equally common in patients without Lyme disease [17–20]. The few studies suggesting relatively more frequent subjective symptoms following treated Lyme disease show no increase in corroborat- ing objective abnormalities [21, 22]. Studies of the general pop- ulation (without Lyme disease) indicate that up to a third of the normal, healthy population experiences the same symptoms to a varying degree [23, 24], the same frequency as that found in the control populations of Lyme disease posttreatment studies. In the absence of any objective evidence of disease in these treat- ed patients, and given that the identical symptoms are equally prevalent in control individuals, it seems plausible that the en- tity PTLDS is simply an example of anchoring bias. Patients who have been treated successfully for Lyme disease and subse- quently experience common symptoms that they have heard are attributable to PTLDS incorrectly conclude that these nonspe- cific symptoms are indeed the sequelae of B. burgdorferi infec- tion, perpetuating the notion of this construct.

Chronic Lyme disease presents even greater challenges, as it is a diagnosis that is often made in the absence of any objective evidence the patient ever had Lyme disease. From an epidemi- ologic perspective, population studies indicate that incapacitat- ing fatigue—a hallmark of chronic Lyme disease—occurs in about 2% [24] of otherwise healthy individuals. Prevalence of chronic Lyme disease symptoms is difficult to estimate, al- though study recruitment data may be informative [15, 16]. In a study of persisting posttreatment fatigue [15], the 10% of screened patients who were enrolled represented about 3% of incident cases in the authors’ catchment area during the study period [25], comparable to the 2% incidence of severe fatigue in the general population. In a study of patients with posttreatment cognitive impairment [16], performed by investigators associat- ed with supporters of the chronic Lyme disease construct, 3368 subjects were screened between January 2000 and April 2004 but only 37 met criteria and were enrolled. Assuming the study drew patients from the surrounding states of Connecticut, New Jersey, New York, and Rhode Island, this represented <0.1% of incident cases reported to the Centers for Disease Control and Prevention (CDC) during that time [26].If patients came from a broader geography, or if the recent CDC estimate that only about 10% of diagnosed, treated Lyme disease cases are reported [27], that 0.1% would decrease substantially (as would the 3% in the fatigue study). Combining the cross-sectional ob- servation that 2% of the general population has such symptoms at any given time, and assuming that the 4 1/3 years of study recruitment represents about 5% of average US adult life expec- tancy, results in an estimated 0.1% risk of any randomly selected healthy individual developing these symptoms by chance

during the study’s enrollment period—comparable to the esti- mated incidence based on study recruitment.

POTENTIAL ETIOLOGIES

These epidemiological observations notwithstanding, it is con- ceivable that there is a small subset of patients treated for Lyme disease who do indeed have a posttreatment syndrome. If so, what mechanisms might underlie this disorder, or, if chronic Lyme disease is a valid concept, its overlapping symptoms? Be- cause additional antimicrobial therapy is not helpful [13, 15, 16], a noninfectious explanation would seem necessary. Several studies suggest that patients who have been treated for Lyme disease may produce antineural antibodies [28, 29]. However, the presence and concentration of these antibodies do not ap- pear to correlate with the presence or absence of post–Lyme dis- ease symptoms [29]. Alternatively, just as there is indirect evidence that cytokines may contribute to the symptoms of Lyme encephalopathy, there is limited evidence suggesting in- terferon α may be elevated in patients with posttreatment Lyme disease. However, levels do not change following treat- ment with either ceftriaxone or placebo, and do not appear to vary with changes in symptomatology [29].

Studies in experimentally infected animals have raised the possibility of posttreatment persistence of B. burgdorferi, with the demonstration of bacterial detritus, consisting of both mor- phologically intact bacterial cells and cell fragments, following antimicrobial treatment [30, 31]. Although there is some evi- dence of transmission of these organisms to feeding ticks, to date there is no evidence that they can transmit symptomatic infection—that is, fulfill Koch’s postulates. In the absence of ev- idence of true ongoing infection, might the bacterial debris play a role? One recent in vitro study suggests that this debris could trigger both an immune response and glial apoptosis [32]. Al- ternatively, a mechanism proposed for posttreatment Lyme ar- thritis might play a role. It has been suggested that persisting spirochete detritus [31] might periodically leak into joints [33], eliciting an inflammatory response [32]—that is, an acute arthritis. Although biologically plausible, this must be rec- onciled with the observations that, unlike Lyme arthritis, PTLDS symptoms are not particularly episodic, and are not as- sociated with any objective evidence of end-organ inflamma- tion, particularly in the nervous system, where CSF is invariably bland and MRI fails to demonstrate any parenchymal CNS inflammation.

It is also important to consider the real relevance of animal and in vitro observations to human disease. Lyme disease is a zoonosis. It naturally occurs in many different species, some of which serve as reservoir hosts, tolerating prolonged, asymp- tomatic infection and even spirochetemia; that is, despite having an intact immune system, these hosts do not eliminate

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infection. Obviously such immune host–spirochete interactions vary among species, making cross-species inferences problem- atic. In humans, the immune system clearly recognizes and at- tacks B. burgdorferi, as evidenced by the inflammatory component of carditis, arthritis, meningitis, or other clinical manifestations essential to the diagnosis of Lyme disease— without which, by definition, PTLDS cannot develop.

On the other hand, even if a few viable spirochetes were to persist in some subjects in a manner that protects the organisms from ongoing interactions with the host’s immune system, their significance is questionable. In general (ie, in other infections) it is improbable that antimicrobial therapy eradicates every micro- organism in every patient. More likely, antimicrobials gener- ally kill the vast majority of microorganisms, with the host immune system either eradicating the remainder or establishing an ongoing, asymptomatic “balance of power.” Clinical obser- vations in many situations suggest that persistence of viable organisms can be harmless (eg, Ghon complexes in tuberculo- sis, herpes viruses in neurons, Treponema pallidum in treated human immunodeficiency virus patients with syphilis [34])— so long as the immune system remains effective. Because Lyme disease has not been found to be an issue in immuno- compromised hosts (and as there is no evidence that patients with chronic Lyme disease are immunocompromised), it can be surmised that treatment in humans results in either com- plete eradication of organisms or such thorough suppression that even compromised immune systems can keep rare persist- ing organisms under control. As in the listed examples of persisting infections, the absence of systemic immune activa- tion makes it unlikely that such a persisting—but contained— infection would play any role causing systemic or other remote symptoms.

The biologic plausibility of chronic Lyme disease is more problematic. The lack of response to antimicrobial therapy and the inability to demonstrate viable organisms in patients, coupled with the fact that many diagnosed patients lack labora- tory support for the diagnosis or a history of characteristic ob- jective abnormalities, renders this entity highly suspect. Proponents have argued that the disorder is caused by small numbers of persisting organisms hidden from the host immune system either by their location or by concealment of spirochete surface antigens. However, such a mechanism creates a logical paradox. If ongoing neurobehavioral symptoms are mediated by soluble neuroimmunomodulators released in response to B, burgdorferi, how would such a process be triggered by a few or- ganisms that are immunologically invisible? The more recent argument that symptoms are due to multiple coinfections with other organisms such as Babesia, Bartonella, Anaplasma, and others that might be similarly concealed, is no more com- pelling, for the same reasons. The only alternative mechanism for “action at a distance” would be if B. burgdorferi—or

coinfecting organisms—released exotoxins. As B. burgdorferi’s genome has been sequenced in its entirety, and does not encode recognizable exotoxins, this seems improbable [35].

Regardless of whether the symptom complexes referred to as PTLDS and chronic Lyme disease are causally related to B. burgdorferi infection, their frequency and impact require con- sideration of other possible etiologies. Although a substantial number of patients have depressive symptoms [36, 37], the ma- jority do not; hence, the syndrome cannot be attributed to de- pression. However, there does appear to be a consistent psychologic substrate. Resilience, an individual’s ability to re- spond to both physiologic and psychological stressors, return- ing to a prior level of normal functioning after a significant adverse experience, is an important, measurable psychological attribute [38]. Presumably related to both underlying neurobio- logic mechanisms and learned behaviors, it is reflected in 2 at- tributes, positive and negative affect. A prospective study of patients treated for Lyme disease found, like others, that 1 year after treatment, one-third of patients reported chronic symptoms that they attributed to Lyme disease. In a multivari- ate analysis, low positive affect at baseline, independent of the severity of acute symptoms, was the single best predictor of which individuals would develop these persisting symptoms. This premorbid characteristic of how an individual responds to the stress of illness may well play a crucial role in the devel- opment of this neurobehavioral syndrome [38–40].

CONCLUSIONS

Of the 4 neurobehavioral syndromes attributed to B. burgdor- feri infection, encephalitis, with clinical, imaging, and CSF findings clearly indicative of focal, structural involvement of the CNS parenchyma, is both rare and clearly related to CNS infection. The diagnosis of Lyme encephalopathy should be used to describe patients with altered cognitive function and active infection that does not involve brain parenchyma. Post–Lyme disease treatment syndrome may or may not exist; if it does, it is probably quite infrequent, and probably represents a neurobehavioral response to illness rather than an immunologic or infectious process. There is no evidence to suggest that chronic Lyme disease, as the term is commonly used, exists as a distinct pathophysiologic entity or is related to B. burgdorferi infection.

Much can be learned from additional studies of this infection. In particular, generalizable insights may be gleaned about neu- robiological effects and mechanisms in other systemic illness. Critical in advancing this understanding, though, will be clearly differentiating among the effects of actual nervous system infec- tion, the neurobehavioral consequences of extraneurologic in- fection, and the neurobiologic consequences of recovery from a significant medical stressor.

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Notes

Acknowledgments. The author is grateful to Drs P. Baker and B. Fallon for providing important insights that contributed to this manuscript. Potential conflicts of interest. Author certifies no potential conflicts of

interest. The author has submitted the ICMJE Form for Disclosure of Potential

Conflicts of Interest. Conflicts that the editors consider relevant to the con- tent of the manuscript have been disclosed.

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