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Neuropsychological and Neuropsychiatric
Functioning in Post-Treatment Lyme
Disease
Pegah Touradji
Introduction
Lyme borreliosis is a tick- borne infectious disease with prominence across temperate regions of the Northern Hemisphere, mostly in North America and Europe
(Steere et al., 2016; Wormser et al., 2006). In North America, prevalence of Lyme
disease is primarily in the northeast, mid- Atlantic, and north- central regions of the
United States, but areas with endemic Lyme disease are expanding and extending
into southern parts of Canada (Kugeler et al., 2021). e United States Centers for
Disease Control and Prevention (CDC) currently estimates approximately 475,000
new cases of Lyme disease yearly in the United States (Kugeler et al., 2021; Schwartz
et al., 2021). In Europe, the incidence of Lyme disease is highest in Scandinavian and
Baltic regions and in central European countries including Austria, Germany, the
Czech Republic, and Slovenia (Marques et al., 2021).
Lyme disease is caused by the spirochete bacteria Borrelia burgdorferi with three
genospecies associated with human Lyme borreliosis. B. burgdorferi sensu stricto is
primary in the United States and presents as arthritogenic, while in Europe B. afzelii
causes skin infections and B. garinii is neurotropic in presentation (Steere, 2001;
Steere et al., 2016). e most common clinical manifestation of Lyme disease is a
characteristic skin lesion— erythema migrans— at the site of an infected Ixodes tick
bite (Steere et al., 2016). In the United States, although the majority of patients present with erythema migrans, which is oen accompanied by other symptoms such
as fatigue, malaise, fever, headache, arthralgias, and myalgias, approximately 18 percent have nonspecic symptoms during summer months without erythema migrans
and about 2– 3 percent present with early to late disseminated infection (Steere &
Sikand, 2003). In Europe, erythema migrans is usually not accompanied by other
symptoms and expands more slowly than cases observed in the United States (Steere
et al., 2016).
Pegah Touradji,
Neuropsychiatric Medicine
© Oxford University Press 2024. DOI: 10.1093/ oso/ 9780192870414.003.0010
Lyme Disease 119
Lyme borreliosis can be diagnosed clinically with observed erythema migrans or
with serological testing when patients present with characteristic symptoms (Steere
et al., 2016). Treatment across North America and Europe typically involves oral antibiotic therapy, but dissemination can occur without appropriate treatment (Steere
et al., 2016).
Early disseminated infection
When untreated, early disseminated infection associated with B. burgdorferi in the
United States can spread to other skin sites, organs, joints, and particularly to the
peripheral and/ or central nervous system (Steere, 2001). Dissemination is not as
common with B. afzelii but can be associated with persistent skin infection (Steere
et al., 2016). Early dissemination associated with B. garinii has a neurotropic presen-
tation impacting the peripheral nervous system with radiculoneuritis and the central nervous system with meningitis (Steere et al., 2016).
Lyme neuroborreliosis presents during early disseminated infection (Steere
et al., 2016) and can occur in 10– 15 percent of patients with Lyme disease in United
States and Europe (Halperin, 2019). Common clinical presentations of Lyme
neuroborreliosis in the United States include episodic headaches, mild neck stiness, cranial neuropathy with facial palsy, or motor or sensory radiculoneuritis associated with lymphocytic meningitis (Pachner & Steere, 1985). In Europe, Bannwarth
syndrome is associated with B. garinii and involves painful radiculoneuritis with as-
sociated lymphocytic meningitis without headache and possible cranial neuropathy
or pareses in the extremities (Ogrinc et al., 2016). While evidence of B. afzelii in
cerebrospinal uid has been identied, there are no clear neurological clinical manifestations (Strle et al., 2006).
Post- treatment Lyme disease
ough late- stage Lyme borreliosis is highly associated with arthritis in North
America and a slowly progressive skin lesion, acrodermatitis chronica atrophicans,
in Europe, chronic neurologic manifestations have also been described (Steere
et al., 2016). Even in those who receive timely and appropriate antibiotic intervention, chronic symptoms may persist with an estimated 10– 20 percent developing
persistent or recurrent symptoms of fatigue, musculoskeletal pain, and/ or cognitive
dysfunction impacting their functional status (Aucott et al., 2013, 2022; Wormser
et al., 2020).
Historically, chronic Lyme disease has been controversial given no clear biological markers, unknown etiology, and variability in clinical and research characterizations. To help with diagnostic standardization and clarity, the Infectious Disease
Society of America (IDSA) proposed a case denition of post- treatment Lyme
Infectious Disease and Neurocognition
disease (PTLD), which includes physician- documented evidence of Lyme disease,
appropriate antibiotic treatment, and onset of subjective symptoms of fatigue, cognitive complaints, and/ or widespread musculoskeletal pain within 6 months of diagnosis and with continuous or relapsing symptoms for at least 6 months following
antibiotic treatment that result in signicant decline in social or physical functioning
(Wormser et al., 2006).
PTLD has no known etiology though development, severity, and persistence are
thought to be multifactorial and related to immunologic, microbiologic, genetic, and
psychosocial factors (Rebman & Aucott, 2020). Review of existing literature found
risks for PTLD- related persistent symptoms to include more severe disease at onset,
objective neurologic diagnostic ndings, pre- existing comorbidities such as chronic
pain, cardiovascular risk factors, and mental health conditions, delays in diagnosis
and treatment, exposure to contraindicated treatments in the context of misdiagnosis, specic immune responses during acute infection, and the presence of particular microbiological factors (Rebman & Aucott, 2020). PTLD patients present
with heterogeneity in symptom reporting, with suggested clinical subgroups based
on symptom phenotypes characterized by primary musculoskeletal pain symptoms
(59 percent), cognitive fatigue symptoms (19 percent), and prominent mood symptoms (22 percent) (Rebman et al., 2021).
is chapter reviews evidence for neuropsychological and neuropsychiatric difculties associated with long- term sequalae of Lyme disease, including in those described as meeting criteria for PTLD.
Neuropsychological functioning
Cognitive complaints have long been reported in subset of patients with history of
Lyme disease and later recognized as a core symptom characterizing PTLD. Early
neuropsychological studies characterized patients with Lyme disease having chronic
symptoms (Krupp et al., 1991; Pollina et al., 1999b; Shadick et al., 1994), “Lyme encephalopathy” (Benke et al., 1995; Kaplan et al., 1992), and “post- Lyme syndrome”
(Bujak et al., 1996; Elkins et al., 1999; Gaudino et al., 1997; Kaplan et al., 1999).
Patient groups had past diagnoses of Lyme disease, antibiotic treatment, and patientreported cognitive diculties. Later studies better characterized these patients with
IDSA- recommended criteria for PTLD (Gorlyn et al., 2023; Keilp et al., 2006, 2019;
Touradji et al., 2019).
Overall, studies support that a vast majority of PTLD patients have subjective
cognitive complaints yet only mild decits are objectively found most consistently
on neuropsychological measures of verbal memory, processing speed, and verbal
uency. ough studies found chronic Lyme and PTLD patients as having worse
performances than controls and other patient groups, studies mostly show neuropsychological performances within average ranges compared to population norms
(Keilp et al., 2019; Touradji et al., 2019).
Lyme Disease 121
Memory
Initial case– control studies of patients characterized as having chronic Lyme symptoms primarily showed poorer performance on free recall measures of verbal list
learning tasks compared with healthy controls (Gaudino et al., 1997; Kaplan et al.,
1999; Krupp et al., 1991; Pollina et al., 1999b; Ravdin et al., 1996; Shadick et al.,
1994). Early studies also compared neuropsychological functioning of chronic Lyme
patients with other patient groups. Patients dened with Lyme encephalopathy
performed worse than patients with depression and bromyalgia on California
Verbal Learning Test (CVLT) recall trials (Kaplan et al., 1992). Further discriminant function analysis found that CVLT delayed recall was sensitive to identifying
group membership (Kaplan et al., 1992). In a European study comparing patients
with long- standing Lyme symptoms to neurologic controls without brain damage,
chronic Lyme patients had lower performance on recall and recognition trials of the
German CVLT, with 50 percent of Lyme patients having memory scores below the
study’s designated cuto for impaired performance (Benke et al., 1995). In a more recent study using the IDSA- proposed case denition for characterizing PTLD, verbal
memory decits on a list- learning test (Hopkins Verbal Learning Test– Revised)
were found in a subgroup of PTLD patients with memory performance signicantly
(two or more standard deviations) below estimated premorbid intellectual ability
(Touradji et al., 2019).
PTLD patients have variably been found to have decits in explicit episodic
memory and story memory. In a small sample of Lyme patients with persistent
symptoms following antibiotic treatment, Lyme patients were found to have lower
scores on Wechsler Memory Scale— Revised (WMS- R) Paired Associates and
Logical Memory compared to healthy controls (Krupp et al., 1991). However, other
studies did not nd dierences between chronic Lyme patients and controls on either Logical Memory (Gaudino et al., 1997; Kaplan et al., 1992) or Paired Associates
(Kaplan et al., 1992; Shadick et al., 1994). To address limitations of early studies, including variable methods for characterizing chronic/ post- Lyme patients and use of
small sample sizes, Keilp and colleagues (Keilp et al., 2006) examined a larger sample
of patients with carefully diagnosed and well- characterized chronic Lyme disease
and found chronic Lyme patients performing signicantly poorer on Auditory
Immediate, Auditory Delayed, Auditory Recognition Delayed, and General Memory
indices of the Wechsler Memory Scale- III (WMS- III) compared to controls. Poorest
subtest performance included Logical Memory, but there was no group dierence
on Paired Associates (Keilp et al., 2006). Patients with well- characterized PTLD consistent with IDSA guidelines had poorer performance on WMS- III Logical Memory
compared to both healthy controls and patients with major depressive disorder
(MDD) (Keilp et al., 2019).
Visual memory has also been examined, and there has been variable evidence of
decits in patients with chronic Lyme or PTLD. Patients characterized with Lyme encephalopathy were found to have worse performance on WMS Visual Reproduction
Infectious Disease and Neurocognition
compared to patient groups with depression and bromyalgia (Kaplan et al., 1992),
but another study comparing Lyme patients to healthy controls did not nd group
dierences on Visual Reproduction (Shadick et al., 1994). PTLD patients were found
to have group dierences on WMS- III Family Pictures (Keilp et al., 2006), but a
subsequent study by the same authors found comparable performance on WMSIII Family Pictures between patient groups (PTLD and MDD) and healthy controls
(Keilp et al., 2019). Visual memory decits have not been found in patients described
with Lyme encephalopathy compared to controls or other patient groups on a complex visual- constructional task (Kaplan et al., 1992, 1999).
Processing speed
Overall, studies have found processing speed as an area of mild decit in those with
chronic Lyme and PTLD although the evidence is inconsistent in part due to variability in measures used for assessing processing speed.
Compared to patients with neurologic diagnoses but no overt brain damage, patients with history of neuroborreliosis were found to have lower accuracy but not
slower reaction times on a computerized timed test of mental exibility and choice
reaction time (Benke et al., 1995). Patients with well- documented Lyme disease
treated with antibiotic therapy at least 2 months prior to neuropsychological evaluation were compared to age- matched and education- matched healthy controls and
found to have signicantly longer response times for mental arithmetic but no dierences in perceptual/ motor speed on a computerized task of perceptual/ motor speed
and mental arithmetic (Pollina et al., 1999b). In a follow- up study using a computerized test of psychomotor speed and mental arithmetic (Alphabet Arithmetic task),
post- Lyme patients had signicantly slower initiation speed but no dierence in
response accuracy or psychomotor processing speed compared to healthy controls
when controlling for age, estimated premorbid IQ, and depression (Pollina et al.,
1999a). Slower reaction time has also been shown in post- Lyme patients on a vigilance task (Gordon Diagnostic System) (Kaplan et al., 1999).
e Trail Making Test has largely not been sensitive to slowed psychomotor processing in chronic Lyme/ PTLD patients compared to controls (Gaudino et al., 1997;
Kaplan et al., 1999; Krupp et al., 1991; Shadick et al., 1994), patients with chronic
fatigue syndrome (Gaudino et al., 1997), or within- group comparison of PTLD patients (Bujak et al., 1996; Touradji et al., 2019). However, one study found that patient
groups with PTLD and MDD performed signicantly worse on Trails B compared
to healthy controls (Gorlyn et al., 2023). With the exception of two early studies
(Kaplan et al., 1999; Krupp et al., 1991), PTLD patients were found to have slowed
processing on the Digit Symbol subtest of various versions of the Wechsler Adult
Intelligence Scale (WAIS) (Gaudino et al., 1997; Gorlyn et al., 2023; Keilp et al., 2006,
2019; Touradji et al., 2019). Keilp and colleagues administered the full WAIS- III
protocols and across studies found decits on the Processing Speed Index, including
decits on Digit Symbol Coding and Symbol Search, in those with PTLD compared
with controls (Keilp et al., 2006, 2019).
Lyme Disease 123
Language
Verbal uency, typically measured as letter uency (e.g., Controlled Oral Word
Association Test), is oen a relative decit in chronic Lyme/ PTLD patients compared with controls (Benke et al., 1995; Gaudino et al., 1997; Gorlyn et al., 2023;
Krupp et al., 1991) though not a consistent nding (Kaplan et al., 1999; Svetina et al.,
1999). PTLD patients had more pronounced verbal uency decits than MDD patients and healthy controls even when controlling for signicant eects of verbal
ability, slowed processing speed, and memory decits on verbal uency performance (Gorlyn et al., 2023).
In a study of patients with conrmed history of Lyme disease, there was a high
frequency of Lyme patients with complaints of word- nding diculties (55 percent)
compared to controls (14 percent), and on objective testing, Lyme patients were
found to have lower mean scores on the Boston Naming Test, a test of confrontation
naming, but not on the Controlled Oral Word Association Test or a semantic uency
test when compared to controls (Svetina et al., 1999). e Boston Naming Test was
examined only in one other study and post- Lyme patients with and without central
nervous system involvement were not found to have signicant performance dierences compared to controls (Kaplan et al., 1999).
Attention and executive functioning
ere is limited and variable evidence of PTLD- related declines in attention
and working memory. Keilp and colleagues found no group dierences on the
Working Memory index of the WAIS- III when comparing PTLD patients with
nonpatients (Keilp et al., 2006), but in a subsequent study, they found signicant
group dierences with PTLD patients having worse performance compared to
healthy controls and patients with MDD (Keilp et al., 2019). Verbal auditory attention, as measured by the Digit Span test, has inconsistently been found as an
area of relative decit in those with PTLD compared to controls and other patient
groups (Gaudino et al., 1997; Kaplan et al., 1992, 1999; Keilp et al., 2006, 2019;
Krupp et al., 1991; Touradji et al., 2019). PTLD patients have not been shown to
have decits on measures of visual scanning and attention (Benke et al., 1995;
Bujak et al., 1996; Kaplan et al., 1999; Krupp et al., 1991; Shadick et al., 1994;
Touradji et al., 2019).
Executive functioning includes broad areas of cognitive functions that can include
problem- solving, planning, mental exibility, and cognitive control. ere has been
limited and inconsistent evidence of disruptions in executive functioning among
chronic Lyme groups (Westervelt & McCarey, 2002) with select studies showing
decits in mental exibility (Benke et al., 1995) and selective attention (Kaplan et al.,
1999). It has been argued that executive functioning drives primary memory retrieval decits found on more cognitively demanding list- learning tests compared
Infectious Disease and Neurocognition
to less consistent evidence of decit on measures with semantic structure (e.g., story
memory) (Westervelt & McCarey, 2002).
Severity of neuropsychological deficits
ough case– control studies consistently found evidence for reduced cognitive test
performances primarily on measures of verbal memory, verbal uency, and processing speed when comparing PTLD patients to healthy controls and other comparison groups, decits are described as mild relative to population norms (Keilp
et al., 2006, 2019; Westervelt & McCarey, 2002). In a study of PTLD patients using
comprehensive neuropsychological batteries of intellectual functioning (WAIS- III)
and memory functioning (WMS- III), standard scores were approximately in the
average range on these instruments, but consistent with other studies, there were
modest decits in processing speed and memory abilities compared to population
norms, and decits were more pronounced when compared to performances of a
nonpatient group (Keilp et al., 2006).
Studies have varied on classications of cognitive impairment, with some studies
relying only on group comparisons to characterize cognitive decits, while other
studies use variable deviations from population norms (e.g., performances from 0.5
standard deviations or more below the normative mean) to dene cognitive impairment. In a study of neuropsychological functioning status in a well- dened group
with PTLD using IDSA criteria, about a quarter of the sample met criteria for cognitive decline using stringent classication for impairment as performance equal to
or greater than two standard deviations below estimated premorbid cognitive ability
on two or more neuropsychological tests (Touradji et al., 2019). Results of this study
also showed mild impairments relative to population norms, but it was argued that
using normative comparison standards does not appear to capture the severity of
cognitive diculties experienced by those with PTLD and thus decits must also be
examined relative to estimated premorbid abilities (Touradji et al., 2019).
Associations with mood and fatigue
Existing studies have primarily examined depression as a possible mood- related
covariate in neuropsychological test performance of individuals with chronic Lyme
or PTLD. Most studies have not found an association between depression and neuropsychological test performance of PTLD groups (Gorlyn et al., 2023; Keilp et al.,
2019; Touradji et al., 2019; Westervelt & McCarey, 2002). Only two studies found
a positive correlation between depression and memory functioning (Gaudino et al.,
1997; Krupp et al., 1991), one study found a negative correlation with depression
on only one measure of memory (WMS Associate Learning) (Kaplan et al., 1992),
but most studies found no associations of depression in relation to decrements
Lyme Disease 125
in memory performance (Bujak et al., 1996; Keilp et al., 2019; Ravdin et al., 1996;
Svetina et al., 1999).
In comparison to patient groups with depressive disorders, PTLD patients had
lower reporting of depressive symptoms and worse performance on select neuropsychological tests (Kaplan et al., 1992; Keilp et al., 2019). On the Minnesota
Multiphasic Personality Inventory, Lyme encephalopathy patients had lower scores
on scales sensitive to depression and anxiety compared to depressed patients and
lower endorsement of somatic concerns relative to bromyalgia patients (Kaplan
et al., 1992). Lyme encephalopathy patients also obtained signicantly lower scores
on measures of memory compared to depression and bromyalgia patients (Kaplan
et al., 1992). Neurocognitive diculties in PTLD patients were not correlated with
depression severity, and PTLD patients had less severity of depressive symptoms
than those with MDD and more pronounced decrements in memory compared to
MDD patients (Keilp et al., 2019).
Fatigue is a prominent symptom associated with PTLD that was shown to have
a negative correlation with memory performance (Krupp et al., 1991; Pollina et al.,
1999b; Ravdin et al., 1996), though the causal relationship of fatigue on cognitive
functioning has come into question (Gaudino et al., 1997). One study found no correlation between fatigue and memory performance or mood in PTLD patients, but
initial presentation of fatigue at time of Lyme disease diagnosis had almost a 50- fold
increase in the likelihood of developing PTLD (Bujak et al., 1996). In a study comparing PTLD to patients with chronic fatigue syndrome, both groups had similar
endorsements of fatigue and mood symptoms, but PTLD patients had greater impairments on tests of attention, verbal memory, verbal uency, and motor speed,
which suggested that cognitive diculties in PTLD are beyond impacts of somatic
and mood complaints (Gaudino et al., 1997).
Neuroradiological findings associated with PTLD
Neuroimaging studies in PTLD patients are relatively sparse. During the acute stages
of Lyme disease, approximately 50– 70 percent of patients diagnosed with Lyme
meningitis, encephalitis, or encephalomyelitis showed punctate white matter lesions
on T2- weighted magnetic resonance imaging (MRI) (Halperin, 2019; Kruger et al.,
1991), yet MRI ndings are generally normal in those with chronic Lyme encephalopathy (Coyle, 1992). In a study of patients with seropositive Lyme disease but
without neuroborreliosis, Lyme meningitis, or encephalitis, anatomical imaging
with MRI and computed tomography studies were generally normal, but 74 percent
of these patients showed hypometabolism in the temporal lobes on positron emission tomography (Newberg et al., 2002).
Brain perfusion and metabolic studies have been more sensitive to showing brain
abnormalities in PTLD patients (Fallon et al., 1997; Logigian et al., 1997). Singlephoton emission computed tomography showed reduced cerebral perfusion in
Infectious Disease and Neurocognition
frontal subcortical and cortical regions in patients with Lyme encephalopathy and
with improved perfusion aer intravenous antibiotic treatment (Logigian et al.,
1997). A positron emission tomography study found microglial activation in PTLD
patients compared to healthy controls that suggests evidence of circulating inammatory markers that may contribute to PTLD- related neurological symptoms
(Coughlin et al., 2018).
Functional neuroimaging studies have also been shown in connection with neuropsychological functioning. Cerebral blood ow and metabolism were decreased in
gray matter and white matter regions, particularly in temporal, parietal, and limbic
areas in PTLD patients (Fallon et al., 2003). Consistent with prior neuropsychological studies, PTLD patients had signicant reductions in verbal memory, and white
matter ow reductions were signicantly associated with decits in memory as
well as visuospatial organization (Fallon et al., 2003). A multimodal neuroimaging
study found PTLD patients performed slower than but as accurately as controls on
a working memory task with functional MRI showing expected brain activation in
controls but hypoactivation in PTLD patients in some brain areas relevant to the
task and novel activation of white matter in the frontal lobe (Marvel et al., 2022).
Additional diusion tensor imaging revealed higher axial diusivity in frontal regions shown to activate on the working memory task that correlated with fewer
cognitive and neurological symptoms (Marvel et al., 2022). Higher white matter activation in the frontal lobes suggested cognitive compensation during the task that
may explain the slower yet accurate performance on the task. Interestingly, higher
axial diusivity was suggested to reect white matter repair rather than pathology
(Marvel et al., 2022). Overall, functional neuroimaging studies suggest white matter
vulnerabilities that may be related to neurocognitive outcomes.
Neuropsychiatric functioning
Evidence for severe Lyme- associated neuropsychiatric disturbance and non- moodrelated psychopathology is not well substantiated and mostly seen in case reports
(Branseld, 2018). Neuropsychiatric symptoms in PTLD patients are primarily reported as mood related with greatest evidence for depressive symptoms (BiniazHarris et al., 2023). Neuropsychiatric symptoms are not ubiquitous in PTLD patients,
and in a study of PTLD symptom phenotypes, prominent mood symptoms were
present in only 22 percent of the PTLD sample (Rebman & Aucott, 2020). In a small
sample of 30 PTLD patients, 37 percent met criteria for a Diagnostic and Statistical
Manual of Mental Disorders, fourth edition, Axis I disorder but with only 20 percent
meeting criteria for an Axis I psychiatric disorder before Lyme onset (Elkins et al.,
1999). Ratings of somatization, obsessive– compulsive, depressive, anxiety, and hostility symptoms were higher for PTLD patients compared to patients with history
of Lyme disease who returned to health on self- report measures of mood and personality (Bujak et al., 1996). Despite these group dierences, symptom reporting on
Lyme Disease 127
these measures of mood and personality were not clinically signicant compared to
normative means (Bujak et al., 1996).
Case– control studies commonly nd higher ratings of depressive symptoms
among chronic Lyme and PTLD groups compared to healthy controls and other
non- psychiatric patient groups (Doshi et al., 2018; Westervelt & McCarey, 2002).
Depression severity in PTLD is signicantly lower compared to MDD patients, and
depressive ratings on self- report measures are typically not clinically signicant relative to population norms (Keilp et al., 2019). PTLD patients (20 percent) were found
to have similar endorsements of suicidal ideation compared to patients with HIV
(27 percent), but both groups had signicantly higher ratings than healthy controls
(5 percent) (Doshi et al., 2018).
Two Danish national epidemiological studies sought to characterize psychiatric illness following Lyme disease. In an epidemiological study of nationwide
population- matched cohort from 1995 to 2015, patients with Lyme neuroborreliosis
did not present with higher risk of psychiatric disease diagnosis or have higher rate
of hospital encounters for psychiatric reasons compared to an age- matched and sexmatched cohort without Lyme neuroborreliosis from the general Danish population
(Tetens et al., 2021). ere was increased incidence of prescribed psychiatric medications during the rst year following positive B. burgdorferi antibody results, but in
subsequent years the rate of prescribed psychiatric medication was similar to that
of the comparison cohort (Tetens et al., 2021). In a larger study including the entire
Danish population, medical record review over a 22- year period showed increased
incidence rates of mental disorders, aective disorders, suicide attempts, and death
by suicide in those with a hospital diagnosis of Lyme borreliosis (Fallon et al., 2021).
Incidence of mental disorder was greatest in the rst year aer diagnosis of Lyme
disease, and the highest rate of suicide in Lyme patients occurred in the rst 3 years
aer diagnosis (Fallon et al., 2021).
Limitations of the available research findings
Limitations of early neuropsychological studies include small sample sizes, broadly
dened criteria for determining chronic Lyme disease, variability in neuropsychological test batteries, and lack of standard classication criteria for determining
cognitive impairment, which likely explains some of the variability in neuropsychological outcomes in these studies. Despite these limitations, these studies generally found evidence of mild impairments in verbal memory, processing speed, and
verbal uency that is consistent with more recent studies that use larger sample sizes
and determine PTLD with more rigorous IDSA criteria.
e generalizability of neuropsychological ndings is limited by the described
variability in existing neuropsychological studies. Further, PTLD patients are heterogenous in symptom presentation, and though case– control studies demonstrate
group dierences showing distinct areas of cognitive decline, only a subgroup of