The phenomenon of �chronic Lyme�; an observational study
U. Ljøstada and A. Myglanda,b,c
aDepartment of Neurology, Sørlandet Hospital, Kristiansand, Norway; bInstitute of Clinical Medicine, University of Bergen, Bergen, Norway;
and cDepartment of Habilitation, Sørlandet Hospital, Kristiansand, Norway
Keywords:
bacterial infections, post-
infectious syndromes
Received 6 August 2011
Accepted 27 January 2012
Purposes: To chart clinical, laboratory, and psychometric profiles in patients who
attribute their complaints to chronic Lyme disease.
Methods: We assessed the patients by clinical examination, laboratory tests, and
questionnaires measuring fatigue, depression, anxiety, health-related quality of life,
hypochondriasis, and illness perceptions.
Results: We found no evidence of ongoing Borrelia burgdorferi (Bb) infection in any
of the 29 included patients using current diagnostic guidelines and an extended array
of tests. Eight (28%) had other well-defined illnesses. Twenty-one (72%) had symp-
toms of unknown cause, of those six met the suggested criteria for post-Lyme disease
syndrome. Fourteen (48%) had presence of anti-Bb antibodies. The patients had more
fatigue and poorer health-related quality of life as compared to normative data, but
were not more depressed, anxious, or hypochondriacal. Their beliefs about the illness
were characterized by negative expectations.
Conclusion: Our patients, who all attributed their symptoms to chronic Lyme disease,
were heterogeneous. None had evidences of persistent Bb infection, but whether
current diagnostic criteria are functional in patients with longstanding complaints is
controversial. Other well-defined illnesses or sequelae from earlier Lyme disease were
probable as main explanatory factor in some cases. The patients were not more de-
pressed, anxious, or hypochondriacal than the normal population, but they had
poorer health-related quality of life, more fatigue, and negative expectations about
their illness.
Introduction
There are major controversies regarding management
of symptoms attributed to Borrelia burgdorferi (Bb)
infection, often labeled chronic Lyme disease. On one
hand, there are guidelines that require objective clinical
signs and laboratory evidences of Bb infection to
diagnose Lyme disease [1–3]. On the other hand, there
are alternative standards for care [4], based on the view
that active Bb infection cannot be ruled out by absent
objective findings or seronegativity [5].
Many patients are confused, and some come forward
to newspapers and the internet with their feelings of
being misdiagnosed, mistreated, and discouraged.
Furthermore, many healthcare providers feel ambiva-
lent when faced with patients who present with dis-
abling symptoms, ambiguous laboratory test results,
and an expressed wish of long-term antibiotic treat-
ment.
Earlier studies have shown that only a small pro-
portion of patients referred to specialized Lyme disease
clinics, have ongoing Bb infection [6–9], and a recent
review concludes that �the assumption that chronic,
subjective symptoms are caused by persistent infection
with Bb is not supported by carefully conducted labo-
ratory studies or by controlled treatment trials� [10].
The generalizability of these studies is, however, called
in question by the spokesmen for existence and severity
of persistent Bb infections [5].
The annual number of reported cases of disseminated
Lyme disease in Norway is around 300 [11], with a
background seroprevalence of 15–20% in the high-en-
demic areas [12].
Our aim was to evaluate possible causes of com-
plaints in Norwegian patients who believe they have
ongoing chronic Bb infection, and to assess the patients�burden of symptoms, psychometric properties, and ill-
ness perception.
Correspondence: U. Ljøstad, Sørlandet Hospital HF, N–4604
Kristiansand, Norway (tel.: +47 38073910; fax: +47 38073911;
e-mail: [email protected]).
� 2012 The Author(s)European Journal of Neurology � 2012 EFNS 1
European Journal of Neurology 2012 doi:10.1111/j.1468-1331.2012.03691.x
Methods
Patients were eligible if they suffered from symptoms
suspected by themselves or their doctor to be caused by
ongoing chronic Bb infection. Objective clinical or
laboratory manifestations of Lyme disease were not
mandatory. They became aware of the study by a small
notice in two nationwide newspapers, or by informa-
tion from others, and were recruited through referral
from primary care, other hospitals, or self-referral.
They were informed that we wanted to chart symp-
toms, laboratory results, quality of life, and coping
strategies. The first 30 referred patients were included.
Data collection took place at Sørlandet Hospital, in
the period May 2010–March 2011. We assessed each
patient by a semi-structured interview, Mini Mental
Status Examination (MMSE), clinical neurological
examination, laboratory tests, and the following ques-
tionnaires: Short-Form 36 (SF-36), the Fatigue Severity
Scale (FSS), Hospital Anxiety and Depression Scale
(HADS), Whiteley Index (WI), and the Illness Percep-
tions Questionnaire-Revised (IPQ-R). Results on recent
brain imaging were obtained from patient records.
MMSE is not validated in Lyme patients, but we re-
garded results as low when below the 25th percentile for
age and education level [13].
The first visit consisted of interview, examination,
lumbar puncture, and filling of questionnaires, and the
second visit of information about our findings. Eight
patients completed the second visit by telephone, and
one by letter.
Patients without evidences of ongoing Bb infection
were classified in three categories;
Category 1: Symptoms of unknown cause with presence
of anti-Bb antibodies in serum or CSF.
Category 2: Symptoms of unknown cause without anti-
Bb antibodies.
Category 3: Symptoms considered to be caused by an-
other well-defined illness, i.e., fulfilling diagnostic cri-
teria for another illness.
Laboratory tests
We analyzed sera for anti-Bb IgG antibodies by ELISA
using deactivated Bb antigen and recombinant VlsE
(Enzygnost Lymelink VlsE/IgG; Siemens, Marburg,
Germany), for anti-Bb IgM antibodies by ELISA using
deactivated Bb antigen (Enzygnost Borreliosis/IgM
Siemens), and for anti-Bb IgG and IgM antibodies by
immunoblot (Anti-Borrelia EUROLINE-RN-AT,
EUROIMMUN, Lubeck, Germany) and by a second
ELISA test using synthetic peptide (C6 peptide) derived
from the VlsE protein as antigen (Immunetics C6; Im-
munetics Inc., Boston, MA, USA). We defined positive
serum anti-Bb antibody status as detection of anti-
bodies by two tier testing (Enzygnost ELISA or C6
ELISA and immunoblot). Detection of anti-Bb IgM
antibodies without simultaneous detection of anti-Bb
IgG antibodies did not qualify for a positive antibody
status, as this argues against late stages of Bb infections,
and as false positive anti-Bb IgM antibodies may be a
result of cross-reactivity or a non-specific response to
other diseases [14]. We detected intrathecal anti-Bb IgG
and IgM antibody production by IDEIA Lyme neuro-
borreliosis kit, using purified native flagella from the
Borrelia afzelii DK1 strain as antigen (OXOID limited,
Hampshire, UK).
We analyzed CSF CXCL13 by ELISA (Quantikine;
R&D Systems, MN, USA), with cutoff ‡1229 pg/ml
[15]. Plasma and CSFs were analyzed for Bb gene
products by a PCR targeting the 16s rRNA and Osp-A
genes (MagNA Pure LC DNA Isolation Kit; Roche,
IN, USA). Sera were tested for Tick-borne encephalitis
(TBE) IgG and IgM antibodies by ELISA (Enzygnost
Anti-TBE/FSME/ETG-Virus, Siemens).
Presence of one or more IgG bands in CSF not found
in parallel serum was defined as oligoclonal bands
(OCBs).
The blood screening included hematologic parame-
ters, renal and liver tests, rheumatoid factor, antinu-
clear antibodies, thyroidal metabolism, ferritin, folic
acid, and vitamin B12.
Questionnaires
Health-related quality of life
SF-36 consists of 36 questions comprising eight multi-
item scales: mental health, vitality, bodily pain, general
health, social function, physical function, and physical
and emotional role limitation. These domains are also
combined into physical and mental component sum-
mary scales (PCS and MCS).
Fatigue
Fatigue Severity Scale measures level of agreement (1–
7) with nine statements. The final score represents the
mean value of the nine items. Scores ‡5 are regarded as
severe fatigue [16].
Depression and anxiety
Hospital Anxiety and Depression Scale comprises seven
items (scored 0–3) for depression (D) and seven for
anxiety (A). Depression and anxiety are defined by
scores ‡8 on HADS-A or HADS-D, respectively [17].
Hypochondriasis
Whiteley Index measures 14 items (scored 0–5). Scores
‡40 identify hypochondriacal patients [18].
2 U. Ljøstad and A. Mygland
� 2012 The Author(s)European Journal of Neurology � 2012 EFNS European Journal of Neurology
Illness perception
Illness Perceptions Questionnaire-Revised assesses pa-
tients� beliefs about their illness, time-line-probable
duration, consequences-effects and outcome, control-
degree of personal and treatment control, emotional
representation-emotional reaction, and illness coherence-
degree of coherent understanding of the illness. Each
dimension consists of 4–6 questions (scored 0–5). High
scores on the control and coherence dimensions reflect
positive beliefs, and high scores on consequences and
timeline dimensions reflect negative beliefs. High scores
on emotional representation reflect negative emotional
response to the illness [19]. The causal domain consists of
18 attribution items (stress/worry, inheritance, bacteria/
virus, eating habits, coincidence/bad luck, poor medical
treatment, pollution, own behavior, own attitude, family
problems/worries, overworked, emotional condition,
aging, alcohol, smoking, accident/injury,mypersonality,
alteration in immune system).
Follow-up letter
Five months (median = 5.5, range = 2–6.5) after the
second consultation, we contacted the patients by letter
and asked them to fill in the FSS and SF-36 question-
naires again. They were also asked: How do you feel
now as compared to the first visit? Were the examina-
tions/explanations of any help? In what degree did you
attribute your symptoms to Bb infection at the first
visit, and in what degree now (much-little-nothing)?
Ethics
All patients gave written informed consent. The study
was approved by the Regional Committee for Medical
Research Ethics in southern Norway, and registered
with ClinicalTrials.gov (NCT01151150).
Statistical analyses
Descriptive statistics are mean, median, or proportions
as appropriate. Independent categorical data were
compared with chi-square test and independent con-
tinuous data with t-test and one-way ANOVA, or Mann–
Whitney and Kruskal–Wallis tests depending on as-
sumed normal distribution. Paired categorical data
were compared with McNemar test, and paired con-
tinuous data with paired sample t-test. P-values <0.05
were considered statistically significant.
Results
Thirty patients were recruited, one withdrew, and 29
patients from nine counties were included. Classifica-
tion of the patients with demographic, clinical, and
laboratory findings is shown in Table 1. Age was the
only parameter that differed between the groups
(P = 0.005). None met the European diagnostic crite-
ria for ongoing Bb infection, none had elevated levels of
CSF CXCL 13, and none had positive Bb PCR. Eight
patients (28%) had other well-defined illnesses consid-
ered to explain the complaints: multiple sclerosis (MS)
(n = 2), polyneuropathy (n = 2), cerebral small vessel
disease (n = 2), reactive arthritis (n = 1), and primary
lateral sclerosis (n = 1). The remaining 21 patients
(72%) had symptoms of unknown cause, nine with
presence of anti-Bb antibodies, and 12 without. Six of
the 21 patients with symptoms of unknown cause met
the suggested criteria for post-Lyme disease syndrome
[3], the others lacked a documented episode of Lyme
disease (n = 14), or onset of symptoms within
6 months of such an episode (n = 1).
The patients reported their most dominant symptom
to be fatigue (n = 15), pain (n = 4), walking impair-
ment (n = 4), memory/concentration problems
(n = 2), headache (n = 2), itching (n = 1), and dizzi-
ness (n = 1). When asked particularly about the fol-
lowing seven symptoms – fatigue, headache, pain,
memory/concentration problems, sensory disturbances,
pareses, and other symptoms – the patients reported a
mean number of 4.93 symptoms (SD = 0.9). The
clinical neurological examination revealed abnormal
findings in 13 patients with symptoms of unknown
cause. The findings were not typical for any neurolog-
ical disease, and did not correspond to any anatomical
structure (non-specific sensory disturbances (n = 7),
reflex deficits (n = 3), slight slowing (n = 1), and un-
steady/stiff walking (n = 2)). Five patients had MMSE
scores below the 25th percentile, four of them one point
below, and one of them three points below (did not
manage subtraction).
Twelve patients had detectable anti-Bb antibodies in
serum and four had intrathecal production of anti-Bb
antibodies, two without anti-Bb antibodies in serum.
Hence, in total 14 patients (48%) had detectable anti-
Bb antibodies, including five with other well-defined
illnesses. Ten patients had CSF OCBs, and three had
slight pleocytosis (one owing to traumatic tap, one to
MS attack, and one of unknown reason). One patient
had positive anti-TBE IgG antibodies. Blood screening
revealed no clinical relevant pathology. Table S1 gives
details of the 29 patients.
Special cases in category 3
One patient was diagnosed with MS. She had a history
of neuroborreliosis (radiculitis, pleocytosis, and intra-
thecal anti-Bb antibody production) 7 years earlier,
The phenomenon of �chronic Lyme� 3
� 2012 The Author(s)European Journal of Neurology � 2012 EFNS European Journal of Neurology
treated 1 week after debut of symptoms with a 2 weeks
course of IV ceftriaxone. Despite several antibiotic
courses during the following years, she suffered from
persistent fatigue. Three months before the first study
visit there were clinical and MRI findings compatible
with cervical myelitis, a CSF cellcount of 8 leukocytes/
mm3, intrathecal anti-Bb antibody production, and
OCBs. The patient was not lumbar punctured during
our study (the only one), but CSF from 3 months ear-
lier was analyzed according to the study protocol.
Serum anti-Bb antibody tests were negative at inclusion
and 3 months earlier. MRI after study start revealed
new brain lesions fulfilling McDonald criteria for MS.
Post-Lyme autoimmunity is a possibility in this patient.
Another patient was diagnosed with polyneuropathy.
He had a history of neuroborreliosis (radiculitis and
intrathecal anti-Bb antibody production) 6 years ear-
lier, treated with a 2 weeks course of IV ceftriaxone
1.5 years after debut of symptoms. He experienced
ataxia and distal sensory loss in the legs from the onset
of neuroborreliosis. His CSF showed normal cellcount,
intrathecal anti-Bb antibody production, and OCBs.
Tissue damage sustained prior to delayed treatment is
probable in this patient.
Brain imaging
Twenty-four patients had performed brain MRI and
two computed tomography (CT). Seventeen of these
were normal, four showed non-specific white matter
lesions [primary lateral sclerosis (n = 1), MS (n = 1)
symptoms of unknown cause without anti-Bb anti-
bodies/angina pectoris (n = 1), symptoms of unknown
cause with anti-Bb antibodies/cranial fracture many
years ago (n = 1)], two vascular pathology (small ves-
sel disease (n = 2)), one a stable pituitary hamartoma,
Table 1 Diagnostic classifications, demographic, clinical, and laboratory findings.
All patients
n = 29
Category 1
Symptoms
of unknown
cause with
Bb antibodies
n = 9
Category 2
Symptoms
of unknown
cause without
Bb antibodies
n = 12
Category 3
Other
well-defined
illness
n = 8
Age median (range) 43 (22–83) 43 (24–83) 40.5 (22–58) 59 (41–78)
Male/Female 16/13 4/5 6/6 6/2
Secondary education 0–3 years/ 4–7 years/ ‡7 years 3/11/15 1/5/3 0/6/6 2/0/6
Duration of symptoms in years median (range) 5 (0.75–20) 5 (1.3–20) 6 (0.75–12) 4.5 (2–12)
Patient recalled possible
Tick bite 25 8 11 6
Erythema migrans 19 7 6 6
Number of reported symptomsa median (range) 5 (2–6) 5 (4–6) 5.5 (4–6) 4.5 (2–6)
MMSE low score n (%) 5 (17) 3 2 0
Antibiotic treatment for Lyme disease
Duration (weeks) median/mean (range) 5/12 (0–78) 6/14 (0–78) 5.5/13 (0–52) 2.5/7 (0–27)
IV antibiotics n (%) 10 (34) 3 4 3
Number of different antibiotics median (range) 2 (0–7) 2 (0–5) 2 (0–7 1.5 (0–4)
Number of antibiotics not in guidelines, mean (SD) 0.7 (1.2) 0.6 (1) 1 (1.7) 0.3 (0.5)
No antibiotic treatment n (%) 3 (10) 1 1 1
Ongoing sick leave owing to current symptoms n (%) 17 (59) 5 8 4
Voluntary leave from studies or work/retiree 3/3 (21) 0/1 3/0 0/2
Working 6 (21) 3 1 2
Fulfilling suggested criteria for post-Lyme syndrome n (%) 6 (21) 3 (33) 3 (25)
Fulfilling Fukuda criteria for chronic fatigue syndrome n (%) 16 (55) 5 11 0
CSF cellcount elevated (>5 leukocytes/mm3) n (%) 3 0 2 1
CSF protein level mean (SD) 0.39 (0.12) 0.37 (0.14) 0.37 (0.13) 0.43 (0.10)
CSF protein level elevated n (%) 10 (34) 2 4 4
Intrathecal Bb antibody production n (%) 4 (14) 1 0 3
Pos Bb PCR in CSF/plasma n (%) 0 0 0 0
CSF OCB�s n (%) 10 (34) 4 2 4
CSF CXCL13 median (range) 0 (0–15.3) 0 (0–15.3) 0 (0–3.5) 0 (0)
CSF CXCL13 > 1229 pg/ml n (%) 0 0 0 0
MMSE, Mini Mental Status Examination.aNumber of reported symptoms amongst the following: fatigue, headache, pain, memory/concentration problems, sensory disturbances, pareses,
other.
4 U. Ljøstad and A. Mygland
� 2012 The Author(s)European Journal of Neurology � 2012 EFNS European Journal of Neurology
one demyelinating lesions (MS), and one calcification in
the basal ganglia.
Questionnaires
Results on the first-visit questionnaires are presented in
Table 2. The patients also specified degree of attribu-
tion (0–5) to 18 suggested causes of illness. The mean
scores were: bacteria/virus 4.3, coincidence/bad luck
3.1, poor medical treatment 2.9, alteration in the im-
mune system 2.9, and stress/worries 2.0. The others
were all scored with mean values <2.
When comparing the three groups of patients (cate-
gory 1/2/3) we found a difference in mean scores on
vitality (33/25/56, P = 0.002), general health (45/36/62,
P = 0.014), and FSS (5.5/6.1/3.9, P = 0.005). Post hoc
analyses showed that patients with other well-defined
illnesses experienced more vitality and less fatigue than
the rest.
Follow-up letter
Twenty-two patients answered the follow-up letter
(Table 3). Eighteen patients (82%) had reduced their
Table 2 First-visit questionnaires
All patients
n = 29 Reference scores (ref)
FSS
Score ‡5, n (%) 20 (69) Severe fatigue definition ‡5 [16]
Mean (SD) 5.3 (1.6)a Reported mean score in 20 American healthy adults: 2.3 [29]
Reported mean score in 50 Norwegian patients treated for neuroborreliosis:
3.5 [30]
HADS mean (SD), Recommended cutoffs for case finding [17]:
HADS-D 5.1 (3.4) HADS-D ‡ 8
HADS-A 5.3 (4.2) HADS-A ‡ 8
HADS n with scores ‡ 8 (%) Reported prevalence rates in Norwegian primary care [27]:
HADS-D 7 (24) HADS-D ‡ 8 = 18.5%
HADS-A 5 (17) HADS-A ‡ 8 = 28.8%
SF-36 sum scores mean (SD) Norwegian normative scores
(SD) [28]:
Mean scores (SD) from 50 Norwegian
patients treated for neuroborreliosis [30]:
PCS Physical component 33.3 (8)a 50.3 (10) 44 (9)
MCS Mental component 47.6 (12) 50.0 (10) 49 (11)
SF-36 subscores mean (SD)
Mental health 78.2 (14) 80.3 (15) 80 (15)
Vitality 36.0 (22)a 60.8 (21) 51 (22)
Bodily pain 48.2 (22)a 73.6 (26) 66 (29)
General health 45.8 (21)a 75.2 (22) 69 (21)
Social functioning 56.0 (28)a 86.3 (21) 84 (25)
Physical functioning 62.6 (23)a 86.4 (20) 80 (17)
Role physical 15.5 (30)a 76.6 (37) 56 (43)
Role emotional 77.0 (39) 84.2 (32) 80 (34)
WI
Mean (SD) 32.4 (7.6) Recommended cutoff for case finding ‡40 [18]
Score ‡40, n (%) 6 (21) Reported prevalence in an American outpatient medicine clinic [18]:
WI ‡40 = 13.8%
IPQ-R mean (SD) Achievable scores, range: Mean (SD) from 63 chronic pain patients
from New Zealand [19]:
Timeline acute/chronic 20.3 (3.7)b 6–30 23.1 (4.4)
Timeline cyclical 12.9 (3.9) 4–20 12.9 (3.9)
Consequences 23.1 (3.8) 6–30 23.5 (3.9)
Personal control 16.1 (5.6)b 6–30 18.4 (4.0)
Treatment control 16.2 (4.8)b 5–25 14.2 (3.4)
Illness coherence 13.8 (4.7) 5–25 13.4 (4.8)
Emotional representation 20.6 (4.4) 6–30 19.8 (4.1)
aDiffer from available normative scores, and from mean scores in 50 Norwegian patients treated for neuroborreliosis 30 months earlier.bDiffer from mean scores in 63 patients with chronic (mean duration 9.9 years) pain from New Zealand.
FSS, Fatigue Severity Scale (scores 1–7, 7 = most fatigue); SF-36, Short-Form 36 (scores 0–100, 100 = best); HADS, Hospital Anxiety and
Depression Scale [HADS-D = depression scale (0–21, 0 = best); HADS-A, Anxiety scale (0–21, 0 = best)], WI, Whiteley Index (14–70, 70 =
most hypochondriasis); IPQ-R, Illness Perceptions Questionnaire-Revised.
The phenomenon of �chronic Lyme� 5
� 2012 The Author(s)European Journal of Neurology � 2012 EFNS European Journal of Neurology
degree of attribution of symptoms to ongoing Bb
infection, but their scores on FSS and SF-36 were not
improved. Seven patients did not reply; they were
proportionally distributed amongst the three categories,
and did not differ from the rest in any matter.
Discussion
Our study population consisted of patients who basi-
cally attributed their complaints to chronic Lyme dis-
ease. The patients reported many symptoms, 70% were
not working, their health-related quality of life was
poor, but none met European diagnostic criteria for
ongoing Bb infection. Is this a result of dysfunctional
diagnostic criteria, dysfunctional patients, or both?
Arguments against ongoing Bb infection are absence
of objective neurologic signs, negative CSF findings
including CXCL13 and Bb PCR, and no sustained
efficacy of a mean antibiotic treatment of 12 weeks.
Further, half of our patients were seronegative, and in
absence of a clinical picture consistent with ongoing Bb
infection, presence of anti-Bb antibodies in the rest can
be regarded as �serologic scars� from earlier exposure to
Bb [20]. There are, however, several caveats when
evaluating the possibility of ongoing Bb infection; no
validated measures can prove that Lyme disease has
resolved, interpreting the clinical relevance of Bb sero-
positivity in patients from areas of high background
seroprevalence is a challenge, and neurologic signs may
be scarce and atypical in neuroborreliosis [20,21].
Nevertheless, even if persistent infection cannot be to-
tally excluded as a differential diagnosis and dysfunc-
tional criteria remains a consideration, we did not find
convincing evidences of ongoing Bb infection in any of
our patients. Then, what are the causes for the patient�slong-standing complaints?
We recognized other well-defined illnesses as main
explanatory factor in eight patients. Four were diag-
nosed during the study, and four had already been
diagnosed, but still attributed their symptoms to
ongoing Bb infection. Three of those stated that a sec-
ond opinion was important to remove their fear of
ongoing Bb infection, and one did not answer the fol-
low-up letter. The differentiation between Lyme disease
and other illnesses is challenging as clinical manifesta-
tions resembling MS, polyneuropathy, cerebral small
vessel disease, reactive arthritis, and primary lateral
sclerosis are reported in Bb infections [22]. We based
our diagnostics on a total assessment including course
of disease, laboratory, and clinical findings. Two of the
well-defined illnesses were temporally related to earlier
neuroborreliosis, and autoimmunity or sequelae after
Lyme disease are possible explanations [23,24]. Persis-
tent infection, although unprobable, can also not be
completely ruled out.
Definition, prevalence, and pathogenesis of post-
Lyme syndrome are much debated. According to sug-
gested diagnostic criteria [3], onset of unspecific symp-
Table 3 Answers to follow-up letter
Answers to written questions n = 22
Feel better/the same/worse 10/8/4
Was the consultations of any help, yes/no/do not know 20/1/1
In what degree did you attribute your symptoms to a Bb infection at the first visit, a great deal/some 14/8
In what degree do you attribute your symptoms to a Bb infection now, a great deal/some/not at all 4/6/12
Questionnaires P-valuea
FSS
Score ‡5, n (%) 16 (72) 0.69
Mean (SD) 5.4 (1.4) 0.34
SF-36 sum scores mean (SD)
PCS Physical component 34.5 (8) 0.60
MCS Mental component 49.9 (8) 0.77
SF-36 subscores mean (SD)
Mental health 79.6 (11) 0.26
Vitality 36.8 (20) 0.78
Bodily pain 54.4 (22) 0.60
General health 53.0 (17) 0.43
Social functioning 60.2 (34) 0.59
Physical functioning 62.6 (25) 0.93
Role physical 20.5 (31) 1.00
Role emotional 88.9 (27) 0.45
FSS, Fatigue Severity Scale.aP-values refer to paired comparison of scores in the 22 patients at first visit and in follow-up letter.
6 U. Ljøstad and A. Mygland
� 2012 The Author(s)European Journal of Neurology � 2012 EFNS European Journal of Neurology
toms within 6 months of a documented episode of
Lyme disease is mandatory. Some use wider definitions
and have shown that fatigue is more prevalent amongst
Bb seropositive, than amongst seronegative persons,
regardless of experienced symptomatic Bb infection
[25]. We found no differences in symptoms between
patients with and without anti-Bb antibodies. On the
other hand, patients with symptoms of unknown cause
had more fatigue and less vitality than those with well-
defined illnesses. The majority of the patients with
symptoms of unknown cause met the criteria for
chronic fatigue syndrome [26]. This fact cannot be used
to exclude Lyme disease, as patients in practice typically
meet criteria for more than one illness, but it illustrates
the burden of symptoms and the diagnostic challenge in
this group of patients. Six (29%) of our patients with
non-specific symptoms had presence of CSF OCBs, a
finding associated with infections, but also with
inflammatory diseases. This actualizes autoimmunity as
underlying factor.
We could not find more depression, anxiety, or
hypochondriasis amongst our patients than reported
amongst healthy persons [18,27], nor did the three
subscores in SF-36 assessing mental health-related
quality of life differ between our patients and normative
data [28]. Illness perception amongst our patients was,
however, characterized by negative beliefs.
In summary, we regard ongoing Bb infection as un-
probable in our patients, and hypothesize that other
well-defined illnesses, permanent tissue damage from
earlier infection, autoimmunity, and negative expecta-
tions about the symptoms were more important illness
predisposing and perpetuating factors than depression,
anxiety, and hypochondriasis.
Two earlier, partly comparable, studies have been
performed. Hassett et al. [8] screened 240 patients at a
Lyme disease center in New Jersey, and found that 60%
suffered from symptoms without a detectable somatic
cause. These patients had higher negative affect, lower
positive affect, and greater tendency to catastrophize
pain than patients with ongoing Bb infection, other
well-defined illnesses, or no symptoms. Djukic et al. [9]
screened 122 patients with suspected chronic Lyme
disease in an outpatient clinic for neuroborreliosis in
Germany, and found that 55% suffered from symptoms
without a detectable cause. Fifty-five patients filled in
different questionnaires, and scored higher on depres-
sion and poorer on quality of life than healthy control
persons.
Our study is not designed to be of hypotheses testing
nature. However, certain strengths should be men-
tioned: thorough history taking, extensive array of
tests, quality controlled and validated laboratory pro-
tocols, and valid and reliable questionnaires.
Conclusion
None of our patients had evidences of persistent Bb
infection, but whether current diagnostic criteria are
functional in patients with longstanding complaints
should be further studied. Other well-defined illnesses
or sequelae from earlier Lyme disease were probable as
main explanatory factor in some cases. The patients
were not more depressed, anxious, or hypochondriacal
than the normal population, but they had poorer
health-related quality of life, more fatigue, and negative
expectations about their illness.
Acknowledgements
We thank Sølvi Noraas, Maria Stokkeland Søbye,
Sivagowri Kasinathan for analyzing laboratory tests,
and Gudrun Elin Rohde for giving advices regarding
SF-36. Funding: South-Eastern Norway Regional
Health Authority.
Disclosure of conflict of interest
The authors declare no financial or other conflict of
interests.
Supporting Information
Additional Supporting Information may be found in
the online version of this article:
Table S1. Clinical and laboratory details of the 29
patients.
Please note: Wiley-Blackwell is not responsible for
the content or functionality of any supporting materials
supplied by the authors. Any queries (other than
missing material) should be directed to the corre-
sponding author for the article.
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