the phenomenon of ‘chronic lyme’; an observational study

8
The phenomenon of Ôchronic LymeÕ; an observational study U. Ljøstad a and A ˚ . Mygland a,b,c a Department of Neurology, Sørlandet Hospital, Kristiansand, Norway; b Institute of Clinical Medicine, University of Bergen, Bergen, Norway; and c Department 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 Ôthe 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 trialsÕ [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 patientsÕ 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]). Ó 2012 The Author(s) European Journal of Neurology Ó 2012 EFNS 1 European Journal of Neurology 2012 doi:10.1111/j.1468-1331.2012.03691.x

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Page 1: The phenomenon of ‘chronic Lyme’; an observational study

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

Page 2: The phenomenon of ‘chronic Lyme’; an observational study

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

Page 3: The phenomenon of ‘chronic Lyme’; an observational study

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

Page 4: The phenomenon of ‘chronic Lyme’; an observational study

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

Page 5: The phenomenon of ‘chronic Lyme’; an observational study

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

Page 6: The phenomenon of ‘chronic Lyme’; an observational study

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

Page 7: The phenomenon of ‘chronic Lyme’; an observational study

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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