The phenomenon of chronic Lyme; an observational study

U. Ljstada and A. Myglanda,b,caDepartment of Neurology, Srlandet Hospital, Kristiansand, Norway; bInstitute of Clinical Medicine, University of Bergen, Bergen, Norway;

and cDepartment of Habilitation, Srlandet Hospital, Kristiansand, Norway

Keywords:

bacterial infections, post-

infectious syndromes

Received 6 August 2011

Accepted 27 January 2012

Purposes: To chart clinical, laboratory, and psychometric proles 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-dened 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-dened 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 [13]. 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 ndings 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 [69], 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 1520% 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 patientsburden of symptoms, psychometric properties, and ill-

ness perception.

Correspondence: U. Ljstad, Srlandet Hospital HF, N4604

Kristiansand, Norway (tel.: +47 38073910; fax: +47 38073911;

e-mail: unn.ljostad@sshf.no).

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 suered 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 rst 30 referred patients were included.

Data collection took place at Srlandet Hospital, in

the period May 2010March 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 rst visit consisted of interview, examination,

lumbar puncture, and lling of questionnaires, and the

second visit of information about our ndings. Eight

patients completed the second visit by telephone, and

one by letter.

Patients without evidences of ongoing Bb infection

were classied 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-dened illness, i.e., fullling 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 dened 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-specic response to

other diseases [14]. We detected intrathecal anti-Bb IgG

and IgM antibody production by IDEIA Lyme neuro-

borreliosis kit, using puried native agella 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 cuto 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 dened 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 nal score represents the

mean value of the nine items. Scores 5 are regarded assevere fatigue [16].

Depression and anxiety

Hospital Anxiety and Depression Scale comprises seven

items (scored 03) for depression (D) and seven for

anxiety (A). Depression and anxiety are dened by

scores 8 on HADS-A or HADS-D, respectively [17].

Hypochondriasis

Whiteley Index measures 14 items (scored 05). Scores

40 identify hypochondriacal patients [18].

2 U. Ljstad 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-probableduration, consequences-eects 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 46 questions (scored 05). High

scores on the control and coherence dimensions reect

positive beliefs, and high scores on consequences and

timeline dimensions reect negative beliefs. High scores

on emotional representation reect 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 = 26.5) after the

second consultation, we contacted the patients by letter

and asked them to ll in the FSS and SF-36 question-

naires again. They were also asked: How do you feel

now as compared to the rst visit? Were the examina-

tions/explanations of any help? In what degree did you

attribute your symptoms to Bb infection at the rst

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 KruskalWallis 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

treated 1 week after debut of symptoms with a 2 weeks

course of IV ceftriaxone. Despite several antibiotic

courses during the following years, she suered from

persistent fatigue. Three months before the rst study

visit there were clinical and MRI ndings 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 fullling 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-specic 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 classications, demographic, clinical, and laboratory ndings.

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-dened

illness

n = 8

Age median (range) 43 (2283) 43 (2483) 40.5 (2258) 59 (4178)

Male/Female 16/13 4/5 6/6 6/2

Secondary education 03 years/ 47 years/ 7 years 3/11/15 1/5/3 0/6/6 2/0/6Duration of symptoms in years median (range) 5 (0.7520) 5 (1.320) 6 (0.7512) 4.5 (212)

Patient recalled possible

Tick bite 25 8 11 6

Erythema migrans 19 7 6 6

Number of reported symptomsa median (range) 5 (26) 5 (46) 5.5 (46) 4.5 (26)

MMSE low score n (%) 5 (17) 3 2 0

Antibiotic treatment for Lyme disease

Duration (weeks) median/mean (range) 5/12 (078) 6/14 (078) 5.5/13 (052) 2.5/7 (027)

IV antibiotics n (%) 10 (34) 3 4 3

Number of different antibiotics median (range) 2 (07) 2 (05) 2 (07 1.5 (04)

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

Fullling suggested criteria for post-Lyme syndrome n (%) 6 (21) 3 (33) 3 (25)

Fullling 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 OCBs n (%) 10 (34) 4 2 4CSF CXCL13 median (range) 0 (015.3) 0 (015.3) 0 (03.5) 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. Ljstad and A. Mygland

2012 The Author(s)European Journal of Neurology 2012 EFNS European Journal of Neurology

one demyelinating lesions (MS), and one calcication in

the basal ganglia.

Questionnaires

Results on the rst-visit questionnaires are presented in

Table 2. The patients also specied degree of attribu-

tion (05) 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

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 dier 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 ndings

including CXCL13 and Bb PCR, and no sustained

ecacy 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 toBb [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 dierential diagnosis and dysfunc-

tional criteria remains a consideration, we did not nd

convincing evidences of ongoing Bb infection in any of

our patients. Then, what are the causes for the patientslong-standing complaints?

We recognized other well-dened 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 dierentiation 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 ndings. Two of the

well-dened 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.

Denition, prevalence, and pathogenesis of post-

Lyme syndrome are much debated. According to sug-

gested diagnostic criteria [3], onset of unspecic 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 rst 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) 0.69Mean (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 rst visit and in follow-up letter.

6 U. Ljstad 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 denitions

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 dierences 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-

dened 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-specic symptoms had presence of CSF OCBs, a

nding associated with infections, but also with

inammatory diseases. This actualizes autoimmunity as

underlying factor.

We could not nd 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 dier 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-dened 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%

suered from symptoms without a detectable somatic

cause. These patients had higher negative aect, lower

positive aect, and greater tendency to catastrophize

pain than patients with ongoing Bb infection, other

well-dened 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% suered from symptoms

without a detectable cause. Fifty-ve patients lled in

dierent 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-dened 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 Slvi Noraas, Maria Stokkeland Sbye,

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 nancial or other conict 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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