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Original Article

Cervicogenic headache in the generalpopulation: The Akershus studyof chronic headache

Heidi Knackstedt1,2, Dalius Bansevicius1,2, Kjersti Aaseth1,2,

Ragnhild Berling Grande2,3, Christofer Lundqvist2,3 and

Michael Bjrn Russell1,2

Abstract

Objective: The objective was to study the prevalence of cervicogenic headache (CEH) in the general population.Methods: An age- and gender-stratified random sample of 30,000 persons aged 3044 years received a mailed question-naire. Those with self-reported chronic headache were interviewed by neurological residents. The criteria of theCervicogenic Headache International Study Group and the International Classification of Headache Disorders, secondedition, were applied.Results: The questionnaire response rate was 71% and the participation rate of the interview was 74%. The prevalence ofCEH was 0.17% in the general population, with a female preponderance. Fifty per cent had co-occurrence of medicationoveruse and 42% had co-occurrence of migraine. The pericranial muscle tenderness score was significantly higher on thepain than non-pain side (p< .005). The cervical range of motion was significantly reduced compared to healthy controls(p< .005). The mean duration of CEH was eight years. Based on patients self-reports, greater occipital nerve (GON)blockage and cryotherapy was reported effective in 90% of those who had this procedure, while other treatmentalternatives were reported less effective.

Keywords

Cervicogenic headache, epidemiology, pericranial muscle tenderness, cervical range of motion

Date received: 20 April 2009; accepted: 26 February 2010

Introduction

Cervicogenic headache (CEH) is a symptomatic head-

ache characterized by chronic unilateral headache and

symptoms and signs of neck involvement (13). CEH is

often worsened by neck movement, sustained awkward

head position or external pressure over the upper cer-

vical or occipital region on the symptomatic side (1,3).

Abolition of the headache following diagnostic anes-

thetic blocks of cervical structures or its nerve may pro-

vide evidence that the pain is attributed to a neck

disorder or lesion (1,3,4).

The prevalence of CEH varies considerably, depend-

ing on the applied diagnostic criteria. A Portuguese

epidemiological survey of the general population

found a prevalence of 1% in headache patients applying

six positive criteria of the Cervicogenic Headache

International Study Group (CHISG). The prevalence

increased to 4.6% when only five criteria were used (5).

A Norwegian population-based survey found a preva-

lence of CEH of 4.1% using the criteria of the CHISG

(68). The prevalence of CEH was 2.5% in the Danish

general population when applying criteria of the

International Headache Society, and the prevalence

increased in persons with frequent headache (9). CEH

was not associated with migraine in a clinic population

(9). Among patients from headache centers the preva-

lence data variy widely, from 0.4% to 80% (1012).

1Innlandet Hospital, Norway.2Akershus University Hospital, Norway.3Oslo University Hospital, Norway.

Corresponding author:

Heidi Knackstedt, Department of Neurology, Innlandet Hospital,

2418 Elverum, Norway

Email: [email protected]

Cephalalgia

30(12) 14681476

! International Headache Society 2010

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DOI: 10.1177/0333102410368442

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The prevalence differences are probably due to different

study designs and populations. The challenge with

identifying and classifying CEH is also reflected in

the different classifications (13). Co-occurrence of

migraine and/or tension-type headache further compli-

cates the diagnostics of CEH (13,14). The pathophy-

siology of the cervical spine is complex, since bothdysfunction of the neck muscles and mechanical cervi-

cal spine pathology can produce painful and limited

cervical movementsthat is, CEH (1517).

The aim of this paper is to provide epidemiological

and clinical data on CEH in persons from the general

population.

Materials and methods

Sampling

An age- and gender-stratified random sample of 30,000

persons aged 3044 years and residing in eastern

Akershus County was drawn from the Norwegian

Population Registry in January 2005. Akershus

County has both rural and urban areas and is situated

in close proximity to Oslo, Norway. The age range of

3044 years was chosen because the headache preva-

lence is relatively higher than in younger age ranges,

whereas in the targeted age range co-morbidity of

other diseases is lower than in older age ranges. The

sample size was reduced to 28,871 because of error in

the address list (N 1,065), emigration (N 32), multi-

handicap (N 28), insufficient Norwegian language

skills (N 2) and decease (N 2). Data fromStatistics Norway show that the sampling area was rep-

resentative for the total Norwegian population regard-

ing age, gender and marital status. Regarding

employment, trade, hotel/restaurant and transport

were overrepresented, while industry, oil and gas and

financial services were underrepresented in the sam-

pling area compared to the total Norwegian popula-

tion. Figure 1 shows a flowchart of the study.

Questionnaire

All persons received a mailed questionnaire with a stan-

dard letter containing information about the project.

Apart from ensuring confidentiality and emphasizing

the importance of participation, it was stated that the

object was to study headache. The questions How

many days during the last month have you had head-

ache? and How many days during the last year have

you had headache? were used to screen for chronic

headache. If the questionnaire evoked no response, a

second and subsequently a third mailing was issued.

The overall response rate of the questionnaire was

71% (20,598/28,871).

Clinical interview, physical and neurological

examination

The study took place at the Akershus University

Hospital between May and December 2005. Persons

with self-reported chronic headache who also consented

by adding their telephone number on the questionnaire,

were invited to a clinical interview and neurological

examination. Self-reported chronic headache was

defined to be headache on 15 days within the last

month and/or headache on 180 days within the last

year. Of the 935 with self-reported chronic headache

within the last month and/or year, 53 persons did not

consent for further contact, and 30 persons had insuf-

ficient Norwegian language skill to participate. Among

the 852 eligible, 139 declined participation and 80 could

not be reached by telephone. The participation rate of

the interview was 74% (633/852). Among the

Sample30,000

(M: 15,000, F: 15,000)

Study population28,871

Not eligible1,129

Responders20,598

(M: 9,475, F: 11,123)

Non-responders8,273

Self-reported chronicheadache 935

(M: 267, F: 668)

Not eligible83

(M: 33, F: 50)

Participants633

(M: 147, F: 486)

Non-participants219

(M: 87, F: 132)

Telephone interviewed143

(M: 31, F: 112)

Interviewed at the clinic490

(M: 116, F: 374)

Cervicogenic headache24

(M: 7, F: 17)(Interviewed at the clinic: 22,interviewed by telephone: 2)

Follow-up19

(M: 4 , F: 15)(Interviewed at the clinic: 12,interviewed by telephone: 7)

Figure 1. Flowchart of the epidemiological survey.

Knackstedt et al. 1469

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participants 77% were examined at the clinic, while

23% were interviewed by telephone. Two neurological

residents (RBG and KAA) experienced in headache

diagnostics conducted all interviews and the neurolog-

ical examinations. CEH was classified according to the

major criteria of CHISG, requiring at least three crite-

ria to be fulfilled, not including a greater occipital nerve

(GON) blockade. The characteristics of some impor-

tance and other features of lesser importance were not

required for diagnosing CEH (Table 1). Otherwise, the

criteria of the International Classification of Headache

Disorders, second edition (ICHD-II) were applied. A

more detailed description of the materials and methods

has been published elsewhere (18,19).

Pericranial muscle tenderness

The palpation of muscles and tendon insertion was con-

ducted with the second and third fingers with small

rotating movements and a certain pressure. The

methodology was trained at the Danish Headache

Center (20). The masseter, pterygoideus lateralis, tem-

poralis, frontalis, sternocleidomastoideus, trapezius

and occipital muscles and the tendon insertions on pro-

cessus mastoideus were palpated. The muscles and

tendon insertion on each side were palpated one at a

time. Each trigger point was scored on a scale from 0 to

3 (0no visible reaction or verbal report of discomfort,

1mild mimic reaction but no verbal report of discom-

fort, 2 verbal report and mimic reaction of painful

tenderness and discomfort, and 3marked grimacing

or withdrawal, verbal report of marked painful tender-

ness and pain). The maximum tenderness score is 24 on

each side and total maximum score is 48.

Cervical range of motion

The passive cervical range of motion (ROM) was tested

by manual flexion, extension, lateral flexion and rota-

tion of the cervical spine and was visually estimated.

Table 1. Diagnostic criteria of cervicogenic headache

Cervicogenic Headache International Study Group criteria (1)

Major criteria* I. Symptoms and signs of neck involvement

Ia. Precipitation of head pain, similar to the usually occurring one:

Ia1) by neck movement and/or sustained, awkward head positioning, and/or:

Ia2) by external pressure over the upper cervical or occipital region on thesymptomatic side.

Ib. Restriction of range of motion (ROM) in the neck.

Ic. Ipsilateral neck, shoulder or arm pain of a rather vague, non-radicular nature,oroccasionallyarm pain of a radicular nature.

II. Confirmatory evidence by diagnostic anesthetic blockades.

III. Unilaterality of the head pain, without side shift.

Head pain characteristics IV. Moderatesevere, non-throbbing pain, usually starting in the neck. Episodes of

varying duration, or: fluctuating, continuous pain.

Other characteristics

of some importance

V. Only marginal effect or lack of effect of indometacin. Only marginal effect or lack

of effect of ergotamine and sumatriptan. Female sex. Not infrequent occurrence of

head or indirect neck trauma by history, usually of more than only medium severity.

Other features of lesserimportance

VI. Various attack-related phenomena, only occasionally present, and/or moderatelyexpressed when present: a) nausea, b) phono- and photophobia, c) dizziness, d) ipsilateral

blurred vision, e) difficulties swallowing, f) ipsilateral edema, mostly in the periocular area.

International Classification of Headache DisordersII criteria (3)

A. Pain, referred from a source in the neck and perceived in one or more regions of the head and/or face, fulfilling

criteria C and D.

B. Clinical, laboratory, and/or imaging evidence of a disorder or lesion within the cervical spine or soft tissues of the neck

known to be, or generally accepted as, a valid cause of headache.

C. Evidence that the pain can be attributed to the neck disorder or lesion based on at least one of the following:

1. Demonstration of the clinical signs that implicate a source of pain in the neck

2. Abolition of headache following diagnostic blockade of a cervical structure or its nerve supply using placebo

or other adequate controls

D. Pain resolves within 3 months after successful treatment of causative disorder or lesion*It is obligatory that one or more of phenomena IaIc are present.

1470 Cephalalgia 30(12)

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Normal ROM was defined according to the results of

the three-dimensional analysis of the cervical spine

motion in normal individuals (21).

Greater occipital nerve blockade and other

treatment modalities

All persons with CEH were invited to undergo GON

blockade between August and September 2007. The

GON blockade included a mixture of 1 ml xylocaine

20mg/ml and 1 ml marcaine 5 mg/ml and was con-

ducted on the symptomatic side by a neurological res-

ident (HKK) according to the procedure (22). The

efficacy evaluation of the GON blockage as well as

other treatments modalities was based exclusively on

the patients self-reports.

Follow-up

Re-interview and re-examination by a neurological res-

ident (HKK) were performed between August and

September 2007. Of the 24 persons with CEH 19 were

follow-up, 3 could not be reached by telephone after at

least six attempts at different times and two were not

eligible due to incorrect phone number. Thus, the par-

ticipation rate among those eligible at the first

follow-up was 86% (19/22).

Data processing

All questionnaires were scanned using TeleForm v9

(Autonomy Cardiff, Vista, CA, USA). Interviewswere recorded electronically using SPSS Data Entry

4.0. The statistical analyses were performed using

SPSS Base System for Windows 15.0 (SPSS, Chicago,

IL, USA). Adjusted prevalence was calculated with a

95% confidence interval (CI) using the Vassar College

(Poughkeepsie, NY, USA) statistics website. We used

the 2- test with a 5% level of significance.

Ethical issues

The Regional Committees for Medical Research Ethics

and the Norwegian Social Science Data Services

approved the project. The participants who received

GON blockade were informed about the procedure

and side effects. All participation was based on

informed consent.

Results

Participants

A total of 24 persons (7 men and 17 women) had CEH

according to revised criteria of CHISG (Figure 1).

Two persons fulfilled six criteria, two persons fulfilled

five criteria, 11 persons fulfilled four and nine persons

fulfilled three.

Prevalence

The prevalence of CEH was 0.13% (95% CI 0.060.28%) in men and 0.21% (95% CI 0.130.34) in

women, while the overall prevalence was 0, 17%

(95% CI 0.110.26%).

Symptomatology

The mean age at onset and duration of CEH was

32 years (95% CI 1935 years) and eight years (95%

CI 511), respectively. Table 2 shows clinical character-

istics of CEH. All had nuchal pain onset and 83% had

radiation of pain to the forehead. Nine persons had

unilateral pain radiation, 14 persons reported bilateral

pain radiation but nuchal onset and pain maximum on

one side, and one person had unilateral pain on both

sides, classified as undetermined pain location. The

majority had moderate-to-severe head pain and 71%

had exacerbation of their pain in relation to physical

activity, stress, mechanical stimuli and/or awkward

head and neck positions and movements.

Accompanying symptoms were rare.

Medication overuse

Analgesic overuse was seen in 50% (N 12) of the per-

sons with CEH. Fifty-eight per cent of those personsoverused only one analgesic medication (43% parace-

tamol and 57% NSAIDs). Forty-two percent overused

more than one analgesic medication. Five persons over-

used opioids, two persons overused tramadol and oxy-

codon and three persons overused codeine.

Co-occurrence of migraine

Forty-two per cent had co-occurrence of migraine. The

mean age at migraine onset was 23 years for both

migraine with (640) and without aura (1234). The

pain onset, intensity and duration of a migraine

attack was distinct from the milder continuous pain

related to CEH. Accompanying symptoms such as

phono- and photophobia and nausea were present in

100% of migraine attacks and 50% had experienced

vomiting during a migraine attack.

Pericranial muscle tenderness

Pericranial muscle tenderness was present in all 22 per-

sons examined. Significant increased muscle tenderness

was seen in all seven muscle groups and the tendon


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insertions on processus mastoideus. The mean total ten-

derness scores were 7 (95% CI 59) for the face and 13

(95% CI 1116) for the neck muscles, respectively. The

total neck muscle tenderness score was significantly

higher on the pain than the non-pain side (p< .005).

Two persons with bilateral pain had the similar

muscle tenderness score on both sides. Data are given

in Table 3.

Table 2. Clinical features of cervicogenic headache in relation to CHISG criteria (1)

Symptom Number (percentage)

I. Symptoms and signs of neck involvement

Nuchal pain onset 24 (100)

1a. Precipitating of the head pain, similar to the usually occurring one:by neck movement and/or sustained, awkward head positioning 17 (71)

by external pressure over the upper cervical or occipital region on the symptomatic side 14 (64)

1b. Restriction of the range of motion in the neck

Significant restriction of the range of motion in the neck (N 22) 16 (73)

Ic. Ipsilateral

neck, shoulder or arm pain of a rather vague, non-radicular nature 9 (38)

or occasionally arm pain of a radicular nature 0 (0)

II. Confirmatory evidence by diagnostic anesthetic blockades

Positive effect of blockage at follow-up (N 10) 9 (90)

III. Unilaterality of the head pain without side shift

Unilateralism of the head pain, without side shift 9 (38)

Bilateral pain, but initial nuchal pain was worse on one side 14 (58)

Undetermined pain location 1 (4)

IV. Head pain characteristics

Mild intensity 3 (12)

Moderate/severe intensity 21 (88)

Pressing/tightening quality 18 (78)

Continuous pain 17 (71)

Fluctuating pain intensity 22 (92)

Fluctuating pain intensity and pain-free hours 7 (29)

Increased pain intensity by neck movements 17 (71)

V. Other characteristics of some importance

Only marginal effect or lack of effect of indometacin Not investigated

Only marginal effect or lack of effect of ergotamine and sumatriptan Not investigated

Head or indirect neck trauma 13 (54)

VI. Other features of lesser importance

Accompanying symptoms (N 22)

Photophobia 3 (14)

Phonophobia 0 (0)

Nausea 6 (27)

CHISGCervicogenic Headache International Study Group.


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Cervical range of motion

The cervical ROM tested by manual flexion/extension,

lateral flexion and rotation of the cervical spine was

significantly reduced in 16 persons, while four persons

had a normal ROM and four were not examined. Data

are given in Table 4.

Grater occipital nerve blockade

GON blockade on pain side resulted in 90% pain

reduction on a Visual Analog Scale (VAS) in five of

six persons who received it. The mean duration of

the GON blockade effect was 2.4 days. Four persons

reported to be pain-free after cryoanalgesic therapy

with a mean pain-free period of 79 days (95% CI. 56

102). Those persons refused additional invasive treat-

ment with GON blockade. Nine persons declined to

participate due to the invasive nature of the procedure.

Management

The effect of indometacin was not explicit tested in this

survey. Medications such as triptans or ergotamine

were not used for treating CEH. In our population

four persons reported treatment with CO2 cryoanalge-

sic therapy. All of them were treated at the same pain

clinic and continued with repetitive cryoanlalgesic

Table 3. Distribution of pericranial muscle tenderness scores (03) in seven muscle pairs and one pair of tendon insertions in the

head and neck

N 22(%)

None (0) Mild (1) Moderate (2) Severe (3) p values

M. masseter dxt. 23 59 13 5

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therapy every third to fourth month because of good

effect. Although only a small number of persons

received cryoanalgesic therapy, this was the treatment

modality with the best subjective efficacy. The efficacy

of alternative treatment such as physiotherapy, acu-

puncture, chiropractic management and other seems

to be poor. Data are given in Table 5.

Discussion

Main findings

Our main finding is the 0.17% prevalence of CEH in

the general population 3044 years old. We found that

the pericranial muscle tenderness score was significantly

higher on the pain than non-pain side and that the cer-vical ROM was significantly reduced compared to

healthy controls.

Prevalence

Our 0.17% prevalence of CEH in the general popula-

tion is much lower than the 0.44.6% prevalence of

CEH found in other studies, even though we used lib-

eral inclusions criteriathat is, requiring only three of

the six CHISG criteria to be fulfilled for the diagnosis

of CEH. However, a risk for underestimation of the

prevalence should be considered using a relatively

young study population, while other epidemiological

studies included individuals with older age (7,10).

Because 77% of the participants were interviewed at

the clinic and only 23% were interviewed by telephone,

the telephone interview is not likely to account for the

low prevalence of CEH in our study. Prevalence is

highly affected by the classification applied. We differ-

entiated between CEH and chronic headache attributed

to whiplash injury, based on unilateral origin of the

pain. CEH has been defined, in principle, as a unilateral

headache without side shift. However, in the most

recent version of CHISG criteria, the strict unilaterality

criterion has been softened. CEH is a complex syn-

drome caused by a variety of lesions that might repro-

duce pain on the contralateral side (23). Many

migraineurs report unilateral migraine, but sometimes

when the pain is particularly intense pain may also

occur, though less pronounced, on the other side.Patients with bilateral headache or neck pain after

whiplash injury are diagnosed as CEH in many head-

ache centers. It is also difficult to be absolutely sure of

how strictly the criterion of unilaterality has been fol-

lowed in other epidemiological studies.

If we had included the persons with chronic head-

ache attributed to whiplash injury (2 men and 18

women) in the CEH group, our prevalence would

have increased from 0.17% to 0.32%still a lower

prevalence compared to other studies (18).

The high prevalence of co-occurrence of migraine

was due to episodic attacks of migraine and not chronic

migraine. The majority of headache days were charac-

terized by a unilateral moderate/severe pressing/

tightening pain without accompanying symptoms, as

shown in Table 2.

None of our participants with CEH had chronic

migraine according to the ICHD-II criteria. The

GON blockade was used as a diagnostic tool according

to the CHISG diagnostic criteria. The diagnostic value

of this procedure is controversial and it might only be

useful in addition to a detailed clinical picture (24).

Clinical features

The nuchal onset of the pain correlates with the peri-

cranial muscle tenderness of the occipital muscles.

Another study showed that CEH had significantly

more posterior onset of pain as compared to migraine

without aura (25,26).The mean duration of CEH was

eight years (95% CI 511). The long duration suggests

that CEH often becomes chronic. Part of this is due to

insufficient pharmacological and non-pharmacological

treatment strategies. Medication overuse is likely sec-

ondary to the chronic pain rather than a confounding

factor, as the medication overuse is of shorter duration

than the CEH. Considering that CEH is a daily chronic

pain, surprisingly only 29.2% had consulted a neurol-

ogist and only 21% had consulted a pain clinic. This

may be due to moderate pain intensity. The lack of

consulting a headache specialist may also contribute

to medication overuse. Although only a small number

of persons received the GON blockade, the treatment

was quite effective in our population. The same applies

to cryoanalgesic therapy although the data were from

the patients reports. This is quite interesting given

that pericranial muscle tenderness was significantly

more pronounced on the pain than the non-pain side.

Table 5. Subjective positive efficacy of different

treatment modalities

Treatment modality NSubjective efficacy

% (N)

Physiotherapy 18 28 (5)

Psychomotoric physiotherapy 1 0 (0)Chiropractic management 8 38 (3)

Naprapathy 1 100 (1)

Acupuncture 11 27 (3)

Cryotherapy 4 100 (4)

Great occipitalis nerve (GON)

blockade on the pain side

6 83 (5)


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The reduced cervical ROM is likely to be secondary to

the pericranial muscle tenderness, although pain eli-

cited from other structures in the neck might also

play a role.

Methodological considerations

The sample size was chosen to ensure adequate numbers

of chronic headache patients for accurate descriptive

and epidemiological statistics. The age range of 3044

years was chosen because the prevalence of chronic

headache is relatively higher than in a younger age

range, while co-morbidity of other diseases is lower

than in an older age range. In addition, use of possibly

interfering medications increase after the age of 4550

(27). As this is an epidemiological survey on headache,

responders of the questionnaire may be overrepre-

sented by those with headache. However, replies to

the first, second and third questionnaires issued did

not imply that this was important in relation to

self-reported chronic headache. Questionnaires are

generally not accurate enough for diagnosing head-

aches (28). However, single simple questions such as

Have you ever had tension-type headache? and

How many days did you have tension-type headache

within the last year? are more valid, as these questions

compared to a clinical interview by a physician showed

kappa values of 0.74 and 0.77, respectively. Thus, our

question about unspecified headache frequency is likely

to be valid. The gold standard has been suggested to

be an interview and a physical and neurological exam-

ination by a physician experienced in headache diag-nostics (2831). For that reason, neurological residents

with experience in headache diagnosis conducted the

investigation. Because three physicians conducted the

investigations, interobserver variation is possible.

However, the third physician confirmed the diagnoses

in all eligible participants, suggesting that interobserver

variation is low regarding cervicogenic headache. The

majority of participants were interviewed at the clinic.

The neurological examination did not reveal abnorm-

alities that caused a change of the headache diagnosis.

We first applied the criteria of CHISG, fulfilling three

of six criteria as a minimum. Then we also used the

stricter revised criteria of CHISG. The central issue of

the ICHD-II criteria is to find evidence that the pain

can be attributed to a neck disorder or lesion.

However, features like neck trauma, mechanical exac-

erbation of pain and reduced ROM are neither unique

nor specific to CEH. According to the criteria of the

ICHD-II and CHISG, GON blockade has a diagnostic

value for CEH; it was performed in the follow-up in

25% of the persons with CEH. Four additional per-

sons received cryoanalgesic treatment and were

pain-free at the time of investigation. Our efficacy

and treatment data for cryoanalgesic therapy are low

in number and exclusively based on patients reports.

We considered them as positive responders in terms of

nerve blockade as well. Nine persons who declined

GON blockade because of the invasive character of

the procedure were still diagnosed as CEH, since at

least three of the other CHISG criteria were fulfilled.However, GON blockade is not an absolute require-

ment of ICHD-II criteria. The application of both

ICHD-II and CHISG criteria makes the diagnoses

unambiguous. Diagnoses for headache associated

with head trauma and whiplash do not have specific

criteria according to ICHD-II, while CHISG requires

more specific criteria. Thus, patients with chronic head-

ache and a head trauma/whiplash injury were classified

so according to the ICHD-II criteria, and those with

more specific criteria that fulfilled the criteria of

CHISG were also classified CEH. If we had applied

only the ICHD-II criteria, none of our participants

would have fulfilled the criteria for CEH. Thus, the

participants would be diagnosed with chronic headache

due to post-traumatic headache/whiplash injury or

chronic tension-type headache.

Thus, even with the many methodological chal-

lenges, our study population is likely to be representa-

tive for CEH in the general population, sas we applied

the most used criteria for inclusion in our study.

Conclusion

CEH is a rare chronic headache in ages 3044 years in

the general population. Although the number of parti-cipants was relatively small, usual pharmacological

management was not effective; GON blockade/

cryotherapy seems to have an effect in 90%, while

other treatment modalities were reported less effective.

The nuchal onset of pain, reduced cervical ROM, uni-

laterality of the pain and the increased ipsilateral peri-

cranial muscle tenderness score as well as the efficacy of

GON blockade suggest that local factors in the neck are

responsible for pain in CEH. Whether this mechanism

is involved in other types of headache cannot be con-

cluded from our study.

Acknowledgements

This study was supported by grants from South-Eastern

Norway Regional Health Authority, Hospital Innlandet and

Faculty Division Akershus University Hospital, University of

Oslo. Hospital Innlandet and Akershus University Hospital

kindly provided research facilities.

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