articulo 1 endo

Reasons for persistent andemerging post-treatmentendodontic diseaseMARKUS HAAPASALO, YA SHEN & DOMENICO RICUCCI

This article is a critical review of the reasons for persistent and emerging post-treatment endodontic disease

(PTED). While there is a strong consensus that micro-organisms, mainly bacteria, are practically the only cause of

primary apical periodontitis, the reasons for persistent apical periodontitis lesions have been more a matter of

debate. The authors of this review focus on the role of micro-organisms in PTED, and while secondary

developments such as cholesterol crystals or foreign material in the periapical area of a tooth with apical

periodontitis may contribute to additional irritation and/or an inflammatory reaction, a detailed analysis of the

available data suggests that evidence supporting a primary role for such secondary factors without the continued

presence of bacteria is lacking. Therefore, even in PTED, elimination of micro-organisms residing within the tooth

structure, root surface, or periapical tissues remains the goal of treatment and the key to long-term success.

Received 12 June 2010; accepted 27 January 2011.

Introduction

Root canal treatment of a tooth with irreversible pulp

inflammation is undertaken in order to remove the

inflamed tissue and to prevent further spread of the

infection. Criteria for successful treatment are lack of

symptoms, radiographic healing, and restored/con-

tinued functionality of the tooth. The first goal in the

treatment of apical periodontitis is to eliminate

the microbial infection from the root canal system of

the affected tooth by chemomechanical preparation

and disinfection. After this, a permanent root filling can

be placed and healing of the periapical (or lateral) lesion

can be expected. The root filling and subsequent

permanent coronal restoration will secure the tooth

against future infection. When the intra-canal infection

cannot be eliminated by conventional root canal

treatment, e.g. complex root canal anatomy, the

treatment may be completed by endodontic surgery.

In some cases, the periapical (or lateral) lesion does

not heal completely (Fig. 1) during a reasonable

follow-up time of approximately four years (1).

Persisting and recurrent apical periodontitis have been

a focus of interest in endodontic research for a long

time (2–8). The persisting lesion may be smaller,

unchanged, or even bigger than the original lesion, and

there may be occasional symptoms, although the

majority of persistent lesions are symptom-free. In

addition to persisting, non-healing lesions, it is also

possible that a new lesion may develop around the apex

of a root-filled tooth which previously did not have a

lesion or where the previous lesion had healed

completely, as judged radiographically (Fig. 2). This

review gives a summary of the various reasons for

persistent and emerging post-treatment disease.

Definition of post-treatmentendodontic disease (PTED)

In this review, post-treatment endodontic disease

(PTED) is defined as the presence of an inflammatory

periradicular lesion (periapical or lateral) in a previously

root-filled tooth when the lesion no longer can be

assumed to be undergoing healing following root canal

treatment. PTED may simply be a persistent infection,

which did not heal as a result of the root canal

treatment, but it may also be an emerging, new

infection in a previously root-filled tooth.

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Endodontic Topics 2011, 18, 31–50All rights reserved

2011 r John Wiley & Sons A/S

ENDODONTIC TOPICS 20111601-1538

Epidemiology

Controlled clinical trials demonstrate a good prognosis

for root canal treatment. However, cross-sectional

epidemiological studies in various countries have

indicated that the prevalence of PTED is high. The

frequency of the presence of periapical radiolucencies

associated with root-filled teeth varies between 16%

and 65%, depending on the study population and type

of teeth included (9–13). It is likely that some of the

teeth in these studies had been treated shortly before

the radiographs used in the studies were taken.

Therefore, it can be assumed that some of the lesions

are in fact undergoing healing and will disappear and

thus should not be diagnosed as PTED. The relative

proportion of the ‘‘healing in progress’’ cases cannot

be analyzed from the radiographs or from any other

information given in the studies and remains unknown.

However, based on the experience that most cases

which heal do so during the first year after treatment

(14–16), there is little doubt that the frequency of true

PTED remains disappointingly high even after deduct-

ing this group from the reported numbers. A detailed

analysis of the epidemiology of PTED is given by

Kirkevang in the next article of this volume, ‘‘Root

canal treatment and apical periodontitis: What can be

learned from observational studies?’’

Diagnosis and differential diagnosisof PTED

Diagnostic tools and criteria

Diagnosis of PTED is based on the findings of clinical

and radiological examinations. Sensibility/vitality test-

ing of the tooth is usually of no help as the tooth is

already root-filled. The presence of a swelling open

sinus tract, tenderness to percussion and palpation, and

a careful study of the occlusion and periodontal

condition are essential components of routine exam-

Fig. 1. A previously root filled tooth where the periapicallesion has not healed. Poor quality of the treatment hasallowed bacteria to remain in the root canal space.

Fig. 2. A new periapical lesion has developed in amandibular molar many years after root canal treatment. (a) The toothafter root canal treatment; the root canal space seems densely filled but may be 1–2mm short in mesial canals.(b) Several years later the tooth is symptomatic and a periapical lesion can be seen.

Haapasalo et al.

32

inations (Fig. 3). Evaluation of the quality of the

coronal restoration is of course important as leakage is a

potential cause for PTED. However, many of the teeth

with PTED are symptom-free, perhaps with the

exception of a slight sensitivity to percussion as

compared to neighboring teeth. Radiographic exam-

ination is often of key importance in determining the

presence or absence of disease in previously root-filled

teeth. In addition to periapical/periradicular health,

the technical quality of the root filling must be

evaluated, together with the possibility of untreated

root canals. Unfortunately, radiographs have well-

known limitations, which are related to the quality of

the radiograph, anatomy of the bone and tooth/roots,

and the size and location of the lesion (17–20).

Inflammatory lesions which are entirely in the cancel-

lous bone and do not engage the cortex are usually not

or only faintly perceptible on conventional radiographs

(Fig. 4) (21–24). A common cause for post-treatment

endodontic disease, untreated MB2 canals of maxillary

first and second molars, are often 1–2mm shorter than

the MB1 canal, and the lesion from this missed canal

may be superimposed (‘‘concealed’’) by the longer

buccal tip of the mesio-buccal root (Fig. 5).

PTED is often asymptomatic and therefore it is of

utmost importance to be careful when making a

diagnosis in the case of a root-filled tooth with a

radiographic periapical lesion. When a gutta-percha

point placed in a sinus tract traces the source to the

Fig. 3. A sinus tract in a previously root-filled tooth is asign of PTED. A gutta-percha point introduced intoan open sinus tract close to the previously root-filledmandibular premolar teeth.

Fig. 4. Conventional periapical radiograph indicates normal bone structure surrounding the mesial root tip of amandibular first molar (pictures in upper row). However, CBCT image reveals inflammatory bone loss around apex(pictures in lower row). Courtesy of Dr. Mahmoud Ektefaie.

Reasons for persistent and emerging post-treatment endodontic disease

33

apical periodontitis lesion of a root-filled tooth, the

diagnosis can be established easily. Also, in cases where a

root filling of poor quality is present in a root with a

clear apical periodontitis lesion and the patient experi-

ences pain or increased sensitivity to percussion, the

diagnosis of PTED can be made readily. At the other

end of the diagnostic spectrum are situations where the

root filling appears to be of high quality, the presence of

a pathosis cannot be verified reliably from the radio-

graph, and the patient’s symptoms cannot be well

localized. In addition, there are several other conditions

that may resemble or simulate apical periodontitis

radiographically and which occur at or project onto

the periapex of a tooth. These include variations of

normal anatomy (e.g. incisive canal, mental foramen),

various cysts (e.g. traumatic bone cyst), healing by scar

tissue (Fig. 6) (common after periapical surgery if both

cortical plates have been perforated), periapical ce-

mental dysplasia, cementoma in its early phase, fibro-

osseous lesions of the jaw, and metastatic tumors.

The introduction of cone beam computed tomogra-

phy (CBCT) to endodontic diagnostics has the

potential to greatly enhance the accuracy and sensitivity

of the diagnosis of periapical conditions. It has been

suggested that CBCT helps to detect more periapical

pathology than traditional 2D periapical films and

digital sensors (25–27). It can be expected that in the

near future CBCT will become a much more common

tool in the diagnosis of endodontic infections, includ-

ing PTED. An in-depth review of the diagnosis of

PTED is presented by Abbott in the article, ‘‘Diagnosis

and management planning for root-filled teeth with

persisting or new apical pathosis’’ in the following issue

of Endodontic Topics.

Etiology and pathogenesis of apicalperiodontitis

Etiology of primary apical periodontitis

Primary apical periodontitis is caused by microbes

which have invaded the root canal space of the affected

tooth via a carious lesion, leaking filling, cracks, or

some other pathway (28, 29). Pulpal necrosis will first

develop with the advancing infection. Due to selective

pressure by the ecological environment, primary apical

periodontitis (no previous root canal treatment of the

tooth) is dominated by anaerobic bacteria, often

together with a few facultative or aerobic bacteria

(30, 31). Yeasts are uncommon in primary apical

periodontitis. The mixed infection in the root canal

interacts with the host tissue via the apical foramen

initiating an inflammatory response. The host reaction,

which can be either acute (symptomatic) or chronic

(asymptomatic), causes destruction of the bone in

the affected area. The periapical inflammatory process

and the concomitant bone resorption can usually

be seen on a radiograph as a dark, radiolucent lesion

around the apex of the tooth. Periapical pathosis

caused by a microbial infection of the necrotic

root canal of a previously untreated tooth is diagnosed

as primary apical periodontitis. Although in rare

occasions other factors such as traumatic occlusion

(severe occlusal interference) can cause widening

Fig. 5. A micro-CT image of the mesio-buccal root of amaxillary first molar shows that the MB2 canal is shorterthan the MB1 canal and ‘‘hiding’’ behind the highestpoint of the root. If not specifically looked for, the MB2

canal may remain undetected even during apical surgery.Courtesy of Paul Brown, 3-DTooth Atlas, eHuman.com.

Haapasalo et al.

34

of the apical periodontal ligament space of a tooth,

microbes are the only etiological factor in primary

apical periodontitis.

Etiology of post-treatment disease

Due to the central role of microbes in the pathogenesis

of primary apical periodontitis, it is logical that

eradication of the microbes from the infected tooth is

regarded as the key to healing (8, 32–34). The technical

and biological goal of root canal treatment is to shape

the root canal(s) in such a way that effective disinfection

can be achieved and the root canal system can be

adequately filled. When the root canal treatment is of

high quality, healing will occur in most cases. If

eradication of the infection cannot be successfully

completed and if the residual microbes (after the

treatment) communicate with host tissues, healing will

be compromised. However, the etio-pathogenesis of

PTED may be more complicated than can be simply

concluded from the above. While in primary apical

periodontitis, microbes are the only cause for the

development of the apical periodontitis lesion, in PTED

several other reasons have also been indicated as possible

causes for the persistence of the periapical pathology.

During the development of the primary apical lesion

and in the course of the root canal treatment, secondary

developments may occur which have been suggested to

prevent or interfere with the healing process. This

review gives a summary and critical review of the

proposed reasons for persistent and emerging post-

treatment disease based on the most recent literature.

Microbial causes of PTED

Intraradicular microbes

Root canal treatment, even when not carried out to the

highest possible technical standard, dramatically changes

the environment in the root canal; availability of oxygen

and nutrients is different, and in many cases substances

with antimicrobial activity are introduced into the root

canal as irrigating solutions and local antimicrobial

medicaments. If the residentmicroflora is not completely

eradicated, the new harsher ecological environment may

in fact contribute to the development of a more resistant

facultative microflora. Post-treatment endodontic infec-

tions are dominated by environmentally tolerant bacteria

and sometimes also by yeasts, which are characterized by

higher resistance to treatment procedures and disinfect-

ing agents than the anaerobic microflora in primary

apical periodontitis (4, 31, 35–38). The microbiology of

PTED is reported in great detail by Figdor & Gulabivala

in the article ‘‘Microbiology of root canals associated

with post-treatment disease’’ later on in this volume.

The importance of the composition of the intracanal

microflora in PTED has been a subject for much

Fig. 6. (a) A large periapical lesion around the apex of tooth #12. Histological analysis verified the diagnosis as aradicular cyst. (b) Follow-up radiograph taken 11 years after root canal treatment and apicoectomy shows healingpartially by scar tissue. The radiolucent area appears to be separated from the resected root apex by a layer of bone. Theoriginal lesion perforated both buccal and palatal cortical lamellae.


35

speculation and discussion. The strong dominance of

Enterococcus faecalis in PTED has lead to an abundance

of studies on the role in infection and sensitivity to

disinfecting agents of this facultative Gram-positive

coccus (39–45). One should remember, however, that

the classical studies by Bergenholtz (29), Sundqvist

(46), Moller et al. (47), and Fabricius et al. (48) clearly

indicated that apparently any species or rather combi-

nation of species which are able to establish themselves

in the necrotic root canal and survive the special

ecological environment are capable of causing apical

periodontitis. The reason for using E. faecalis as a

model organism in many of the studies should

probably be seen from the following two perspectives.

First, E. faecalis is de facto the most common finding in

PTED. Second, it is more resistant to harsh environ-

mental conditions and to many medicaments, e.g.

calcium hydroxide, than most other bacteria (49, 50);

see disinfection of the root canal in PTED by Zehnder

& Paque in the next volume (51). Therefore, the

rationale for using E. faecalis as the test organism has

been partially based on the assumption that methods

and chemicals which are effective in eliminating this

resistant and tolerant species are likely to be effective

against most other microbes as well. Until shown

otherwise, the possibility that E. faecalis is in fact one

of the microbes that play a key role in many cases of

PTED cannot be ignored.

Fig. 7. (a) A radiograph showing a large apical lesion in a root-filled mandibular canine. (b) Histological section(modified Brown and Brenn staining) passing approximately at the center of the apical root canal. Overview shows ananticipated foramen. Dark material in the middle is the root filling. (c-d) Higher magnification images from (b)demonstrating (the biofilm) bacterial aggregates (dark blue) intermixed with necrotic debris in the apical root canal walland in a cross-cut apical ramification, respectively. Reprinted modified with permission from Ricucci D. Patologia eClinica Endodontica. 2009; Edizioni Martina, Bologna, Italy.

Haapasalo et al.

36

Localization of the resident microbes in the filled root

canal is probably muchmore important to the outcome

of the root canal re-treatment than the composition of

the flora. As indicated by the classical studies, most if

not all bacteria have the ability to cause apical perio-

dontitis if they can survive in the root canal. Therefore,

the ability of the residual flora to communicate with the

periapical or periradicular host tissue is what determines

the progression of the disease. When the residual

bacteria are completely entombed by the root filling,

blocking all communication with the tissues, healing

will occur and the bacteria are expected to either die or

survive but cause no harm, depending on the survival

capability of each species. However, when residual

bacteria or new invaders are located in areas with a

connection to the tissue of the host, development or

continuation of periapical inflammation is likely to

result. The main root canal, especially the most apical

part of it, and the apical delta (apical lateral canals) are

the most common sites for bacteria to remain and cause

PTED (Fig. 7). Bacteria also reside in dentinal tubules

(Fig. 8) in most teeth which have apical periodontitis

(52–54). However, the role of microbes that have

invaded deeper into the dentin has been questioned

(55, 56). Nevertheless, when root surface cementum

has been resorbed, as often happens around the apical

foramen in apical periodontitis, bacteria may more

easily invade the entire thickness of the root via dentinal

tubules (Fig. 9) and develop a biofilm on the external

root surface (57, 58). In such teeth there is a strongly

increased possibility that invasion of dentin bymicrobes

from the main root canal is an important factor in the

development of PTED.

In addition to the location of the microbes in various

parts of the canal system and in relation to the apical

foramen/foramina, the fact that microbes are organized

into complex structures referred to as biofilms (Figs. 9a

and b) plays a major role in the development and

resistance to treatment of endodontic infections. Biofilms

are structured microbial communities embedded in a

highly hydrated matrix of extracellular polymeric sub-

stances produced by the microbial cells (59). The

polymeric substances are partially responsible for impor-

tant biofilm functions including cellular cohesion, surface

adhesion, and nutrient dynamics (60). Generally, bacteria

in biofilms are responsible for a variety of persistent

infections (61). The difficulty in eradicating such in-

fections is caused by several factors including reduced

susceptibility of micro-organisms in biofilms to anti-

microbial agents (62, 63). Due to the central role of the

biofilm in endodontic infections, it has been suggested

that both primary apical periodontitis and PTED should

be regarded as biofilm-induced diseases (64).

The role of lateral canals in endodontic infections has

been a controversial subject. The fact that lateral canals

can contain bacteria/bacterial biofilm which cause

lateral lesions is not a matter of debate (Fig. 10).

Differences in opinion are related to the treatment:

whether it is necessary to clean (even if possible) and fill

the lateral canals to secure healing of the lateral lesion. A

recent report by Ricucci & Siqueira (56) based on

extensive clinical material indicated that eradication of

Fig. 8. (a) Persisting apical periodontitis in a root-filled mandibular incisor. A histological section of the apical canaldemonstrates bacteria/biofilm on irregularities of the apical root canal wall, untouched by instruments (b) andpenetration of bacteria into dentinal tubules (c). Black particles in (b) represent root fillingmaterial. Reprintedmodifiedwith permission from Ricucci D. Patologia e Clinica Endodontica. 2009; Edizioni Martina, Bologna, Italy.


37

bacteria/biofilm from the lateral canals remains a

challenge even though the canals may seem to be filled

with sealer or other root filling material as judged from

the radiographs. However, histological sections of

extracted teeth revealed that lateral canals were never

completely cleaned and, when filled with a root filling

material, they also contained vital or necrotic pulp tissue

and on many occasions bacteria as well (56). Never-

theless, as long as there is nomethod to completely clean

and disinfect the lateral canals predictably, microbes in

the lateral canals remain one possible reason for PTED.

In summary, there is a widely accepted consensus that

the microbes which are the cause of PTED usually

reside somewhere inside the root canal system of the

tooth. Key preventive measures include high-quality

chemomechanical preparation of all canals to the

correct length, effective irrigation and disinfection,

permanent root filling of optimal quality and with

antibacterial activity, and adequate coronal restoration

of the tooth to secure the root canal system against the

possibility of coronal leakage and thus re-infection.

Extraradicular microbes

While intracanal microbes remain the main cause of

PTED, extraradicular bacteria have also been claimed

to be present in some infections (41, 65–71).

Conventional root canal treatment, including instru-

mentation, disinfection, and root filling, can only affect

those microbes which are within the confines of the

root canal system. In acute apical periodontitis with an

abscess or an open sinus tract, bacteria are regularly

found in the tissue (31, 72, 73). This is not problematic

because the host defense system is expected to

eliminate these microbes quickly and effectively with

no negative impact on the long-term prognosis.

However, bacteria (or yeasts) which have succeeded

in establishing a colony/biofilm on the root surface or

in the periapical tissue are beyond the direct reach of

conservative (non-surgical) treatment methods. A

special variation of root surface biofilm is calcified root

surface biofilm. Precipitation of minerals in E. faecalisbiofilm on dentin in vitro has been described by Kishen

et al. (74), and there are some reports where calculus-

like deposits on the apical external root apex were

responsible for root canal treatment failure (75). Figure

11 shows calcified biofilm on apical root surfaces.

Traditionally, Actinomyces spp., and A. israelii in

particular, have been isolated from periapical specimens

of some persistent infections identified as periapical

actinomycosis (Fig. 12). During the last 10–15 years, a

number of studies have indicated that bacteria other

than Actinomyces spp. can also create actinomycosis-like

colonies in the periapical tissue (68–70, 76, 77). While

there is no disagreement on the presence of biofilm

Fig. 9. (a)Histological specimenof the root tip area of thepatient in Figure 8; section not passing through the apicalcanal. (b) Higher magnification of the area indicated bythe arrow in (a). A biofilm is present on the external rootsurface showing a dense network of bacteria embedded inextracellular substance, EPS (modified Brown and Brennstaining). Reprinted modified with permission fromRicucci D. Patologia e Clinica Endodontica. 2009;Edizioni Martina, Bologna, Italy.

Haapasalo et al.

38

colonies in the periapical tissues of some persistent

infections, their independence or dependence on

intracanal infection remains a matter of debate (78).

Although it has been suggested that apical actinomycosis

represents the most typical example of extraradicular

infection independent of the intraradicular infection,

there is no strong evidence supporting this statement.

The vast majority of studies and case reports have

examined only apical periodontitis specimens taken after

periradicular surgery or extraction, but the correlation

with the bacteriological conditions of the associated root

canal has not been investigated. While the prognosis of

treatment following surgical removal of the infected

periapical tissue in periapical actinomycosis is excellent, it

should be recognized that the procedure routinely also

includes the removal of the root tip and placement of an

apical root-end filling. Therefore, the existence of apical

actinomycosis as a pathological entity independent of

the root canal infection and its involvement as the

exclusive cause of treatment failure remains to be proven.

Periapical biofilm colonies, like biofilms in general,

are assumed to be resistant to systemic antibiotic

treatment (62, 63). In addition to such biofilms inside

the periapical tissue, there are several reports of bacteria

growing in biofilms on the root surface close to the

apex (75, 79–81). There are probably two main routes

of infection resulting in root surface biofilms: one is

continuous expansion of microbial growth through the

apical foramen or through lateral canals, and the

second alternative is through dentinal tubules in an

area where root surface cementum has been resorbed

away (57, 58). The presence of a long-standing sinus

tract may also play a role in allowing bacterial

penetration from the oral cavity (75, 81). Irrespective

of the pathway of infection, when actinomycosis-like

colonies in the tissue or root surface biofilm have

developed, surgical treatment including apicoectomy

and removal of the infected hard and soft tissue has

been shown to be effective with an excellent long-term

prognosis (65, 82–84).

Fig. 10. (a) A histological section of a tooth shows bacterial presence (dark blue staining) in themain canal and in a largelateral canal. (b) A higher magnification image of bacteria in the lateral canal. (c) A further magnification showsmicrobial biofilm in the center of the lateral canal as well as attached to the dentin wall (modified Brown and Brennstaining).


39

From the point of view of treatment planning and

prevention, it would be useful to know the frequency of

extraradicular periapical infections as well as the details

of the pathogenesis of periapical actinomycosis. Un-

fortunately there is no reliable data about either. Study

populations have usually been poorly described in

reports of extraradicular infections. In addition, reli-

able diagnosis should be based on histological exam-

ination where sections have been prepared and

examined throughout the lesion. It is the opinion of

the authors that studies where only culturing or DNA

methods have been usedmay not always reflect the true

nature of the periapical condition/infection, and even a

temporary presence of bacteria in the tissue may be

confused with true extraradicular infection. The

possibility of true positive findings is supposed to be

higher and false positive findings lower when the

presence of the biofilm structure in tissue can be

Fig. 11. (a) Apical section of an extracted tooth stained with modified Brown and Brenn staining reveals bacteria (darkblue) in the root canal as well as on the apical root surface. (b) A high magnification image of the root surface showsbacteria embedded in calculus-like structure. The tooth had no deep periodontal pockets.

Fig. 12. (a) Actinomyces-like colony (biofilm) close to the root surface in a tooth with (persistent apical lesion) primaryapical periodontitis. The bacteria are surrounded by a dense accumulation of inflammatory cells. (b) A highmagnification of Figure 12a shows several Gram-positive filamentous bacteria in the periapical biofilm.

Haapasalo et al.

40

visualized in the sections. In a recent study, Ricucci &

Siqueira (64) evaluated the prevalence of bacterial

biofilms in untreated and treated root canals of teeth

with apical periodontitis. Extraradicular bacterial bio-

films were observed in six out of 100 specimens (6%),

four from teeth with untreated canals and two from

teeth with treated canals.

As previously mentioned, the development of root

surface biofilm supposedly occurs by growth of the

root canal microflora via apical foramen/foramina or

through the whole width of the infected root dentin

when root surface cementum has been resorbed.

Contrary to this, the pathogenesis of periapical

actinomycosis or actinomycosis-like extraradicular in-

fection is less obvious. Many of the species, including

Actinomyces spp., are non-motile bacteria, and yet they

are found as separate islands in the tissue. Furthermore,

how can bacteria travel in tissue and survive the host

defense before the protective biofilm is formed?

Individually, most if not all bacteria isolated so far

from periapical actinomycosis and other extraradicular

microbial lesions are sensitive to phagocytic ingestion

and killing. Although not known with certainty, one

possibility that cannot be ignored is that ready-formed

mature biofilms are transferred from the root canal into

the periapical area. This would help the bacteria avoid

the dangers of host defense as the biofilm is first formed

in the shelter of the necrotic root canal. Later, when in

the tissues, the biofilm provides the necessary protec-

tion. Kishen (85), based on measurements of liquid

movement in the apical root canal caused by occlusal

activity, suggested that this may allow transfer of

bacteria from the canal to the apical tissues. Another

possibility is that root canal biofilms are pushed into the

periapical tissue during instrumentation of the necrotic

root canal during the course of root canal treatment.

Radicular cyst

A radicular cyst develops subsequent to apical perio-

dontitis. Therefore, it can be classified under micro-

biological reasons, even though the cyst itself usually

does not contain bacteria. First, apical periodontitis

develops as a result of bacterial presence in the root

canal. Then, in some cases, epithelial cells in the

periapical area start to multiply, which may result in the

formation of a radicular cyst. While apical periodontitis

can in most cases heal by conservative root canal

treatment, the relationship between root canal treat-

ment and the healing of radicular cysts remains unclear.

Simon (86) and later Nair (7, 71) suggested that there

are two main types of radicular cysts, bay cysts

(periapical pocket cysts) and true cysts, and presented

the view that bay cysts have the better chance of healing

when only conservative root canal treatment is used.

On the contrary, in true cysts the epithelial lining is not

connected to the tooth and there is no communication

between the interior of the cyst and the root canal.

Therefore, it has been suggested that true cysts are

likely to require surgical removal to ensure healing of

the area (7). However, the hypothesis regarding the

requirements for healing of true cysts is a matter of

debate. Ricucci et al. (75) suggested that although the

use of serial sections may disclose a true cyst with no

apparent communication with the root canal, these

lesions cannot be regarded as a separate disease entity.

Lin et al. (87) argued that large cyst-like apical

periodontitis lesions or apical true cysts are formed

within an area of apical periodontitis and cannot form

by themselves. Therefore, both large cyst-like apical

periodontitis lesions and apical true cysts are of

inflammatory and not of neoplastic origin. According

to Lin et al. (87), lesions of apical periodontitis,

regardless of the histological type (granuloma, abscess,

cyst), that do not heal after conservative root canal

treatment persist for one reason: the presence of an

intraradicular and/or extraradicular infection. There

are no studies in the literature showing the absence of

microbes in the apical root canal, on the root surface, or

outside the tooth in cases of persisting radicular cysts. If

the microbial presence is terminated by the treatment,

the cystic lesions may regress by apoptosis, similar to

the resolution of inflammatory apical pocket cysts.

However, the clinical reality is that, mostly for

anatomical reasons, complete elimination of the

microflora cannot be obtained in all cases by con-

servative treatment. In situations where surgery is

performed to remove the cyst, it is important to

eliminate the areas of the tooth apex which are likely to

harbor the residual infection (87). Since clinicians are

unable to establish beforehandwhether or not there is a

cyst (true or pocket) (54, 88), the effect of treatment

cannot be established in retrospect regardless of the

methods (conservative or surgical treatment) used.

The estimates of the frequency of radicular cysts

accompanying apical periodontitis show wide variation

between 6 and 55%; for review, see Nair (89). Nair et al.

(90) reported that, in a histological study of 256 apical


41

periodontitis lesions, 52% contained epithelial growth

but serial sectioning through the whole lesion revealed

that in fact only 15% were radicular cysts. The authors

suggested that histological analysis of only part of the

lesionmay easily lead to overdiagnosis of radicular cysts

if the mere presence of epithelium is used as the

criterion (90). It should be noted that, in most studies,

lesions which are surgically removed and examined

histologically do not represent random lesions of

primary apical periodontitis as, in the great majority

of primary cases, there is no need for surgery.

Vertical root fracture

Vertical root fracture (VRF) can be regarded as a special

type of PTED (91–94). VRF can occur in teeth that

have not been endodontically treated, but it is most

common in roots which have a root filling (with or

without a post). Although VRF is not true apical

periodontitis, it causes signs and symptoms which are

often misinterpreted as persistent or emerging apical

periodontitis (Fig. 13). Vertical root fracture can occur

in any tooth (incisor, canine, premolar, or molar) and it

is always bucco-lingual. It starts in the root and is often

invisible at the beginning, both clinically and radio-

graphically, except for the possibility of pain. Later a

narrow pocket develops all the way to the apex of the

tooth, which can be incorrectly diagnosed as a

‘‘regular’’ deep periodontal pocket or endodontic sinus

tract which mimics a pocket. The infection is caused by

bacteria residing in the fracture line, escaping from the

host defense. There is no treatment for VRF other than

extraction; therefore it is important to make an early

diagnosis in order to avoid unnecessary treatment.

Crack tooth and split tooth

Crack tooth is another type of longitudinal tooth

fracture (95). Unlike VRF, it starts in the crown, it is

mesio-distal, and occurs only in premolars and molars

(Fig. 14). Similar to VRF, it is not a true endodontic

infection. However, it often causes symptoms that can

be confused with PTED. A common consequence of

infection caused by a crack is a narrow mesial or distal

pocket. The crack itself is always invisible radio-

graphically but the bone loss caused by the infection

can often be seen. Clinically, the pocket may be difficult

to locate without careful probing. Another site of tissue

destruction caused by a crack is at the furcation, if a

deep crack extends through the pulp chamber floor. As

in VRF, bacteria remain in the crack and cannot be

eliminated without removing the dental hard tissue

surrounding the crack. In deep cracks this is not

possible and the tooth must be extracted. Split tooth is

Fig. 13. Vertical root fracture in a maxillary canine. Atypical pear-shaped lesion can be seen ‘climbing’ up theroot.

Fig. 14. Crack tooth. A distal fracture line in a maxillarymolar. The line is stained, indicating that it is not new.The depth of the fracture will determine the fate of thetooth. When the fracture extends below the marginalbone level, a narrow pocket and diffuse symptoms can bedetected.

Haapasalo et al.

42

a continuation of a crack tooth; in split tooth there are

always two separate tooth fragments (Fig. 15). Split

tooth is therefore easy to diagnose; the only available

treatment option is extraction.

Coronal leakage

Inmany reports, coronal leakage has been suggested as a

possible cause for PTED (31, 96–100). A legion of

laboratory studies have indicated that at least some

bacteria can penetrate deeply into the root-filled canal in

only a few weeks if the canal and root filling are not

properly sealed with a coronal restoration.Most of these

studies have shown contamination of the liquidmedium

at the apical end of the root by bacteria which were

placed in a coronal reservoir within a few weeks or

months, while some studies have demonstrated bacteria

between the canal wall dentin and the gutta-percha–

sealer complex using microscopic techniques (101–

106). Despite the vast amount of such information,

the true importance of coronal leakage has not been

fully demonstrated. The few studies in humans have

indicated that, although possible in teeth treated

according to less than ideal technical standards, good

fillings in optimally prepared canals may resist bacterial

penetration, even after long-standing exposure to the

oral environment (34, 107, 108).However, a new lesion

after a technically good root filling is not uncommon

either. It is therefore likely that a widely accepted

consensus regarding the clinical importance of coronal

leakage for the long-term prognosis of root-filled teeth

will remain a challenge for the future. The major reason

for this is ethical problems in conducting a clinical study

where root-filled teeth would be intentionally left

without protection by the coronal restoration in the

oral cavity for different time periods and then followed

for long-term prognosis after finishing the coronal seal.

Non-microbial causes for PTED

As mentioned earlier, primary apical periodontitis is

practically always caused by microbes. The situation in

PTED is to some extent different. While the primary

inflammation (inflammatory response/reaction of the

host tissues) is caused by an infection (microbial

presence in the root canal or even in the periapical

tissues), secondary developments caused either by the

inflammatory reaction itself or by treatment procedures

may contribute to the continuation of the inflamma-

tion. In the following, the most common secondary

factors and their relationship to persisting infection

within the tooth structures in PTED will be discussed.

Cholesterol crystals

Cholesterol is a steroid lipid present in human and

animal cells. Under some conditions, cholesterol can

form crystals and contribute to disease development,

e.g. atherosclerotic plaque in coronary disease (109,

110). Cholesterol crystals are also commonly found in

apical periodontitis (111–113). The origin of choles-

terol in the periapical area (Fig. 16) is most likely the

dying cells during chronic inflammation (111, 112). At

sites of inflammation, granulocytes generate reactive

oxygen metabolites which have been shown to

promote cholesterol crystal formation (114). Experi-

mental studies have shown that the presence of

cholesterol crystals in the tissue attracts accumulations

Fig. 15. (a-b) Split tooth. A previous crack in amandibular molar developed further, splitting the tooth into two halves.(c) A histological section of the distal mid-root verifies the mesio-distal direction of the fracture line. (d) Highermagnification reveals microbial biofilm (stained blue) in the dentin wall of the fracture line. Reprinted modified withpermission from Ricucci D. Patologia e Clinica Endodontica. 2009; Edizioni Martina, Bologna, Italy.


43

of host defense cells, macrophages in particular,

probably in an effort to remove the crystals by

phagocytosis (115–117). However, macrophages are

unable to eliminate the crystals, maybe partially due to

their large size as compared to the cells. The effort

nevertheless contributes to a local inflammatory

reaction via release of inflammatory mediators such as

interleukin 1a by the macrophages and other defense

cells at the site (117). In summary, cholesterol crystals

are not originally present in the periapical tissue of a

healthy tooth but, during long-standing chronic apical

periodontitis, crystals may develop locally in the tissue.

However, it should be emphasized that there are no

reports of failed cases where adequate histological

processing has shown the presence of cholesterol in

periapical tissue in the absence of infection, and a

recent histological study on failed cases did not

describe cholesterol as responsible for the failures (8).

Foreign body reaction

Foreign material may become lodged in the periapical

tissue and cause irritation and inflammation in the area,

leading to the delay or prevention of healing. Foreign

material can enter the periapical tissue (Fig. 17)

through the root canal when the tooth is left open

into the oral cavity or during endodontic procedures.

Another route is by traumatic injury through the

mucosa or during endodontic surgery. Foreign materi-

al can cause or contribute to periapical inflammation by

at least two different mechanisms. First, it can have

microbes/biofilm attached to its surface (obtained

from the root canal) and provide a protective platform

for further microbial growth in the tissues. Second,

even without any microbial contamination, foreign

material may cause a giant cell response as the body

tries to remove it. Giant cells and macrophages, similar

to the situation with cholesterol crystals, secrete

inflammatory mediators during their often chronic

effort to clear the area of foreign material.

Fig. 16. A histological section (haematoxylin-eosinstaining) shows numerous cholesterol crystals and aheavy accumulation of inflammatory cells in a specimenobtained from a tooth with a periapical inflammation.

Fig. 17. (a) A histological section of a periapicalinflammatory lesion with foreign material. (b) A close-up of the area with foreign material (dark particles,possibly sealer) shows multinuclear giant cells next to thematerial, surrounded by inflammatory cells. The reasonfor persisting apical periodontitis was the intraradicularpresence of bacteria. Reprintedmodifiedwith permissionfrom Ricucci D. Patologia e Clinica Endodontica. 2009;Edizioni Martina, Bologna, Italy.

Haapasalo et al.

44

Gutta-percha is usually well tolerated if a non-

contaminated tip of a gutta-percha cone is extruded

during root filling to the periapical area. Nair et al.

(118) have shown that gutta-percha will be encapsu-

lated by multilayered collagen fibers with little or no

invasion of inflammatory cells surrounding the capsule.

In other experiments, Sjogren et al. (115) demon-

strated that when gutta-percha is processed into small

particles and introduced into vital tissue in experi-

mental animals, it is surrounded by mononuclear

inflammatory cells. A situation where gutta-percha

may be associated with continuing periapical inflam-

mation is when a piece of gutta-percha from an existing

root filling, covered with a biofilm, is left or pushed

into the periapical area during re-treatment.

Endodontic sealers are often extruded into the

periapical area during root filling, in particular with

various thermoplastic root filling techniques (119,

120). Small amounts of sealer are not expected to cause

major problems for healing. Most commercially avail-

able sealers become practically inert after some time

(34). In a histological study of 51 root-filled human

teeth healed after long-term observation periods and

extracted for various reasons, Ricucci et al. (34)

concluded that it is very unlikely that any material

toxicity would be discernible as tissue changes. No

clinical association with outcomes could be observed

when comparing the long-term treatment results of

different sealers used in this study (34). However, if the

sealer is contaminated by bacteria from a poorly

instrumented and disinfected canal, it will be a center

of continuing inflammation and thereby PTED. Also,

larger volumes of extruded sealer, even when not

contaminated, are likely to cause a foreign body reaction

by giant cells and macrophages, resulting in some

degree of continuing inflammatory reaction (121, 122).

In rare situations, even quite small amounts of either

sealer, gutta-percha, or both may be extruded outside

the root canal on the bone surface under the periosteum.

This may occur when the apical foramen is naturally

located in this area. Clinical experience has shown that

the area remains sensitive to palpation even for several

months, and spontaneous pain may also be experienced

by the patient, both an indication of PTED. Radio-

graphic examinationmay not reveal anything of concern,

but the irritation can only be solved by exploratory flap

operation and removal of the extruded material.

Other filling materials such as amalgam, gold,

silver, glass ionomer, composite materials, or compo-

nents of disinfection pastes can also be found in the

periapical tissues in some cases of PTED (123). Similar

to the materials described earlier, microbial contam-

ination is possible with all of these materials, usually

from the root canal microflora, the material itself acting

in a ‘‘supporting’’ role by offering a platform for the

bacteria to form a biofilm on its surface. The continued

infection and inflammation is caused by the microbes

while the material may contribute to the inflammation

by stimulating a foreign body reaction as explained

earlier. In many occasions the filling materials present

in periapical tissues originate from a root-end filling

that was loosened or where parts of it weremisplaced to

begin with during periapical surgical. Silver cones may

undergo corrosion and, if overfilled, the part in the

tissue may separate and stay in the lesion, causing a

foreign body reaction (Fig. 18). Amalgam and gold

may also originate from a restoration or a crown if the

metal powdered during burring falls into the root canal

and is pushed further into the periapical area.

Cellulose-containing materials and plant cells areknown to be able to cause a chronic inflammatory

reaction if present in the periapical tissue (71, 124,

125). Cellulose is foreignmaterial and the human body

does not have enzymes to degrade cellulose. The above

studies have demonstrated the presence of cellulose

Fig. 18. A separated piece of a silver point can be seen inthe periapical lesion of a first mandibular molar severalyears after root canal treatment. However, the reason forthe unhealed lesion is persisting infection in the root canalsystem of the tooth, not the silver point per se.


45

from paper points in the lesion; another possible source

is cotton pellets. Contamination of paper points with

bacteria will further add to the development of a

stronger inflammatory response. The earlier practice of

using paper points as vehicles for root canal medica-

ments, leaving the points in the canal between

appointments, should be advised against because the

points may disintegrate or become fragile during the

inter-appointment period in the root canal. Periapical

surgery and careful cleaning of the bone cavity is the

best way to completely eliminate the irritation (and

PTED) from cellulose-containing materials. These

materials are not visible radiographically and therefore

they cannot be diagnosed pre-operatively.

Plant cells are probably a relatively rare reason for

PTED. However, if they find their way to the periapical

tissue of a tooth, the pathogenesis of continuing

inflammation is similar to that when cellulose-contain-

ing fibers from paper points are found in this area.

Small pieces of vegetables could be pushed down the

canal to the periapical tissues when the tooth has been

left open or a temporary filling has fallen out. Figure 19

shows a case of persistent infection where microscopic

pieces of green vegetables were found inside the lesion.

Summary and conclusions

Micro-organisms are practically the only cause of

primary apical periodontitis. Although bacteria and

sometimes yeasts are regarded as the main etiological

explanation for post-treatment endodontic disease,

other reasons have also been suggested. These include

cholesterol crystals or a true cyst that may have

developed during the primary infection. However, it

has been proposed that they may become an independ-

ent reason for the persistence of the inflammation even

after the elimination of the infection. In this article the

authors critically review earlier literature and emphasize

that the evidence which would rule out the role of

residual micro-organisms is, in fact, weak or lacking.

Therefore, despite the possible contributing role of

non-microbial factors in periapical inflammation,

complete eradication of micro-organisms from the

root canal system remains the most important target of

successfully eliminating PTED.

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