Endodontic Topics 2011, 18, 3150

All rights reserved

2011 r John Wiley & Sons A/S

ENDODONTIC TOPICS 2011
1601-1538

Reasons for persistent and

emerging post-treatment
endodontic disease
MARKUS 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/continued 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 (28). 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-treatment
endodontic 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.

31

Haapasalo et al.

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 (913). 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
(1416), there is little doubt that the frequency of true
PTED remains disappointingly high even after deducting 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 diagnosis

of PTED
Diagnostic tools and criteria

Fig. 1. A previously root filled tooth where the periapical

lesion has not healed. Poor quality of the treatment has
allowed bacteria to remain in the root canal space.

Diagnosis of PTED is based on the findings of clinical

and radiological examinations. Sensibility/vitality testing 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. 2. A new periapical lesion has developed in a mandibular molar many years after root canal treatment. (a) The tooth
after root canal treatment; the root canal space seems densely filled but may be 12 mm short in mesial canals.
(b) Several years later the tooth is symptomatic and a periapical lesion can be seen.

32

Reasons for persistent and emerging post-treatment endodontic disease

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

Fig. 3. A sinus tract in a previously root-filled tooth is a

sign of PTED. A gutta-percha point introduced into
an open sinus tract close to the previously root-filled
mandibular premolar teeth.

compared to neighboring teeth. Radiographic examination 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 wellknown 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 (1720).
Inflammatory lesions which are entirely in the cancellous bone and do not engage the cortex are usually not
or only faintly perceptible on conventional radiographs
(Fig. 4) (2124). A common cause for post-treatment
endodontic disease, untreated MB2 canals of maxillary
first and second molars, are often 12 mm 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. 4. Conventional periapical radiograph indicates normal bone structure surrounding the mesial root tip of a
mandibular first molar (pictures in upper row). However, CBCT image reveals inflammatory bone loss around apex
(pictures in lower row). Courtesy of Dr. Mahmoud Ektefaie.

33

Haapasalo et al.
tissue (Fig. 6) (common after periapical surgery if both
cortical plates have been perforated), periapical cemental dysplasia, cementoma in its early phase, fibroosseous lesions of the jaw, and metastatic tumors.
The introduction of cone beam computed tomography (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 (2527). It can be expected that in the
near future CBCT will become a much more common
tool in the diagnosis of endodontic infections, including 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 apical

periodontitis
Etiology of primary apical periodontitis
Fig. 5. A micro-CT image of the mesio-buccal root of a
maxillary first molar shows that the MB2 canal is shorter
than the MB1 canal and hiding behind the highest
point of the root. If not specifically looked for, the MB2
canal may remain undetected even during apical surgery.
Courtesy of Paul Brown, 3-D Tooth Atlas, eHuman.com.

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 experiences 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 radiograph, and the patients 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

34

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

Reasons for persistent and emerging post-treatment endodontic disease

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

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, 3234). 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 posttreatment 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 resident microflora 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 infections are dominated by environmentally tolerant bacteria
and sometimes also by yeasts, which are characterized by
higher resistance to treatment procedures and disinfecting agents than the anaerobic microflora in primary
apical periodontitis (4, 31, 3538). 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

35

Haapasalo et al.

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 an
anticipated 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 wall
and in a cross-cut apical ramification, respectively. Reprinted modified with permission from Ricucci D. Patologia e
Clinica Endodontica. 2009; Edizioni Martina, Bologna, Italy.

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 (3945). 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 combination 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.

36

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

PTED. Second, it is more resistant to harsh environmental 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.

Reasons for persistent and emerging post-treatment endodontic disease

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

Localization of the resident microbes in the filled root

canal is probably much more 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 periodontitis 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
(5254). 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 by microbes

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 substances produced by the microbial cells (59). The
polymeric substances are partially responsible for important 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 infections is caused by several factors including reduced
susceptibility of micro-organisms in biofilms to antimicrobial 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

37

Haapasalo et al.
material, they also contained vital or necrotic pulp tissue
and on many occasions bacteria as well (56). Nevertheless, as long as there is no method 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

Fig. 9. (a) Histological specimen of the root tip area of the

patient in Figure 8; section not passing through the apical
canal. (b) Higher magnification of the area indicated by
the arrow in (a). A biofilm is present on the external root
surface showing a dense network of bacteria embedded in
extracellular substance, EPS (modified Brown and Brenn
staining). Reprinted modified with permission from
Ricucci D. Patologia e Clinica Endodontica. 2009;
Edizioni Martina, Bologna, Italy.

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

38

While intracanal microbes remain the main cause of

PTED, extraradicular bacteria have also been claimed
to be present in some infections (41, 6571).
Conventional root canal treatment, including instrumentation, 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. faecalis
biofilm on dentin in vitro has been described by Kishen
et al. (74), and there are some reports where calculuslike 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 1015 years, a
number of studies have indicated that bacteria other
than Actinomyces spp. can also create actinomycosis-like
colonies in the periapical tissue (6870, 76, 77). While
there is no disagreement on the presence of biofilm

Reasons for persistent and emerging post-treatment endodontic disease

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

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, 7981). 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, 8284).

39

Haapasalo et al.

Fig. 11. (a) Apical section of an extracted tooth stained with modified Brown and Brenn staining reveals bacteria (dark
blue) in the root canal as well as on the apical root surface. (b) A high magnification image of the root surface shows
bacteria 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) primary
apical periodontitis. The bacteria are surrounded by a dense accumulation of inflammatory cells. (b) A high
magnification of Figure 12a shows several Gram-positive filamentous bacteria in the periapical biofilm.

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. Unfortunately there is no reliable data about either. Study
populations have usually been poorly described in
reports of extraradicular infections. In addition, reliable diagnosis should be based on histological examination where sections have been prepared and

40

examined throughout the lesion. It is the opinion of

the authors that studies where only culturing or DNA
methods have been used may 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

Reasons for persistent and emerging post-treatment endodontic disease

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 biofilms 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 infection 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 protection. 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 periodontitis. Therefore, it can be classified under microbiological 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 conservative 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 beforehand whether 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

Haapasalo et al.
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
lesion may 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.

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

Vertical root fracture
Vertical root fracture (VRF) can be regarded as a special
type of PTED (9194). 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-

Fig. 13. Vertical root fracture in a maxillary canine. A

typical pear-shaped lesion can be seen climbing up the
root.

42

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 radiographically 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. 14. Crack tooth. A distal fracture line in a maxillary

molar. The line is stained, indicating that it is not new.
The depth of the fracture will determine the fate of the
tooth. When the fracture extends below the marginal
bone level, a narrow pocket and diffuse symptoms can be
detected.

Reasons for persistent and emerging post-treatment endodontic disease

Fig. 15. (a-b) Split tooth. A previous crack in a mandibular 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) Higher
magnification reveals microbial biofilm (stained blue) in the dentin wall of the fracture line. Reprinted modified with
permission from Ricucci D. Patologia e Clinica Endodontica. 2009; Edizioni Martina, Bologna, Italy.

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
In many reports, coronal leakage has been suggested as a
possible cause for PTED (31, 96100). 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 liquid medium
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 inflammation. 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 (111113). The origin of cholesterol 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). Experimental studies have shown that the presence of
cholesterol crystals in the tissue attracts accumulations

43

Haapasalo et al.

Fig. 16. A histological section (haematoxylin-eosin

staining) shows numerous cholesterol crystals and a
heavy accumulation of inflammatory cells in a specimen
obtained from a tooth with a periapical inflammation.

of host defense cells, macrophages in particular,

probably in an effort to remove the crystals by
phagocytosis (115117). 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 material can cause or contribute to periapical inflammation by
at least two different mechanisms. First, it can have
microbes/biofilm attached to its surface (obtained

44

Fig. 17. (a) A histological section of a periapical

inflammatory lesion with foreign material. (b) A closeup of the area with foreign material (dark particles,
possibly sealer) shows multinuclear giant cells next to the
material, surrounded by inflammatory cells. The reason
for persisting apical periodontitis was the intraradicular
presence of bacteria. Reprinted modified with permission
from Ricucci D. Patologia e Clinica Endodontica. 2009;
Edizioni Martina, Bologna, Italy.

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.

Reasons for persistent and emerging post-treatment endodontic disease

Gutta-percha is usually well tolerated if a noncontaminated 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 encapsulated by multilayered collagen fibers with little or no
invasion of inflammatory cells surrounding the capsule.
In other experiments, Sjogren et al. (115) demonstrated that when gutta-percha is processed into small
particles and introduced into vital tissue in experimental animals, it is surrounded by mononuclear
inflammatory cells. A situation where gutta-percha
may be associated with continuing periapical inflammation 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 available 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. Radiographic examination may 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-

Fig. 18. A separated piece of a silver point can be seen in

the periapical lesion of a first mandibular molar several
years after root canal treatment. However, the reason for
the unhealed lesion is persisting infection in the root canal
system of the tooth, not the silver point per se.

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 contamination 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 were misplaced 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 are
known to be able to cause a chronic inflammatory
reaction if present in the periapical tissue (71, 124,
125). Cellulose is foreign material and the human body
does not have enzymes to degrade cellulose. The above
studies have demonstrated the presence of cellulose

45

Haapasalo et al.

Fig. 19. A piece of a plant (green salad) was found during

periapical surgery in the periapical abscess of a maxillary
lateral incisor. Courtesy of Dr. Stefaan Vandenwijngaert
in: Visual Endodontics, 2010.

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 independent 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.

References
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 medicaments, 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-containing 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

46

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