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Paolo Martelletti

The Journal of Headache
                           and Pain
Martelletti The Journal of Headache and Pain  (2017) 18:11 
DOI 10.1186/s10194-016-0709-7ERRATUM Open AccessErratum to: 1st Joint ANIRCEF-SISC
Congress (meeting abstracts)
Paolo MartellettiErratum
Following publication of this supplement [1] it was
brought to our attention that the affiliations of
Dr Francesco Pierelli and Dr Ferdinando Nicoletti
were incorrectly listed in a number of the abstracts
published as part of this supplement [2–15].
Please note that for twelve abstracts listed [2–13]
Dr Francesco Pierelli’s affiliation should be as follows:
1. Department of Medico-Surgical Sciences and
Biotechnologies, Sapienza University of Rome,
Rome, Italy
2. I.R.C.C.S. Neuromed, Pozzilli, Italy
Further to this, for two abstracts listed [13, 14] Dr
Ferdinando Nicoletti’s affiliation should be as follows:
1. Department of Physiology and Pharmacology,
University Sapienza of Rome, Rome, Italy
2. I.R.C.C.S. Neuromed, Pozzilli, Italy
Received: 7 December 2016 Accepted: 7 December 2016
References
1. The Authors. 1st Joint ANIRCEF-SISC Congress. The Journal of Headache and
Pain 2015, 16(Suppl 1)
2. Di Lenola D et al (2015) O024. Transcutaneous supraorbital nerve stimulation
enhances somatosensory thalamic activity in migraine between attacks: a
central mechanism of clinical efficacy? J Headache Pain 16(Suppl 1):A160
3. Bracaglia M et al (2015) O017. Cortical functional correlates of responsiveness
to short-lasting preventive intervention with ketogenic diet (KD) in migraine:
a multimodal evoked potentials study. J Headache Pain 16(Suppl 1):A58
4. Porcaro C et al (2015) O027. Sub-cortical sources of the somatosensory
pathway are hypoactive in migraine interictally: a Functional Source
Separation analysis. J Headache Pain 16(Suppl 1):A55
5. Coppola G et al (2015) O025. Excitability of the motor cortex in migraine
changes with the distance from the last attack. J Headache Pain
16(Suppl 1):A158
6. Anastasio MG et al (2015) O044. Frequency-dependent habituation deficit of
the nociceptive blink reflex in migraine with and without aura. J Headache
Pain 16(Suppl 1):A59Correspondence: paolo.martelletti@uniroma1.it
Dipartimento di Medicina Clinica e Molecolare Sapienza, University of Rome,
Rome, Italy
© The Author(s). 2017 Open Access This article
International License (http://creativecommons.o
reproduction in any medium, provided you giv
the Creative Commons license, and indicate if7. Perrotta A et al (2015) O043. Frequency-dependent habituation deficit of
the nociceptive blink reflex in cluster headache and paroxysmal hemicrania.
J Headache Pain 16(Suppl 1):A91
8. Coppola G et al (2015) O026. An abnormal transduction of the chromatic
stimuli from the outer to the inner retinal layers may contribute to cause
photophobia in migraine. J Headache Pain 16(Suppl 1):A54
9. Coppola G et al (2015) O028. Thalamo-cortical network changes during the
migraine cycle: insights from MRI-based microstructural and functional
resting-state network correlation analysis. J Headache Pain 16(Suppl 1):A52
10. Perrotta A et al (2015) O042. Phase-dependent defective functional activity
of the default mode network and facilitated temporal processing of
nociceptive stimuli in cluster headache. J Headache Pain 16(Suppl 1):A90
11. Di Lorenzo C et al (2015) O045. Cluster headache improvement during
Ketogenic Diet. J Headache Pain 16(Suppl 1):A99
12. Di Lorenzo C et al (2015) O060. Rotigotine improves drug-resistant cluster
headache: a case series. J Headache Pain 16(Suppl 1):A106
13. Di Lorenzo C et al (2015) O041. GRIA3 (glutamate receptor, ionotropic,
ampa 3) gene polymorphism influences cortical response to somatosensory
stimulation in medication-overuse headache (MOH) patients. J Headache
Pain 16(Suppl 1):A49
14. Nicoletti F (2015) Kynurenine pathway metabolites in migraine. J Headache
Pain 16(Suppl 1):A1
15. Curto M et al (2015) O066. Kynurenine pathway metabolites in cluster
headache. J Headache Pain 16(Suppl 1):A87is distributed under the terms of the Creative Commons Attribution 4.0
rg/licenses/by/4.0/), which permits unrestricted use, distribution, and
e appropriate credit to the original author(s) and the source, provide a link to
changes were made.


Erratum to: 1st Joint ANIRCEF-SISC Congress (meeting abstracts)

MiRNA expression in the cartilage of patients with osteoarthritis

Low intensity interventions for Obsessive-Compulsive Disorder (OCD): a qualitative study of mental health practitioner experiences

Convex Variational Methods on Graphs for Multiclass Segmentation of High-Dimensional Data and Point Clouds

A Phase I study of intravenous PI3K inhibitor copanlisib in Japanese patients with advanced or refractory solid tumors

JOURNAL CLUB
Dystonia: opportunities to gain insights into underlying
pathophysiological mechanisms
K. J. Peall1 • N. P. Robertson1
Published online: 10 February 2017
 The Author(s) 2017. This article is published with open access at Springerlink.com
Introduction
Dystonia is one of the most common movement disorders,
a core component of the isolated and combined dystonias
as well as contributing to the motor phenotype of several
neurodegenerative movement disorders, such as Parkin-
son’s disease and Huntington’s disease. In spite of this, the
pathophysiological mechanisms underlying dystonia
remain poorly understood with the current thinking cen-
tered on a circuit-based disorder, with altered synaptic
plasticity impacting higher neuronal circuits and networks.
In this review, we discuss three publications with distinct
approaches in attempting to elucidate these mechanisms.
These articles also highlight how the combination of gene
discovery, cellular assays, and systems-based analysis can
each contribute to building an understanding of complex
disorders.
Mutations in the histone methyltransferase gene
KMT2B cause complex early onset dystonia
This paper describes a stepwise approach to a novel gene
discovery and confirmation of pathogenesis in a cohort of
patients with an undiagnosed childhood-onset dystonia.
Ten individuals were identified with overlapping
heterozygous interstitial microdeletions involving a region
on chromosome 19 containing two genes, KMT2B and
ZBTB32. The next generation sequencing techniques
identified KMT2B heterozygous variants in six further
cases, a single case by Sanger sequencing, and a further ten
cases from national and international collaborations.
Meyer and colleagues provide a detailed description of
the clinical characteristics and investigational findings of
those identified with KMT2B mutations. The majority had
an early childhood onset (1–9 years) of dystonia symptoms
with no evidence of gender bias. The dystonic symptoms
began predominantly in the craniocervical region or limbs,
progressing to a more generalized form 2–11 years after
presentation. Additional clinical features included charac-
teristic facial appearances (elongated face and bulbous
nasal tip), developmental delay, intellectual disability, and
systemic symptoms involving skin, renal, and respiratory
symptoms. Cerebral imaging identified symmetrical
hypointensity of the globus pallidi, although no abnor-
malities were observed following neurotransmitter analysis
of CSF. Deep brain stimulation (DBS) in ten cases pro-
vided symptomatic improvement, whilst oral medical
therapy was ineffective. No overt genotype–phenotype
relationship was immediately observed, although those
with the rarer missense mutations tended to develop
symptoms at a later age.
A key component of a novel gene discovery is demon-
strating that the mutations are likely to impact the normal
function of the encoded protein. KMT2B encodes a histone
lysine methyltransferase that is involved in the methylation
of histone 3 at lysine 4 (H3K4), an important epigenetic
modification associated with active gene transcription. In
silico homology modeling techniques predicted that a
number of the identified variants would impact the struc-
ture–function properties of the KMT2B protein. Analysis
of healthy donor adult and foetal tissue found the protein to
be ubiquitously expressed throughout the brain, with the
highest levels observed in the cerebellum, while
& N. P. Robertson
robertsonnp@cardiff.ac.uk
1 Institute of Psychological Medicine and Clinical,
Neurosciences, Cardiff University, Cardiff CF14 4XW, UK
123
J Neurol (2017) 264:616–618
DOI 10.1007/s00415-017-8411-5
quantitative RT-PCR of patient-derived fibroblasts
demonstrated overall lower KMT2B levels than controls.
Fibroblast and CSF protein expression analysis were also
used to determine whether KMT2B mutations could impact
on other known dystonia-related pathways. These identi-
fied reduced THAP1 and TorsinA transcripts (genes
involved in DYT6 and DYT1 dystonia, respectively), a
reduction in CSF dopamine-2-receptor (D2R) and
increased Tyrosine Hydroxylase levels.
Comment: KMT2B has been given the DYT28 identifier,
making it the most recent in a growing number of disease-
causing genes for dystonia. The ongoing development and
reducing costs of the next generation sequencing tech-
niques suggest that this number is likely to continue to rise,
providing increasing opportunity to understand the mech-
anisms that underpin this complex set of disorders.
Although mutations in each of these individual genes
remain rare, their identification and subsequent interroga-
tion of function on a cellular and system-based level pro-
vide an opportunity for the identification of overlapping
pathways, or points of commonality that may be amenable
to therapeutic intervention.
Meyer E et al (2017) Nat Genet 49(2):223–237.
Functional genomic analyses of mendelian
and sporadic disease identify impaired elF2a
signaling as a generalizable mechanism
for dystonia
This paper outlines the stepwise approach taken to identi-
fying, and building upon, the evidence for elF2a signaling
pathway involvement in Mendelian and seemingly spo-
radic forms of dystonia.
An initial step involved a successful validation of a
cellular-based assay for DYT1 dystonia (GAG deletion in
TorsinA) based on a known Torsin1a biology. Expression
of wild type and mutant Torsin1a in human embryonic
kidney (HEK) cells demonstrated a distinct and readily
identifiable pattern of protein expression. Having estab-
lished a reliable cellular assay, small interfering RNAs
(siRNAs) were utilized to undertake a hypothesis-free
genome-wide screen. siRNAs are double-stranded RNA
molecules that interfere with gene expression by degrading
post-transcriptional mRNA and prevent translation to the
protein product. Using a quality control (QC) index of a
minimum three standard deviation improvement to Tor-
sin1a localization, whole genome screen and subsequent
pathway analysis identified 93 high stringency and high-
quality genetic hits. Further validation identified 11 over-
represented signaling pathways with the elF2a signaling
pathway the most enriched.
The elF2a pathway is a ubiquitous cellular pathway
known as the integrated stress response (ISR). ElF2a
phosphorylation is thought to contribute to synaptic plas-
ticity, being required for long-term depression (LTD) at
cortico-striatal synapses. The rate-limiting elF2a complex
subunit is phosphorylated by one of four upstream stress-
sensitive kinases, knock down of which resulted in increased
abnormal Torsin1a localization, indicating that it is
decreased activity of the signaling pathway that contributes
to pathogenesis. Pharmacological testing provided further
confirmation still with elF2a phosphorylation inhibitors
(e.g., Salubrinal) normalizing Tosrin1a localization in a
dose-dependent manner. Compounds targeting other sig-
naling pathways identified in the whole genome screen
(notch and glucocorticoid signaling) found no effect, sug-
gesting that these effects were specific to the elF2a pathway.
ElF2a phosphorylation also appears to be involved in
the function of other genes implicated in the pathogenesis
of dystonia. Whole exome sequencing of 20 unrelated
individuals with sporadic isolated dystonia identified 12
exons with rare coding variants, one of which being the
first exon of ATF4, one of several genes upregulated by
elF2a phosphorylation. Sanger sequencing of 239 sporadic
cervical dystonia cases found ATF4 functional variants in
8.8% (3/239) cases compared to 0.5% in controls. Within
the DYT1 sample, patient-derived fibroblasts also demon-
strated reduced ATF4 upregulation with basal increases in
negative feedback proteins (CReP and GADD34) attenu-
ating the acute phase elF2a signaling. Interestingly,
PRKRA (mutations of which are seen in DYT16 dystonia)
encodes an upstream elF2a kinase activator, with the most
common PRKRA mutations thought to reduce elF2a
phosphorylation.
Comment: Overall, this extensive series of experiments
provides some preliminary evidence of a common mech-
anistic pathway, disrupted in distinct ways to give rise to
multiple forms of dystonia. This provides a platform to
determine not only whether disrupted elF2a signaling is
central to other forms of dystonia, but also whether there is
a selective brain and/or regional vulnerability to these
processes. Moreover, this work provides an exciting inroad
for therapeutic development, potentially necessitating
treatments that are able to target multiple points within the
elF2a pathway.
Rittiner JE et al (2016) Neuron 92:1238–1251.
Cervical dystonia: a neural integrator disorder
In this publication, Shaikh et al. seek to re-explore the role
of the midbrain in the control of head movements, and
more specifically cervical dystonia and dystonic tremor.
J Neurol (2017) 264:616–618 617
123
The idea that the midbrain may play a role in the three-
dimensional orientation of the head was first suggested in
the 1950s, but has gained further traction over the past
decade following work addressing the direction and
velocity of head movements in individuals with cervical
dystonia. This has led to a body of work suggesting a role
for a ‘head neural integrator’ located within the midbrain.
The authors first set out their theory from over a decade
ago, providing several analogies to ocular motor integrators
involved in the control of eye movements, and disruption
to which leads to gaze-evoked nystagmus. They also detail
the importance of neuronal integration in the medulla and
midbrain, more specifically the interstitial nucleus of cajal
(INC), in regulating horizontal, vertical, and torsional eye
movements. A clear description of the individual compo-
nents of disrupted eye movements is outlined, with cor-
rective saccades/quick phases being seen when the eyes
look in one direction, drifting back involuntarily, and then
quickly corrected back to the original direction of gaze. In
contrast, the slow-phase velocity changes are dependent on
the position of the eye in the orbit, with changes decreasing
as the eye position gets closer to the central/straight ahead
position, and increasing as they move further from this
point.
Klier and colleagues were the first to suggest that an
analogous system might be involved in dystonia following
pharmacological inactivation of the INC in non-human
primates. However, this hypothesis struggled to gain trac-
tion at the beginning of the century owing to the lack of
involvement of the basal ganglia and/or cerebellum, two
regions traditionally considered pivotal in the generation
and propagation of dystonia. However, this publication
seeks to address some of these conceptual difficulties,
extrapolating this original hypothesis to include feedback
mechanisms involving the visual system, neck proprio-
ception, and cerebellum to the head neural integrator.
Previous work from the same group has shown that
vibration of the paraspinal neck muscles increases cen-
tripetal head drift during eccentric loading, while others
have shown that removal of visual feedback causes the
head to drift from the eccentric position towards a central
null. The combination of retained visual feedback with
vibration-induced distorted proprioception caused the head
to drift with rapid corrective movements, resembling dys-
tonic tremor or ‘head nystagmus’.
Comment: In spite of the theme of the article, the
authors clearly state that these research findings and pro-
posed mechanisms do not necessarily imply that the
pathophysiology underlying cervical dystonia is intrinsic to
these midbrain regions. Neurophysiological and imaging
studies of this region also support an integrative, rather
than generator, role for the midbrain with abnormalities in
neural excitatory outflow and asymmetry of white-matter
projections between the pallidum and the midbrain.
Although potentially generating some controversy in
challenging the more traditional models of dystonia, this
work invites a re-thinking or adjusted view of how dystonia
is generated and that similar end phenotypes may be caused
by heterogenous underlying biological disruption con-
verging on a common anatomical pathway. Arguably this
hypothesis has an additional clinical importance, indicating
the need to explore alternative or additional targets for
stimulation with DBS and future targeted therapies.
Shaikh AG et al (2016) Brain 139:2590–2599.
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://crea
tivecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a
link to the Creative Commons license, and indicate if changes were
made.
618 J Neurol (2017) 264:616–618
123


Dystonia: opportunities to gain insights into underlying pathophysiological mechanisms

Measurement properties of the EQ-5D across four major geriatric conditions: Findings from TOPICS-MDS

Peter Pickkers

Didier Payen

Intensive Care Med
DOI 10.1007/s00134-017-4738-8
WHAT’S NEW IN INTENSIVE CARE
What’s new in the extracorporeal 
treatment of sepsis?
Peter Pickkers1*  and Didier Payen2
© 2017 The Author(s). This article is an open access publication
Reportedly, it was Hippocrates (ca. 460–370 BC) and 
Galenos (Galen of Pergamum; ca AD 129–199) who first 
stated that a poison, and not evil spirits, must be respon-
sible for symptoms such as fever, vomiting and diar-
rhea [1]. Naturally, the nature of this ‘poison’ remained 
unclear. Richard Pfeiffer (1858–1945) discovered that 
a toxic substance was associated with the membrane of 
bacteria, and called it ‘endotoxin’ [2]. Endotoxin infusion 
mimics many of the inflammatory, metabolic, cardiovas-
cular changes observed in sepsis patients and represents 
one of the main inducers of shock in sepsis. The discov-
erer of its receptor (the Toll-like receptor 4) [3], Nüsslein-
Volhard was awarded the Nobel prize for this discovery 
in 1995, further propelling this field of research.
Clinical research has shown that endotoxin is indeed 
circulating in the blood of up to 50% of sepsis shock 
patients [4] and associated with impaired clinical out-
come [5]. In view of the pivotal role of endotoxin in 
sepsis patients, the idea of ‘blood purification’ emerged. 
Polysterene fiber filters coated with polymyxin B are able 
to bind endotoxin (Fig. 1). A meta-analysis of trials pri-
marily of Japanese origin indicated a survival benefit for 
patients treated with polymyxin B hemoperfusion [6]. 
Since then, two randomized trials from Europe and one 
from USA/Canada have been conducted.
In 2009, the Euphas-trial (Early Use of Polymyxin B 
Hemoperfusion in Abdominal Septic shock), an open-
label randomized study performed in Italy, was published 
[7]. Sixty-four patients with abdominal severe sepsis 
or septic shock were treated with PMX hemoperfusion 
(or standard of care) within 6  h following surgery. The 
primary end-point of this study was the change (from 
day 0 to 3) in hemodynamic stability. Secondary end-
points included change in SOFA-score and mortality. 
The authors reported an improvement in hemodynamic 
stability in the PMX hemoperfusion group, while this 
was not the case in the control group. In addition, sur-
vival time analysis showed a significant improvement in 
the treatment group. The trial was stopped prematurely 
based on these results. A discussion emerged [8], as it 
was highlighted that no significant differences between 
the 2 groups were present, and that polymyxine B 
hemoperfusion appears to prolong time to mortality, but 
did not significantly affect day 28 mortality. Early termi-
nation of the study was deemed unfortunate [8].
Six years later, the Abdomix-trial from France was pub-
lished [9]. Again, abdominal septic shock patients were 
randomized to PMX-hemoperfusion treatment (n = 119) 
or to the control group (n = 113). The first hemoperfu-
sion session started within 12  h following surgery and 
was repeated 24  h later. Adequacy of surgical proce-
dure was blindly evaluated by an independent surgeon 
and classified as adequate, sufficient, or inadequate. The 
28-day mortality was 28% in the PMX-group versus 20% 
in the control group (p = 0.1). Incomplete PMX sessions 
occurred in 11% of the patients due to circuit coagula-
tion mainly during the 1st session. Importantly, also in 
the subgroup having received adequate surgery and two 
uneventful complete PMX sessions, no sign of a ben-
eficial effect of treatment was observed. Finally, neither a 
more rapid improvement in SOFA-score in the treatment 
group nor a more rapid decrease in circulating cytokines 
was found in this study [10]. Potential reasons for these 
findings were discussed [11, 12].
In the recently finalized Euphrates trial [13] (Evaluating 
the Use of Polymyxin B Hemoperfusion in a Randomized 
controlled trial of Adults Treated for Endotoxemia 
and Septic shock), PMX hemoperfusion was applied 
in a blinded manner in patients with septic shock and 
*Correspondence:  peter.pickkers@radboudumc.nl 
1 Department of Intensive Care Medicine (710), Radboud University 
Medical Centre, Geert Grooteplein Zuid 10, P.O. Box 9101, 6500 
HB Nijmegen, The Netherlands
Full author information is available at the end of the article
confirmed endotoxemia, as measured by the endotoxin 
activity assay (EAA). The trial, conducted in the United 
States and Canada, was powered to enroll 360 patients to 
detect an effect on 28-day all-cause mortality. Similar to 
the previous trials, treatment consisted of two sessions 
of PMX hemoperfusion 24  h apart. Unique features of 
this trial included patient enrichment by use of EAA to 
confirm endotoxemia (EAA > 0.6) and use of a detailed 
“façade” hemoperfusion event as a blinding mecha-
nism. Following the second interim analysis, the study 
was resized to 650 patients. However, after 446 evalu-
able patients were included, the trial was terminated. 
The study has not yet been published, but Spectral, the 
company of the EAA, has stated that it failed to meet its 
primary end-point. There was a non-significant 5% mor-
tality reduction in the per protocol population, and it is 
mentioned that ‘other positive benefits were observed’ in 
treated septic shock patients compared to standard treat-
ment [14]. Currently, no further details have been made 
public and it remains unclear to what extent timing of the 
intervention and the amount of endotoxin adsorped by 
the membrane may play a role.
New developments are emerging. Coupled plasma 
filtration adsorption is another extracorporeal blood 
purification therapy for sepsis which adsorbs both pro-
inflammatory and anti-inflammatory mediators from 
filtered plasma. Effects on clinical outcome are awaited. 
The ‘Cytosorb’-filter, with polymer beads that have pores 
that can adsorb hydrophobic molecules in a size range 
of approximately 10–55 kD (sufficient to remove almost 
all known cytokines, including HMGB-1, but not endo-
toxin), has a huge absorption area of 40,000  m2, and 
several case series have been published. Unfortunately, 
in a small (n =  37 patients) blinded, randomized study 
in cardiac surgery patients, installment of the adsorber 
on the cardio-pulmonary bypass machine had no effect 
on surgery-induced cytokine release or hemodynamic 
stability measures [15]. The ‘oXiris’-filter is designed to 
adsorb endotoxin as well as cytokines, but no adequately 
powered human study is currently available.
While removal of endotoxin/cyokines is theoretically 
seen as a beneficial effect, other potentially detrimen-
tal effects may also occur. As both pro-and anti-inflam-
matory cytokines may decrease, the net effect is 
uncertain. In addition, other nutrients and therapeutic 
drugs (including antibiotics) may also be removed from 
the circulation, with potential negative impact on organ 
function and recovery.
The high incidence and morbidity, mortality, and asso-
ciated costs of septic shock illustrate that the medical 
need for an adjuvant treatment is still unmet. Endotoxin, 
one of the most potent mediators of sepsis, is found in 
high levels in approximately half of patients with sep-
tic shock. Polymyxin B (PMX) hemoperfusion has been 
shown in numerous studies to successfully remove 
endotoxin and potentially improve outcomes. Although 
numerous case series and small studies suggest that these 
beneficial effects may also be present in sepsis patients, 
larger randomized controlled trials have not confirmed 
these findings. While blood purification in sepsis is a 
valid approach, the potential efficacy of LPS/cytokine 
elimination using these membranes currently cannot be 
estimated without positive clinical data from randomized 
trials.
Author details
1 Department of Intensive Care Medicine (710), Radboud University Medical 
Centre, Geert Grooteplein Zuid 10, P.O. Box 9101, 6500 HB Nijmegen, The 
Fig. 1 Extracorporeal endotoxin binding by polymyxin B hemoperfusion
Netherlands. 2 Department of Anesthesiology and Intensive Care, Hôpital 
Lariboisière APHP, Université Paris 7 Denis Diderot, UMR INSERM 1160, 2 Rue 
Ambroise Paré, 76010 Paris, France. 
Compliance with ethical standards
Conflicts of interest
P. Pickkers has received honoraria from Gambro-Baxter. D. Payen received 
unlimited grant from Toray Med Ltd (Japan) and Sté Meditor (France) to design 
and perform the ABDOMIX randomized Clinical Trial.
Open Access
This article is distributed under the terms of the Creative Commons Attribu-
tion-NonCommercial 4.0 International License (http://creativecommons.org/
licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and 
reproduction in any medium, provided you give appropriate credit to the 
original author(s) and the source, provide a link to the Creative Commons 
license, and indicate if changes were made.
Received: 24 January 2017   Accepted: 22 February 2017
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What’s new in the extracorporeal treatment of sepsis?

Tor Haldorsen

Jan Ivar Martinsen

Kristina Kjærheim

Tom K. Grimsrud

Adjustment for tobacco smoking and alcohol consumption by simultaneous analysis of several types of cancer

R. B. Tröbs

B. Yilmaz

C. Roll

M. Alrefai

CASE REPORT Open Access
Direct bladder hernia after indirect hernia
repair in extremely low birth weight babies:
two case reports and a review of the literature
R. B. Tröbs1*, B. Yilmaz2, C. Roll3 and M. Alrefai1
Abstract
Background: Inguinal hernia repair is the most common surgical procedure in babies. Despite a meticulous
technique, relapses may occur. The occurrence of a direct bladder wall hernia in relapses has never before been
reported in the literature.
Case presentation: Here, we report two cases of direct bladder herniation: a white baby boy born after 25 weeks
of gestation and a white baby boy born after 26 weeks of gestation. Both of the formerly extremely low birth
weight babies were affected after open bilateral hernia repair. Recurrent hernias developed on the right side, and
direct bladder herniation was identified intraoperatively. In one case, laparoscopy was applied to identify a
supravesical type of hernia. Immaturity and a difficult postnatal course might have contributed to hernia relapse in
these cases.
Conclusions: Misinterpretation of bladder herniation might have disastrous consequences. Laparoscopy is a helpful
tool in comparable cases.
Keywords: Bladder hernia, Pediatric hernia, Direct hernia, Hernia relapse, Case report
Background
The incidence of inguinal hernias is much higher among
preterm babies than among term-born babies, children,
and adults. Such hernias affect 30% of babies with birth
weights (BWs) below 1000 g [1], and surgical repair in
preterm babies can be challenging. The optimal timing
for hernia repair in these delicate patients remains
controversial. Early repair may prevent incarceration and
is therefore recommended by many pediatric surgeons
[2]. However, major concerns associated with early
repair include cardiorespiratory instability during and
after surgery and increasing evidence that anesthetic and
sedative agents may have direct toxic effects on the
developing brains of preterm babies even after these
babies have reached postmature age. Therefore, surgery
is often delayed until term-equivalent age, particularly
for the most vulnerable preterm babies [3].
Relapses might occur as indirect or direct hernias [4].
Rare forms of inguinal hernias may occur [5], and the
surgeon must be aware that the urinary bladder can be
involved in indirect and direct hernias [6–16].
Here we report two cases of secondary bladder hernia
in babies after the open repair of bilateral indirect
inguinal hernias. To the best of our knowledge, the
occurrence of a direct bladder wall hernia after primary
inguinal hernia repair in babies has never before been
reported in the literature.
Case presentation
We retrospectively identified two cases involving bladder
herniation between 2010 and 2014. During this 5-year
observation period, 1100 inguinal hernia repairs were
performed in the reporting pediatric surgical unit, with
the vast majority of patients below 1 year of age. In both
reported cases, we initially performed hernia repair
under caudal anesthesia. Shortly afterward, the external
ring was exposed with an incision of a few millimeters,
and the hernia sac and cord structures were separated.
After the sac was dissected, closure was performed with
* Correspondence: ralf-bodo.troebs@elisabethgruppe.de
1Department of Pediatric Surgery, St. Mary’s Hospital Herne, St. Elisabeth
Group, Ruhr-University of Bochum, Widumer Str. 8, 44627 Herne, Germany
Full list of author information is available at the end of the article
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Tröbs et al. Journal of Medical Case Reports  (2017) 11:15 
DOI 10.1186/s13256-016-1171-5
a purse string suture (Case 1) or transfixation (Case 2).
In addition, this suture was used to anchor the stump of
the sac within the inguinal channel (backward suture
through an internal oblique muscle and an external
oblique fascia and tied externally). Any excess sac was
cut away. The inguinal canal was reconstructed by
fixation of the internal oblique muscle to the inguinal
ligament with one stitch, and the edges of the external
oblique fascia were adapted to the inguinal ligament
with two stitches.
Case 1
A white baby boy was born after 25 weeks of gestation
with a BW of 600 g. He had respiratory distress syn-
drome that was treated with surfactant in the delivery
room and was on mechanical ventilation from birth,
followed by continuous positive airway pressure (CPAP)
for 2 months. At postnatal ultrasound, residuals of a
first-degree prenatal intraventricular hemorrhage were
obvious. He developed moderate bronchopulmonary
dysplasia and presented with large scrotal bilateral
inguinal hernias. At a prior surgery, no clinical signs of
neurological impairment were observed by the neonat-
ologist. Bilateral hernia repair was performed at the
postnatal age of 4 months (a corrected age of 42 weeks)
when his body weight was 4050 g. At the age of
11 months, recurrent inguinal bulging at the level of the
scar of his right inguinal region occurred, and a unilat-
eral relapse was evident. Both testes were descended and
of adequate size. Laparoscopic surgery was begun, and a
small dimple at the right internal inguinal ring was
visible. However, no internal hernia ring could be identi-
fied. Because a hernia sac was clearly externally palpable,
open exploration was used to continue the surgery. After
the identification of the external aponeurosis, a thick-
walled hernia sac was identified (Fig. 1). A 6 Ch
transurethral catheter was inserted. The filling of his
bladder with saline enabled the identification of his
protruded bladder. After bladder repositioning, recon-
struction of the transversalis fascia and the muscular
borders was performed. Repeated laparoscopy at the end
of the procedure revealed the anatomical constellation
of a prior supravesical hernia (Fig. 2). No recurrence was
observed over a 4-year follow-up period (information
from the family’s pediatrician).
Case 2
A white baby boy was born after 26 weeks of gestation
with a BW of 506 g; he was small for gestational age
(SGA). He had respiratory distress syndrome and was
treated with mechanical ventilation followed by CPAP
therapy. Bilateral scrotal hernias developed; at 3 months
postnatal age (a corrected age of 40 weeks), bilateral
open closure of these indirect hernias was performed.
Because his right testis was in an inguinal high position,
orchidopexy according to Shoemaker was required.
His postoperative course was complicated by fever,
desaturations, and elevated C-reactive protein (10.3 mg/dL)
due to septicemia caused by Staphylococcus aureus. No
external signs of wound infection occurred. Two months
later, recurrent groin swelling that spontaneously reduced
was observed on his right side. An open inguinal revision
was begun, and a direct bladder hernia separate from the
funiculus was found (Fig. 3) in a more medial position.
Protruded fat indicated the herniation of his anterior
bladder through the prevesical space. After bladder
Fig. 1 The protruded bladder (star) mimics a thickened hernia sac.
The funiculus (arrow head) is separated by a loop
Fig. 2 Laparoscopic view after bladder hernia repair. A peritoneal
dimple above the bladder (arrow) and medially to the medial
umbilical fold (star) indicates the former hernia site
Tröbs et al. Journal of Medical Case Reports  (2017) 11:15 Page 2 of 5
repositioning, two-layer closure of the hernia ring was per-
formed. Revision of the funiculus revealed no further path-
ology. During 4 months of follow-up, no recurrence was
observed, and both testes were in a scrotal position.
Table 1 provides a short summary of both cases.
Discussion
Cadaveric and radiographic studies have indicated that
transitory extraperitoneal herniation of the bladder, a
phenomenon known as “bladder ears,” may occur in sig-
nificant numbers of babies, children, and even adults
[13]. According to these observations, the bladder may
herniate into the internal ring, and the bladder’s grade of
protrusion depends on bladder filling.
Among adults, the incidence of bladder involvement
in low abdominal hernias reportedly ranges from 1 to
10% [6]. Direct and indirect hernias are involved with
equal frequency, with hernias predominantly occurring
on the right side [6].
The rate of bladder involvement during indirect
inguinal hernia repair is not well known. Shaw and
Santulli used a flap technique to repair sliding hernias
with involvement of the urinary bladder in 27 female
patients [1]. Several additional case series describe
bladder involvement during pediatric hernia repair. Six
cases with recognized bladder involvement and one case
involving unrecognized bladder injury were reported by
Colodny [2]. In contrast, in a large single-surgeon series
of 6361 cases, only two patients (0.03%) had sliding
bladder hernias [9].
Reports on pediatric bladder hernias and certain near-
catastrophic iatrogenic urinary bladder injuries are col-
lected in Table 2. Eight out of the nine presented cases
involved male patients. Bladder hernias affected the left
side in three cases and the right side in two cases. In
three cases, the affected side was not reported, and in
one extraordinary case, a median protrusion occurred.
No patients in the presented series had previously
undergone surgery for inguinal hernia repair. Injuries of
the bladder occurred due to either the prolapse of the
bladder into the indirect hernia sac or a misplaced
approach medial to the inguinal canal.
In contrast with the observations above, bladder
herniation occurred in our patients as a relapse after the
primary repair of indirect inguinal hernias. In both cases,
the bladder wall was prolapsed directly through an
opening in the prevesical abdominal wall. The medial
margin of this opening was lined by the lateral border of
the rectus sheath (Hesselbach’s triangle) [17].
In general, hernia recurrence rates of 0.8 to 3.8% have
been reported following open hernia repairs in children
[11]. An increased incidence of direct herniation after
the repair of congenital indirect hernias is a well-known
phenomenon. In a previous series, 20 out of 62 children
had direct hernias [11]. In another series of over 1600
inguinal hernias, six patients presented with nine recur-
rent hernias [18].
Several factors that may predispose patients to indirect
inguinal hernia recurrence have been reported. Hernia
recurrence in otherwise healthy children may be caused
by inadequate surgical technique (failure to ligate the sac
sufficiently high and inadvertent tearing of the sac) [18];
injury to the floor of the inguinal canal due to operative
trauma; the inherent weakness or friability of tissues;
and postoperative wound infection or hematoma [11]. In
the two presented cases, the primary surgery and the
repair of the relapse were performed by the first author
(RBT). The applied technique was a modified “classical”
hernia repair, as described in detail by Ladd and Gross
Fig. 3 The protruded urinary bladder is found after incision of the
former transverse inguinal incisional scar (second case). Preperitoneal
fat is seen below the bladder
Table 1 Summary of the two reported cases
Patient Gestational
age
Birth
weight
Postnatal
(corrected) age
Weight at
surgery
Primary hernia Postoperative
course
Time to
relapse
Side of bladder
hernia
1 25 wk. 600 g 4 months
(42 wk.)
4050 g Large scrotal hernia on the left,
smaller scrotal hernia on the right
Uneventful 7 months Right
2 26 wk. 506 g
(SGA)
3 months
(40 wk.)
2520 g Large bilateral scrotal hernias Sepsis
(Staphylococcus aureus)
2 months Right
SGA small for gestational age, wk. weeks
Tröbs et al. Journal of Medical Case Reports  (2017) 11:15 Page 3 of 5
[8]. For both babies, during relapse surgery, surgical
exploration through the previously used inguinal access
revealed a right extraperitoneal bladder hernia. This
predilection for the right side may be supported by the fact
that 59% of indirect hernias occur on the right side [9].
Laparoscopy was an important tool for specifically
localizing the type of relapsed hernia in Case 1; however,
laparoscopy was not used in our second case. In both
cases, direct bladder herniation occurred extraperitone-
ally in the form of a direct hernia.
In both reported cases, the family history was un-
remarkable, and there were no clinical signs of relevant
neurological impairment. Prematurity and multimorbid-
ity might have contributed to the development of
secondary bladder herniation. Increased intra-abdominal
pressure due to CPAP ventilation and repeated squeez-
ing of the immature intestine are additional predisposing
factors. In our cases, the role of the primary surgical
technique remains debatable. The narrowing of the
enlarged inguinal canal by placing a suture at the margin
of the internus muscle and the aponeurosis of the
obliquus externus might have contributed to weakening
the medial portion of the inferior abdominal wall.
Conclusions
The surgeon should take into account that bladder
herniation might occur in babies with inguinal hernia
relapse. Laparoscopy allows identification of the
underlying type of hernia. Bladder injury has to be
avoided.
Abbreviations
BW: Birth weight; CPAP: Continuous positive airway pressure; SGA: Small for
gestational age
Acknowledgements
None.
Funding
None.
Availability of data and materials
Not available.
Authors’ contributions
RBT and MA prepared the manuscript. CR and BY made substantial
contributions to the conception and design of this paper. All authors read
and approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Consent for publication
Written informed consent for the publication of this case report and any
accompanying images was obtained from the patients’ legal guardians. A copy of
the written consent is available for review by the Editor-in-Chief of this journal.
Ethics approval and consent to participate
Not applicable.
Author details
1Department of Pediatric Surgery, St. Mary’s Hospital Herne, St. Elisabeth
Group, Ruhr-University of Bochum, Widumer Str. 8, 44627 Herne, Germany.
2Clinic of Surgery and Pediatric Surgery, Friedrich-Ebert-Str. 13, 33699
Bielefeld, Germany. 3Center of Perinatology, Department of Neonatology and
Pediatric Intensive Care, Vest Children’s Hospital, University of
Witten-Herdecke, Dr.-Friedrich-Steiner Str. 5, 45711 Datteln, Germany.
Received: 14 May 2016 Accepted: 5 December 2016
Table 2 Reports on pediatric bladder injuries at the time of inguinal hernia repair
Reference Age at surgery Sex Side Type of hernia Surgical finding Assumed mechanism
[1] Shaw and Santulli
1967
3.5 mo. M Not given Inguinal hernia,
bilateral
Partial excision of the bladder Either paraperitoneal or intraperitoneal
bladder herniation into the indirect
hernia sac
[1] Shaw and Santulli
1967
9 mo. M Not given Not given Not given
[2] Colodny 1974 3 mo. M Left Inguinal hernia,
incarcerated
Purse string on the left side of
the bladder
Bladder injured with the closure of the
hernia sac
[6] Bell and Witherington
1980
1 yr. M Midline Infraumbilical
fascial defect
Fascial closure without
problems
Prematurity, penis malformation
[3] Redmann et al. 1985 4.5 wk. M Right Inguinal hernia,
bilateral
Subtotal bladder resection,
dissection of the funiculus
Bladder incorporated into the indirect
hernia sac
[3] Redmann et al. 1985 5 wk. M Left Inguinal hernia,
bilateral
Near-total bladder resection,
dissection of both ureters
[4] Chung and Yu 1999 18 mo. M Right Inguinal hernia Near-total bladder resection Bladder incorporated into the indirect
hernia sac
[14] Koot et al. 1998 3 mo. F Left Inguinal hernia Bladder open at the top,
persistent indirect hernia
on the left
Prematurity, overly medial incision and
dissection of the transversalis fascia
[5] Bakal et al. 2015 Infant M Not given Inguinal hernia Intraperitoneal and
extraperitoneal injury
Incision on the medial site of inguinal
canal
F female, M male, mo. months, wk. weeks, yr. year
Tröbs et al. Journal of Medical Case Reports  (2017) 11:15 Page 4 of 5
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Direct bladder hernia after indirect hernia repair in extremely low birth weight babies: two case reports and a review of the literature

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