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Clinical Nuclear
Medicine
in Pediatrics

Luigi Mansi
Egesta Lopci
Vincenzo Cuccurullo
Arturo Chiti
Editors

123
Clinical Nuclear Medicine in Pediatrics
Luigi Mansi • Egesta Lopci
Vincenzo Cuccurullo • Arturo Chiti
Editors

Clinical Nuclear
Medicine in Pediatrics
Editors
Luigi Mansi Vincenzo Cuccurullo
Nuclear Medicine Nuclear Medicine
Second University of Naples Second University of Naples
Napoli Napoli
Italy Italy

Egesta Lopci Arturo Chiti

Nuclear Medicine Nuclear Medicine
Humanitas Research Hospital Humanitas Research Hospital
Rozzano Rozzano
Milano Milano
Italy Italy

ISBN 978-3-319-21370-5 ISBN 978-3-319-21371-2 (eBook)

DOI 10.1007/978-3-319-21371-2

Library of Congress Control Number: 2015953158

Springer Cham Heidelberg New York Dordrecht London

© Springer International Publishing Switzerland 2016
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,
broadcasting, reproduction on microfilms or in any other physical way, and transmission or information
storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology
now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, express or implied, with respect to the material contained herein or for any errors
or omissions that may have been made.

Printed on acid-free paper

Springer International Publishing AG Switzerland is part of Springer Science+Business Media

(www.springer.com)
Foreword

Life-threatening disease is rare in pediatric patients. When it occurs it is complex

to manage and devastating for the patient and the family. To care for the patient,
age-appropriate techniques for diagnosis, staging, and therapy, as well as the
most experienced pediatric practitioners, should be available. This textbook is
written to provide nuclear medicine physicians with the information necessary to
deliver timely and appropriate care to children with these serious illnesses. Each
chapter is written by recognized experts in their subspecialty of pediatric nuclear
medicine.
The textbook is comprised of 20 chapters. The topics covered range from standards
published by international organizations about indications and technical factors to per-
form each study, to considerations about possible long-term effects of diagnostic and
therapeutic ionizing radiation exposure, to detailed discussions about procedures in
specific diseases.
Clinical chapters describe the circumstances where radionuclide procedures
can provide data for patient management. Technical information about patient
preparation, administered dose of the radiopharmaceutical, interval between
injection and imaging, and approaches to interpret the images are provided. In the
sections describing radionuclide therapy procedures, the authors focus on impor-
tant developmental and social aspects of management. This includes providing
essential information about the therapy rooms (and if possible a pretreatment
visit), a chance to meet the staff, the requirements for specialized nursing, and
participation of radiation physicists. The authors also provide suggestions about
meeting with the patients’ family to instruct them about how to prepare their child
for the procedures.
The text presents information on both benign and malignant conditions. In
the chapters on pediatric cancer, the authors describe the clinical presentation
and genetic abnormalities associated with the tumor and information that can be
gleaned from radionuclide procedures at the time of diagnosis, staging, and in
follow-up surveillance.

v
vi Foreword

Dealing with severely ill children is complex and difficult. By providing key
information about performing procedures in the safest and most appropriate fash-
ion, this textbook makes an important contribution to pediatric nuclear medicine.

H. William Strauss, MD
Attending Emeritus, Molecular Imaging and Therapy Service,
Memorial Sloan Kettering Cancer Center, New York, NY, USA

Professor of Radiology, Weill Cornell Medical Center, New York, NY, USA
Contents

1 Peculiar Aspects and Problems of Diagnostic

Nuclear Medicine in Paediatrics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Luigi Mansi, Vincenzo Cuccurullo, and Maria Rosaria Prisco
2 PET/MR in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Marco Salvatore, Carmela Nappi, and Alberto Cuocolo
3 Current Issues in Molecular Radiotherapy in Children . . . . . . . . . . . . 29
Mark N. Gaze, Jennifer E. Gains, and Jamshed B. Bomanji
4 Radiation Risk from Medical Exposure in Children . . . . . . . . . . . . . . . 51
Michael Lassmann and Uta Eberlein
5 Pediatric Nuclear Medicine in Acute Clinical Setting . . . . . . . . . . . . . . 61
Reza Vali and Amer Shammas
6 Nuclear Medicine in Pediatric Cardiology . . . . . . . . . . . . . . . . . . . . . . 115
Pietro Zucchetta
7 Endocrinology: Diagnostics in Children and Adolescents . . . . . . . . . 127
Giovanna Weber and Maria Cristina Vigone
8 Radionuclide Studies with Bone-Seeking Radiopharmaceuticals
in Pediatric Benign Bone Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Diego De Palma
9 Nuclear Medicine in Pediatric Gastrointestinal Diseases . . . . . . . . . . 149
Angelina Cistaro and Michela Massollo
10 Nuclear Medicine in Pediatric Nephro-urology . . . . . . . . . . . . . . . . . . 173
Pier Francesco Rambaldi and Pietro Zucchetta
11 The Problem of Cancer in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
Marta Podda, Veronica Biassoni, Cristina Meazza,
Elisabetta Schiavello Serena Catania, and Maura Massimino
12 Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
Egesta Lopci and Arnoldo Piccardo

vii
viii Contents

13 Neuroblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
Vittoria Rufini, Maria Vittoria Mattoli, and Maria Carmen Garganese
14 Pediatric Sarcomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
Natale Quartuccio, Leonard Wexler, and Heiko Schöder
15 Cerebral Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
Alice Lorenzoni, Alessandra Alessi, and Flavio Crippa
16 Thyroid Cancer in Childhood and Adolescence. . . . . . . . . . . . . . . . . . 317
Robert Howman-Giles and Christopher Cowell
17 Other Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
Hossein Jadvar and Barry L. Shulkin
18 Diagnostic Imaging in European Eastern Countries:
a Russian Experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
L.S. Namazova-Baranova, A.A. Baranov, I.E. Smirnov,
A.V. Anikin, A.N. Getman, A.K. Gevorkyan, N.L. Komarova,
O.V. Kustova, O.V. Komarova, E.V. Komarova, and E.V. Antonova

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371
Peculiar Aspects and Problems
of Diagnostic Nuclear Medicine 1
in Paediatrics

Luigi Mansi, Vincenzo Cuccurullo, and Maria Rosaria Prisco

Contents
1.1 Nuclear Medicine as Molecular Imaging 2
1.2 Cost/Effectiveness in Diagnostic Imaging 4
1.3 Cost/Effectiveness of Nuclear Medicine in Paediatrics 5
1.3.1 General Capabilities of NM 6
1.3.2 General Limitations of Nuclear Medicine 6
1.4 Technical Problems of NM in Paediatrics 7
1.4.1 How to Approach the Paediatric Patient in Nuclear Medicine 7
1.4.2 The Paediatric Environment in Nuclear Medicine 9
1.4.3 Patient Preparation 10
1.4.4 Patient Positioning 10
1.4.5 Patient Restraining 11
1.4.6 Sedation (and Narcosis) 11
1.4.7 Radioactive Dose 11
1.4.8 Image Acquisition and Other Technical Points 12
1.5 Nuclear Medicine in Paediatrics as Compared with Alternative Procedures 12
1.5.1 Risks and Prejudices 13
1.5.2 Peculiarities of Alternative Diagnostic Procedures in Paediatrics 14
1.6 Nuclear Medicine in the Diagnostic Scenario in Paediatrics 16
References 17

L. Mansi (*)
Nuclear Medicine Unit, Department of Clinical and Experimental Internistic
“F.Magrassi, A.Lanzara”, Second University of Naples, Naples, Italy
Medicina Nucleare, Seconda Università di Napoli
P.zza Miraglia, 2-80138, Naples, Italy
e-mail: luigi.mansi@unina2.it
V. Cuccurullo • M.R. Prisco
Nuclear Medicine Unit, Department of Clinical and Experimental Internistic
“F.Magrassi, A.Lanzara”, Second University of Naples , Naples, Italy

© Springer International Publishing Switzerland 2016 1

L. Mansi et al. (eds.), Clinical Nuclear Medicine in Pediatrics,
DOI 10.1007/978-3-319-21371-2_1
2 L. Mansi et al.

1.1 Nuclear Medicine as Molecular Imaging

In the third millennium, diagnostic imaging is becoming a match field where there
is no more only fighting between alternative techniques, as it was typical in the past
decades. In fact, in the definition of a rational diagnostic workup, it is today consid-
ered more productive to search for cooperative elements and points of convergence.
Many are the reasons for this Copernican revolution, having as major result the
creation of the new paradigm called “tailored medicine”, centred on the patient and
no more on the disease [1].
The first motivation is certainly dependent on the extremely fast technological
evolution and in particular on the new opportunities, incredible only few years ago,
allowed by computers. The change from analogical to digital imaging, representing
by now the standard also for old techniques, as traditional radiology, created new
premises that have been particularly productive in the creation of hybrid images,
more recently producible also using hybrid tools.
A second major improvement has been reached in the field at the same time
technological and cultural. In the recent past, diagnostic imaging was centred on
the anatomical and pathological gold standard. In this sense, the major contribution
to diagnosis was mainly due to morphostructural techniques, such as computed
tomography (CT), ultrasounds (US), magnetic resonance (MRI) and traditional
radiology (Rx). The information achievable with functional techniques was con-
sidered less relevant and more frequently intended as a second diagnostic level.
The advent and the diffusion of positron emission tomography (PET), since the
1980s, and in particular the evidence of the pivotal clinical information obtainable
with the glucose analogue F-18 fluoro-deoxy-glucose (FDG), have significantly
changed the general approach to the disease, with main, but not exclusive, rele-
vance in oncology.
In fact, thanks to FDG, tracing glucose, and to PET scanners, and acquiring
images with a higher sensitivity and spatial resolution with respect to traditional
machines, the great general advantages of radionuclide techniques have appeared
more evident. At first, functional information given by NM may precede pathologi-
cal changes, therefore allowing an earlier diagnosis with respect to morphostruc-
tural techniques. Furthermore, being the pathophysiological information also
expression of a prognostic content and more strictly connectable with therapeutic
strategies, it is possible to better define disease characteristics in individuals, acquir-
ing data better allocable within the new scenario of the tailored medicine.
It has to be pointed out that the PET revolution has revalued the whole NM acting
as tip of the iceberg, stimulating a new point of view. In fact, the relevance of func-
tional information achievable by PET-FDG highlighted the true core of radionuclide
procedures, i.e. its “molecular” content, previously hidden and not obvious.
Nuclear medicine is able to provide a molecular imaging since its clinical origin
in the 1940s, starting from the use of the first utilized radiopharmaceutical, I-131
iodide; going back to older historical premises, associated with the Nobel graduate
George de Hevesy, who firstly introduced the concept of radiotracer, these abilities
may be individuated as founding essence of our discipline. Therefore, although the
1 Peculiar Aspects and Problems of Diagnostic Nuclear Medicine in Paediatrics 3

term is actually more frequently referred to advanced procedures, mainly preclinical

and applied in the “omics” categories, molecular imaging could be considered, at
least in humans, almost a synonymous of nuclear medicine.
Living creatures are made by biomolecules in dynamic equilibrium between
themselves. This condition, called homeostasis, is studied by physiology, while the
unbalanced situation, i.e. the disease, may be evaluated and understood by patho-
physiology [2].
The best way to perform an in vivo “molecular” analysis is to use tracers, i.e.
molecules having an almost identical (when utilizing isotopes of the same atom) or
however similar chemical structure with respect to the native molecule. This condi-
tion may determine a “biological identity or analogy”, indispensable to produce an
almost overlapping in vivo kinetic, with the maintenance of the functional activity
which characterize the molecule that has to be studied.
A molecular imaging requires a further condition: the labelling of the tracer with
a tag strongly linked, without altering its biological behaviour, which allows its
visualization from outside of the body. This possibility may theoretically hold all
diagnostic techniques. As examples, a tracer for CT may be labelled with iodine,
MR contrast media may include a paramagnetic atom, tracers for US may be based
on microbubbles, optical imaging (OI) can make use of fluorescent agents and
nuclear medicine tracers may be labelled with radionuclide. Unfortunately, the
availability of a labelled tracer which maintains the functional activity of the native
molecule is a necessary but not sufficient condition in producing a clinically useful
in vivo image. In fact, to avoid an influence on the molecular process that has to be
studied or else to prevent toxic effects, the administration of a little number of trac-
ing molecules with respect to the number of native molecules involved in the system
under evaluation is requested. Generally, the administered tracer’s quantity has to be
in the order of pico or nanomoles, a ponderal amount at present only associable with
the tracers used in optical imaging and nuclear medicine. Nevertheless, although it
has its own fascinating premises, allowing a molecular imaging up to the omics
level, OI is affected by a major problem for a clinical use in humans: the non-
penetration of light photons through the body. Therefore, OI may produce intrigu-
ing results in preclinical imaging or in evaluating superficial layers, as the skin, eyes
or mucosa, when using endoscopic techniques, but, using this approach, the meta-
static involvement of a liver by external probes cannot be detected.
As consequence, at present, nuclear medicine may interpret a primary role in
the modern diagnostic imaging, being the most effective in producing an in vivo
molecular imaging able to detect or characterize the majority of human diseases. It
has however to be pointed out that NM doesn’t exert its clinical role always through
a molecular approach; in many cases radiopharmaceuticals concentrate on the
basis of non-metabolic mechanisms, such as those associated with nanocolloids
subcutaneously injected to individuate sentinel lymph nodes or with albumin mac-
roaggregates intravenously injected to diagnose a pulmonary embolism. Even so,
also in these cases, the image is an expression of a concentration’s difference and
never of a density’s variation, as it happens using morphostructural techniques. In
this sense, while using, for example, standard CT, it is not possible to distinguish a
4 L. Mansi et al.

living body from a corpse, radionuclide procedures are only feasible in living crea-
tures. As consequence, being based on pathophysiological premises, functional
images can produce an earlier diagnosis or provide complementary information on
prognosis and on the relationship with therapy with respect to the one obtained
with morphostructural exams. Conversely, because the image in nuclear medicine
doesn’t represent differences in density, but in concentration, the anatomical detail
is typically poor, being furthermore impossible the topographic analysis of the
relation between contiguous structures not showing a radiotracer’s uptake. As
example, when using a radio-colloid which concentrates in the liver and spleen, it
is not possible to evaluate the spatial relationship with the adjacent right kidney,
non-concentrating the radiocompound. For these reasons, it has been a major
improvement in diagnostic imaging the advent of a digital system that allows the
production of fused images showing together either the pathophysiological and the
morphostructural content. Even more the commercial availability of hybrid
machines has been a revolution, producing almost simultaneous images obtained
with radiological and nuclear medicine tools allocated in the same gantry.
Does it mean that the toolbox of diagnostic imaging, because of the great pre-
rogatives of radionuclide studies and of the integrated information given by hybrid
scanners, may be today only filled with nuclear medicine instruments? The answer
is certainly no.
To better understand this point, it is appropriate to introduce the concept of cost/
effectiveness.

1.2 Cost/Effectiveness in Diagnostic Imaging

A cost-effectiveness analysis (CEA) evaluates relative costs and outcomes in the

comparison between two or more lines of action. It is typically used in the medical
field, where a cost-benefit analysis, more strictly connected with a monetary value
in measuring the effect, may be unethical. Nevertheless, health is priceless.
Healthcare has a budget that unfortunately is too low to answer to all health requests.
Therefore, the goal is to give a sustainable response, hopefully effective, to the larg-
est number of subjects, being impossible to provide the best to all of them.
A cost-effectiveness analysis in medicine is conditioned by a large series of
items, starting from the general scenario where priorities have to be chosen. In this
context, widely varying in different countries, the worst condition may derive from
the absence of funding necessary to support the health system, as it especially
occurs in third-world countries. Unfavourable may also be the context for poorest
people in countries where the health system is mainly based on private contribu-
tions, being scarcely guaranteed welfare policies. Unfortunately, because of very
high and ever-increasing general costs dependent by many issues, as population
ageing and rising value of health facilities, very difficult choices may occur also in
the best health systems, which may however fail to fully satisfy the demand for
health. This negative trend can lead to the possible exclusion from the right to health
of “weak” categories, such as older patients with a limited life perspective, mainly
1 Peculiar Aspects and Problems of Diagnostic Nuclear Medicine in Paediatrics 5

when nonautonomous and affected by chronic diseases, infants with rare diseases
and individuals requiring the utilization of very expensive drugs, tools and proce-
dures, unsustainable for the general population.
It is not the aim of this chapter to discuss more widely and deeply this very rel-
evant issue. Major points for reflections are however to be introduced to create a
new culture able to optimize the distribution of available resources.
The first change of the way of thinking is to consider the cost not as the sum of
prices of the different techniques separately taken. Using this traditional approach,
the first choice is frequently directed to the cheapest technique, often not having the
capability to solve alone the clinical problem. As consequence, an increasing cost
will derive from the addition of further procedures, from a delay in diagnosis and
eventually of hospitalization times and from the choice of a less effective (and fre-
quently more expensive) therapeutic choice. It is therefore important to learn to
have an a priori vision of the whole diagnostic and therapeutic tree, individuating
the most effective course.
The second cultural revolution has to be centred on the understanding of the
concept “tailored medicine”. The true consequence of this vision, having the
patient in the centre of the medical reasoning, is to introduce in the way of think-
ing the knowledge of the probability of disease for each individual patient, trying
also to understand a priori which could be the best therapeutic choice. In general,
this capability is strictly associated with diagnostic procedures giving not only a
diagnosis but also an information connected with prognosis and therapy. This is
what happened with the so-called functional techniques, first of all with nuclear
medicine.
These issues should be taken in consideration in each context and for each clini-
cal indication, as it can be read in the following chapters. In this script we want to
refer to the most frequent policy carried out in the specific field of paediatrics, as it
has to be applied in the so-called advanced and emerging countries, where a state-
of-the-art standard diagnosis may be achieved routinely.

1.3 Cost/Effectiveness of Nuclear Medicine in Paediatrics

As it can be read in Table 1.1, the clinical role of a procedure is at first dependent on
its own capabilities and limitations.

Table 1.1 Conditions determining Its own capabilities and limitations

the choice of a diagnostic procedure
Capabilities (and limitations) of alternative procedures
in a clinical workup
Clinical questions:
Diagnosis, prognosis, connection with therapy
Local scenario:
Instruments and procedures routinely used
Epidemiological and socio-economic issues
Risks and prejudices
6 L. Mansi et al.

1.3.1 General Capabilities of NM

In the paragraphs above, we described how effective nuclear medicine can be

because of its capability to produce a molecular and/or pathophysiological imaging.
Furthermore, with respect to other procedures, as the US, NM is advantaged because
it is reproducible and not operator dependent. This point in favour is also accompa-
nied by a panoramic view, not allowed by US. Furthermore, mainly in case of posi-
tive indicators, as FDG and Tc-99 m diphosphonate, showing a more intense uptake
in pathological tissues with respect to the normal ones, a whole-body scan, very
helpful in staging and restaging, may be acquired. Using radionuclide techniques is
also standardizable and therefore more reliable quantitative analyses, allowing a
better evaluation of nonfocal diseases and/or a more precise definition of changes
which appear in the follow-up, eventually as response to therapy.
A further positive issue connected with NM is dependent on the capability to
define a prognostic information, as it happens with FDG in oncology. Using radio-
compounds, as FDG or radiolabelled white blood cells (WBC), is also possible to
define disease activity in many chronic inflammatory conditions, finding a relevant
role in recruiting only patients that may successfully undergo to therapies. With
respect to therapeutic strategies, a major advantage may be acquired in the presence
of radiopharmaceuticals that may be labelled either with γ or β + emitters and with
β-radionuclides, as it happens for radioiodine, metaiodobenzylguanidine (MIBG)
and somatostatin analogues. Using this approach, it is possible to forecast a thera-
peutic efficacy, on the basis of an a priori evaluation obtained with a similar radio-
compound, administered at a significantly lower radiation dose. As reported above,
the complementary contribution given in prognosis and therapy may create a clini-
cal indication for NM also as second-line diagnostic procedure after a first “patho-
logical” diagnosis has been already obtained.

1.3.2 General Limitations of Nuclear Medicine

Being based on difference of concentration and not of density, NM cannot give an

anatomical information. Moreover, radionuclide procedures don’t allow a loco-
regional staging, mandatory before a surgical choice, as an example to individuate
relationships between mass and adjacent vessels. Many of these limitations have
been recently solved by the availability of hybrid machines, including PET/CT,
SPECT/CT and more recently PET/MRI, which permitted a significant increase in
accuracy, either decreasing false-negative or false-positive results, with respect to
the individual procedures considered alone.
A major limitation associated with NM is certainly related to the presence of
ionizing radiations, a disadvantage shared with CT and traditional Rx. Nevertheless,
in the presence of an effective clinical indication, there are no absolute contraindica-
tions for radionuclide techniques, although radioisotopic procedures have to be
always “justified”. It means that no scintigraphies or PET or SPECT studies may be
performed when alternative procedures permit the achievement of a similar
1 Peculiar Aspects and Problems of Diagnostic Nuclear Medicine in Paediatrics 7

information without radiations. This rule is more restrictive in paediatrics (and even
more in pregnant women), being the stochastic risk associated with nuclear medi-
cine conditioned either by the percentage of cells that multiply, higher in infancy, or
by the life expectancy, longer for paediatric patients. It has however to be pointed
out, as we will see below in the paragraph evaluating risks, that the calculation of a
cost/effective balance is not always easy, mainly in comparison with MRI, nega-
tively affected by a minor diffusion and frequently accompanied by higher costs and
by a high rate of studies non-executable in paediatrics without narcosis.
As a negative counterpart for nuclear medicine, it has to be remembered that
problems for radioprotection may be increased considering the radiation charge for
physicians, nurses, technicians and relatives or other caregivers, the presence of
which may be requested to facilitate the procedure. In this sense, although the dose
of radiation and an increasing incidence of cancer are typically very low, a justifica-
tion is mandatory both for the patient and for accompanying persons.

1.4 Technical Problems of NM in Paediatrics

Although they are not exclusive of paediatric patients and not present in all the sub-
jects, also because of the wide differences existing, for example, in early childhood
with respect to the adolescence, some technical problems are peculiar in this popu-
lation; they may be due to factors such as the body’s structure and size; difficulties
in injecting radiopharmaceuticals, due to the small calibre and fragility of the ves-
sels; inability to collaborate which may cause disturbing movements or an increased
risk of contamination; psychological structure frequently governed by fear of the
unknown; and so on.
While it is impossible to exclude ionizing radiations from radionuclide studies,
to perform a study allowing an effective clinical response at the lowest cost, which
has also to consider risks and the reliable solution of technical problems, it has to be
a professional duty [3].

1.4.1 How to Approach the Paediatric Patient in Nuclear

Medicine

In paediatric imaging, a successful diagnostic examination is obtained when the

achievement of quality images, without degradation due to technical problems,
occurs without mental or physical detriment to the patient. The ability of a child to
remain sufficiently immobile during the scan depends upon his or her behaviour and
the administered technique itself. Infants and small children are unable to cooperate
and to follow verbal directions. Many older children are cooperative with adequate
support and guidance during the exam.
It has to be remembered that paediatric patients in the NM department are often
subjected to unexpected procedures that cause pain and increased anxiety and dis-
tress, like intravenous or subcutaneous injections and urethral or angiocatheter
8 L. Mansi et al.

insertions. The use of topical creams to provide topical anaesthesia has been shown
to reduce the pain associated with these procedures. Conversely, anaesthesia has to
be avoided as much as possible, because, although it may allow a “technically per-
fect” scan, it is dangerous and expensive. Furthermore, it may negatively affect the
examination conditioning the pharmacokinetic of the injected radiotracer. Similarly,
sedation has to be performed only exceptionally and when absolutely needed,
because of serious associated risks, such as hypoventilation, apnoea, airway obstruc-
tion, laryngospasm and cardiopulmonary impairment. These adverse reactions,
which may occasionally occur during and/or after sedation, can be minimized with
a procedure carefully performed, but not completely eliminated.
Children’s weight varies from premature neonates, weighing less than 1 kg up to
100 kg and more in teenagers. This condition creates a huge diversity in physiology,
pathology and psychology. Therefore, starting from the arrival of the patient in the
department, a sufficient time is needed to allow an individual assessment, based on
many issues as an interactive discussion in acquiring a consent, including the activa-
tion of special preparation procedures to the exam, such as a play therapy.
When possible, information about the procedure should be given beforehand
through information sheets sent to the family or through a phone call with prepara-
tion instructions. In general parents, or other close relatives such as grandparents
and uncles, may better help the children when they are prepared as well. Therefore
the procedure has to be explained to the parent (and/or to the alternative caregiver),
and any question or concern has to be addressed as required. It is essential to give to
the accompanying person the sufficient time to ask questions or express concerns at
any point, particularly when one is dealing with frightened or anxious children, who
may be less cooperative if they do not understand what is happening to them.
Conversely, it is important to restrict the number of interacting relatives, individuat-
ing only one or two of them as possible caregiver, to avoid confusion and the activa-
tion of negative behaviours [4].
A child-friendly approach and patient preparation are major issues for the suc-
cess in the large majority of nuclear medicine procedures. Children should be pre-
pared for what they will face, to lessen their anxiety and promote their cooperation.
Such preparation should be based upon the developmental level of the child. The
role of the parent should be supported when possible. Most kin and children have a
desire to be together during procedures. Policies should be developed to offer this
opportunity. The presence of a parent is comforting to a child and can lessen anxi-
ety. Allowing a protective person to remain in the room during the scan time can
also give the child a sense of security, helping an otherwise uncooperative subject to
successfully complete the scan without the need for sedation. It can be also helpful
to allow the little patient to bring a favourite toy or stuffed animal into the scanning
room, if possible. This toy can be placed above the head of the subject or held in his
or her hands, out of the field of view.
Children need to know what will be required to them to gain their cooperation.
Therefore they should be prepared for the experience they will encounter in the
nuclear medicine department. They should be given an age-appropriate explanation
of what they will feel, hear, see and/or taste. Medical and paramedical personnel
1 Peculiar Aspects and Problems of Diagnostic Nuclear Medicine in Paediatrics 9

should provide encouragement and ample praise. The subjects should be approached
with the positive expectation of success, to increase the rate of cooperative scans.
Distraction is a commonly used non-pharmacologic pain and fear management
technique used by both healthcare professionals and parents to attenuate procedural
hurt and distress. Distraction operates on the assumption that, by shifting a child’s
focus to something engaging and attractive, his or her capacity to attend to painful
stimuli is hindered. Thereby pain, distress and anxiety are reduced. A number of
behavioural distraction techniques, such as watching a movie, listening to a story, or
listening to music, can increase the child’s ability to tolerate the examination.
Natural sleep in infants can be induced by food, comfort and warmth and represents
a condition greatly facilitating the scan.
When restraining a child, it is important not to use excessive strength; the used
force should be appropriate to the child’s age. The safety of the staff restraining a
strong patient is also paramount to good practice. Training of professionals in effec-
tive risk minimization when restraining should be given. As with any paediatric
procedure, intravenous access can be problematic depending on patient cooperation
and hydration status. Establishing an intravenous line before injection allows the
little patient time to recover, as the experience can often be painful and stressful. All
the personnel involved with the patient should be familiar with the patient’s posi-
tioning, having also knowledge on the scan’s duration. Medical equipment and
patient intravenous lines have to travel safely with the patient through the scanner,
to maintain the patient safety and to have the capability to intervene, if necessary.
Once scanning is complete, images should be reviewed before the patient is
transferred off the scanning bed, to ensure that no further imaging is required.
The management of uncooperative children should take into account their indi-
vidual needs and fears, within the context of the illness, and in partnership with the
parents or guardians. Ideally, the wishes of the child should be respected, and, if a
competent subject is resistant to the persuasive powers of parents and professionals,
the investigation must be delayed and reassessed [5].

1.4.2 The Paediatric Environment in Nuclear Medicine

If the disease “scares”, this happens even more frequently for younger patients, who
have a greater fear of the unknown. In this sense, it is very important to create a
familiar environment, where colours, lights, waiting rooms and tools of distraction,
including televisions, toys, cartoons and so on may play an important role in creat-
ing an atmosphere of relaxation, in which the smiling staff professionalism is a
fundamental added value. Of course, an important element favouring this goal is
determined, as widely explained above, by the communication with the patient,
when big enough to understand, and/or with his or her relatives. If part of the fear is
connected with the unknown, the a priori knowledge of the steps that will be lived
in the next few minutes or hours can certainly increase the collaboration of the
young patient. As previously reported, it is very important to have interactive con-
nection with the relatives that have to be tranquilized and eventually may be
10 L. Mansi et al.

authorized to keep company to the kid after correct information of risks associated
with ionizing radiations. In this sense, while a pregnant mother should never get in
the authorized “hot” area, the cooperative participation of grandparents has to be
stimulated with respect to the presence of younger caregivers. Of course, the contri-
bution of nurses, technicians, physicians and/or other professionals involved may be
requested, if needed. Considering that fear, pain, family dynamics, previous experi-
ence with diagnostic and therapeutic strategies can determine problems, it’s impor-
tant to work for the best understanding of the procedure, trying to determine the
more strict cooperation between all the actors of the study, first of all with the little
patient. A psychological expertise by the physicians and professionals involved is
very important, because information of the patient and of caregivers may also
become detrimental, mainly in case of anxious subjects. A mandatory rule is never
leave the children unattended.

1.4.3 Patient Preparation

With respect to the intravenous injection, the most important rule is never inject
radioactive if you’re not sure you’re in the vein. To reach this goal, strategies utiliz-
ing butterfly needles and/or three-way catheters are helpful, and these operations
have to be performed in the more relaxed situation, before the injection of the radio-
pharmaceutical. Of course, this suggestion is particularly critical when dynamic
studies have to be acquired. We will not discuss here, devoting this information to
following specific chapters, other invasive and painful procedures, such as the ure-
thral catheterization in radionuclide cystography. We want only to remember that all
the strategies having as their aim the reduction of pain and/or of risks of infection
have always to be adopted. In this context, have also to be evaluated conditions that
may reduce radiation dose to the patient, as those related to hydration and urinating.
The risk of contamination has to be avoided using impermeable sheets. Similarly,
the need of fasting; the knowledge of haematochemical data, as glycaemia before a
PET-FDG scan; and the eventual relevance of the suspension of a therapy have to be
well known before the radiocompound’s administration.

1.4.4 Patient Positioning

This is a major technical issue in paediatric imaging, because a correct position is

essential not only for the anatomic evaluation but also to reduce the acquisition
time. Positioning is also critical to determine the best counting rate from the inter-
ested area. In this sense, it is very important to define a field of view minimizing the
contribution on the count rate coming from outside the area that has to be studied.
This strategy is particularly important in presence of a possible activity in the blad-
der that has therefore to be emptied when possible. It has also to be remembered that
a zoom may better define the image but doesn’t avoid the counting of radiations
emitted outside of the field of interest, if they are included in the field of view.
1 Peculiar Aspects and Problems of Diagnostic Nuclear Medicine in Paediatrics 11

1.4.5 Patient Restraining

Movements create problems either in the definition of the signal to noise ratio
and in the construction of a reliable image, obtainable with a satisfactory spatial
resolution. This is particularly true for dynamic and tomographic studies, with
main respect, because of the worst technical condition, for SPECT with respect
to PET.
To solve these problems, a solution that has to be carefully considered for each
individual patient can be the restraining (in proper anatomic position); clearly this
strategy is more useful, and sometimes mandatory, in youngest subjects. The immo-
bilization system has to be efficient but comfortable (avoiding forcible restraint),
also because crying can determine movement. Of course, when possible, this tech-
nical supplement is preferably to be avoided; in older kids a cooperative interaction
either with the patient or with his or her caregivers may create a more favourable
operative condition. A possible alternative to restraining, generally applicable in
kids up to 24 months, is to hold the infant. When needed the restraining may be
performed with different tools, as using sandbags and Velcro straps.

1.4.6 Sedation (and Narcosis)

Being radionuclide procedures based on pathophysiological premises, sedation may

determine a disturbing effect in pharmacokinetics of some radiotracers. In this
sense, it has to be utilized only if really needed and in the absence of alternative
strategies which may avoid the administration of drugs. In general, this condition
may be required only in children of 4 years or less and only in limited non-
collaborative case. This request can be mainly indicated in whole-body and SPECT
examinations. In the majority of cases, sedation may be averted in older patients, if
there is an interactive cooperation with the subject, having been explained with the
procedure carefully.
When performed, the sedative procedure should be administered by personnel
trained in paediatrics anaesthesiology and resuscitation. In the following phase,
skill and experience of nursing staff (and eventually of nuclear physicians), which
guarantees a careful monitoring, limit the risks.

1.4.7 Radioactive Dose

This book is presenting a specific chapter on dosimetry. Here we want only to

express some general suggestions. The two main rules are apparently contradicto-
ries: any dose must be calculated to avoid radiation overexposure, but at the same
time the dose has to be calculated, avoiding the risk of injecting an activity too low
to produce clinically useful images. This situation has also to consider the amount
that remains in the syringe and the possibility of extravasation. Therefore, as it will
be better explained in the next chapters, although the paediatric dose should be
12 L. Mansi et al.

calculated proportionally to the dosage of the adult, with reference on body surface
area (BSA) preferably with respect to weight, a minimal threshold activity higher,
mainly in littlest patients, with respect to the mathematically calculated dose has to
be considered. Similarly, a more careful evaluation has to be done when the injec-
tion is performed as bolus in dynamic studies, being more frequent in these cases
the probability of inappropriate administration [6, 7].

1.4.8 Image Acquisition and Other Technical Points

Differences in image acquisition between adult and children are relatively few. To
improve the signal to noise ratio, in some cases, the use of a camera with a little field
of view can be preferred, determining a count rate more strictly dependent on the
region that has to be studied. A further peculiarity, almost lost with the advent of
SPECT systems, is connected with the use of collimators. As an example, the pin-
hole has been widely utilized in paediatric nuclear orthopaedics, while collimators
with a higher sensitivity may be preferred in cases when a faster scan, a lower dose
and the recovery of a static examination in case of a radiocompound’s extravasation
may support the choice of a highest sensitivity with respect to a better spatial resolu-
tion. To acquire a more standardized study, less influenced by individual variations
and movement, planar scintigraphy using multiple projections may be sometimes
preferred with respect to SPECT, as how it happens in many centres for renal scar
detection.
A further difference with respect to the adult may be individuated in dynamic
studies. A typical example may be found in the use of sequential renal scintigra-
phy. In case of a “partially” wrong injection, however, allowing the acquirement
of the most relevant clinical information requested by the clinician, a second
injection is in general contraindicated. In these subjects, in the report, it has to be
referred how the technical problem has created the impossibility to acquire
reliable quantitative data.

1.5 Nuclear Medicine in Paediatrics as Compared

with Alternative Procedures

As it can be derived from Table 1.1, the role of NM in paediatrics is dependent on

the comparison with alternative techniques, which have the capability to answer to
the same clinical question. However, a possible utilization may be also justified as
supplementary contribution to diagnosis, when further relevant information, better
answering to a different question related to prognosis and therapy, may be obtained.
Of course, all the choices have to be made on the basis of a cost-effectiveness analy-
sis considering instruments, expertise and procedures routinely used in the specific
scenario where individual decisions may also be based on waiting lists and epide-
miological and socio-economic issues.
1 Peculiar Aspects and Problems of Diagnostic Nuclear Medicine in Paediatrics 13

1.5.1 Risks and Prejudices

In the definition of a cost/effective balance in paediatrics, remembering the funda-

mental principle “primum non nocere” (first do no harm), the evaluation of associ-
ated risks has to be very critical. In this sense, techniques utilizing ionizing radiations
have to be utilized only when a similar information cannot be obtained from an
alternative procedure not utilizing radiations, as US. Nevertheless, it has to be
pointed out that the alternative utilization of MRI has to deal with the analysis of a
wider number of considerations, including higher cost, lower diffusion and exper-
tise and elevated technical complexity.
In this context, it has to be evidenced that risks deriving from ionizing radiations,
stochastic and not lethal, are only a little part, and certainly not the more dangerous,
of the risks that may be associated with diagnostic imaging. Nuclear medicine is not
affected by absolute contraindications, being diagnostic radionuclide examinations
performable in all the subjects, in the presence of a clinical justification, without
risks which may determine the patient’s death. Conversely, a patient may die
because of a reaction to the administration of contrast media used in traditional
radiology and CT or, also if more rarely, in MRI and ultrasonographic techniques.
High risks may be dependent on drugs or narcosis, the latter frequently required in
infants when performing MRI studies; subjects undergoing MRI may also face
problems due to eventual metallic components and/or to other tools influenced by
the magnetic field. Risks may also be associated with the administration procedure,
as it may happen in angiography, in endoscopy and, more in general, in invasive
approaches.
Together with risks associated with the diagnostic technique, even greater prob-
lems may be born in case of an unjustified delay in the activation and execution of
a diagnostic tree, of a too long duration of the whole diagnostic procedure, mainly
in emergency, because of the lack of resuscitation supports and expertise. Between
all possible risks, the greatest are certainly due to diagnostic mistakes. In this sense,
to avoid the choice of a radionuclide study because of the fear of ionizing radiations
may create in many cases an unfavourable cost/effective ratio, either in the diagnos-
tic course and/or in the definition of therapeutic strategies. In this sense, nuclear
medicine has to be considered a primary diagnostic support, for example, in cases
when it can reduce false-negative and false-positive results or when it can more
safely recruit patients that have to be hospitalized and/or avoid a too-early
discharge.
To make a rational choice including radionuclide techniques, it is however nec-
essary to uncover and destroy the prejudices against them. In other words, it is
important to fight against the so-called September 12’s syndrome [8], confusing
the risk with the irrational risk’s perception. According to this syndrome, in
September 12, 2001, i.e. the day after the criminal collapse of the twin towers in
New York, there was a huge decrease in the number of passengers by plane world-
wide. To destroy prejudices against radionuclide procedures, it has to be clarified
that nuclear medicine is at Hiroshima and Fukushima as a drug is to a poison.
14 L. Mansi et al.

It means that if radioactivity at a high dosage is certainly a danger, the very low
number of radiations associated with diagnostic radionuclide procedures may very
rarely determine a negative effect, either because of the low probability of a bio-
logical oncogenic mutation or of the great capability of humans to recover genetic
damages. To better understand this concept in a wider evaluation, it has also to be
remembered that dosimetry associated with diagnostic radionuclide procedures is
very low, determining stochastic risks favourably comparable to the large majori-
ties of those present in a day life. In particular, the radiation charge is comparable
with natural radiations: it has been calculated that the radiation dose given by a
renal scan is corresponding to that received by a pilot or a passenger flying for only
80 h. To give further information on comparative risks, epidemiological studies
have calculated that the number of deaths derived from diagnostic nuclear medi-
cine is very low (35–250 cases per million), corresponding to the number of deaths
associated with 3000 km in motorcycle, 75 min of climbing mountains and 17 h of
a day life of a 60-year-old man.

1.5.2 Peculiarities of Alternative Diagnostic Procedures

in Paediatrics

As noted many times above, in the definition of a cost/effective balance nuclear

medicine in paediatrics has to confront its peculiarities with qualities and limita-
tions of techniques having capability to answer to the same clinical question, being
clearly easier to individuate a diagnostic space for exclusive indications.
In this scenario, traditional Rx is advantaged because of its widely diffusion,
being as well cheap, fast and easy to be performed, also at bedside. For these rea-
sons, it may save also today a primary role as first-line technique in a little group of
indications, mainly concerning the chest and bone. Nevertheless, negatively affected
by ionizing radiations, traditional Rx only rarely allows a final diagnosis, with main
reference to pathologies affecting internal organs. With respect to the past, a more
limited clinical space is today identifiable for dynamic techniques, such as urogra-
phy and cystography. These procedures, having capability to provide a functional
information in the presence of a high anatomical resolution, may be mainly helpful
when a precise diagnosis of malformation has to be obtained. These studies are
affected by a high and frequently unjustified radiation charge and by major limita-
tions with respect to the corresponding radionuclide techniques, which allow a more
sensitive and precise result, also because of a better physiological and quantitative
content, obtained at a lower radiation dose. A competition further decreasing the
clinical interest may derive from the availability of functional studies performable
with MR, although not yet widely diffused [9].
By now consolidated awareness of the absence of side effects represents a major
undoubted advantage of ultrasound techniques in paediatrics. Being diffuse, cheap,
fast and easily performable, also at bedside, these procedures are proposed as first-
line methods for a large number of indications. Nevertheless, they are not feasible
in several patients and in some anatomical locations and most frequently require
1 Peculiar Aspects and Problems of Diagnostic Nuclear Medicine in Paediatrics 15

further procedures to complete the diagnostic course. A major problem is dependent

on the fact that these methods are operator dependent, moreover not allowing a
panoramic view of the field of interest. This point may represent a major disadvan-
tage in paediatrics where a standard approach and a consolidated experience of the
operator may be mandatory in the solution of many difficult clinical problems. The
negative effect of this limitation on the achievement of the best cost/effectiveness
ratio can be understood by the evaluation of the ultrasonographic technique used for
the detection of the vesico-ureteral reflux (VUR), based on the intra-vesical admin-
istration of a contrast medium for US. The diagnostic information has to be obtained
following continuously for tens of minutes the possible reflux of the contrast from
the bladder to the kidneys. Unfortunately, being the method non panoramic, a path-
ological information can be lost when it occurs in the contralateral side with respect
to the one observed in that moment. Furthermore, because of the criticality of the
information in the decision of a therapeutic strategy, the procedure requires the
involvement of an expert sonographer for a too long a time, with negative effects on
costs and on the quality performance in other fields. Interestingly, as it will be better
described in one of the further chapters of this book, the most effective procedure in
detecting VUR is cystoscintigraphy, which has to be preferred for its higher sensi-
tivity, although the presence of ionizing radiations. Allowing typically a morpho-
structural information when performed using a standard approach, US may also
give functional data. Using Doppler and contrast media, useful information, also
quantitative, on flow, vascularity and perfusion may be acquired, although only
rarely they are conclusive in the diagnostic course.
Standard computed tomography (CT), largely diffuse in all the diagnostic depart-
ments, including emergency, represent at the present the most important technique,
mainly in oncology, for diagnosis, staging and restaging, occupying a central role in
guidelines. The procedure, also utilizing contrast media to increase the diagnostic
accuracy, is effective in a large number of patients, having capability to allow a
clinical result, useful to define the successive therapeutic strategy. As further advan-
tage, the technique is fast and well tolerated and therefore feasible in the majority of
cases without the need of narcosis or of other disturbing tools. A major quality may
be found in its panoramic view, being also the technique not operator dependent. As
limitations, contraindications for contrast media, a high radiation dose and the
scarce ability to provide functional information have to be remembered.
A great advantage in paediatrics for magnetic resonance techniques is deter-
mined by the absence of ionizing radiations. Furthermore, MR techniques allow a
multi-parametric imaging, further improved by the possible addition of functional
techniques either with or without the administration of contrast media. In this way
better information with respect to CT may be obtained in some fields, such as in the
evaluation of soft tissues and/or in analysing anatomical territories, as the head,
neck and pelvis, or diseases characterized by slight changes in density, as demyelin-
ating pathologies. Being less effective with respect to CT in evaluating the lung and
bone, MR is also affected by a scarce diffusion, high costs and technical complex-
ity; general contraindications include the presence of metallic components or pace-
makers, claustrophobia and so on. A major problem in paediatrics is derived from
16 L. Mansi et al.

the length of the examination and by difficulties occurring in the local support to the
little patient. As consequence a narcosis is frequently required, further complicating
the procedure and increasing associated risks. For these reasons CT is frequently
preferred, although the presence of ionizing radiations.
A particular evaluation has to be made in paediatrics for angiography and other
invasive approaches, which may represent the best approach, but only in a little
number of cases. The presence of severe contraindications and of high risks creates
the need to choose this approach only when other diagnostic strategies are not
effective.

1.6 Nuclear Medicine in the Diagnostic Scenario

in Paediatrics

As described above, the diagnostic scenario in paediatrics is occupied by very effec-

tive procedures, all of them with favourable peculiarities which support their pro-
posal in the diagnostic course. In particular, US are the most frequently utilized first
line; Rx can be cost-effective, mainly in the first evaluation of pulmonary and skel-
etal diseases; CT has a pivotal role in oncology; and MR and newer approaches
enlarged the clinical boundaries of “traditional” imaging also outside of the mor-
phostructural fence, having acquired the ability to allow also a functional and quan-
titative evaluation.
In this context nuclear medicine needs to express comparatively its qualities
[10]. At first, nuclear medicine is the only technique with an imaging exclusively
based on pathophysiological premises, feasible in all the patients, with a reproduc-
ible and reliable production of quantitative data. Having capability to evaluate the
living function of normal parenchyma and of pathological tissues, radionuclide pro-
cedures, when based on molecular uptake mechanisms, may define an early diagno-
sis and a better connection with prognosis and therapy. Being already in the clinical
field, the use of radiocompounds permitting the analysis of complex mechanisms,
such as neurotransmission, apoptosis and angiogenesis, has already gone through
the first steps in the road to the future of molecular medicine where genomics, pro-
teomics, pharmacogenomics and antisense and gene therapy will find their clinical
role. Furthermore, nuclear medicine has, with respect to alternative diagnostic tech-
niques, consolidated supremacy in defining accurate quantitative methods, which
may permit an increased diagnostic accuracy, a disease detection also in absence of
focal lesions, a better evaluation of therapy and/or of a prognostic evolution and a
better analysis of stress test [11].
Waiting for the full realization of a diagnostic scenario dominated by molecular
imaging, where nuclear medicine could play a major role, because of its abilities in
answering at best to questions made in a pathophysiological language, we have to
consider where its position today in the routine practice, in our actual working place.
In this scenario, NM can certainly give an important contribution in diagnosis,
further increased by the capability to better evaluate prognosis and the connection
with therapeutic strategies. The dominance in the diagnostic imaging scenario could
1 Peculiar Aspects and Problems of Diagnostic Nuclear Medicine in Paediatrics 17

already start in many fields, first of all in oncology, thanks to the ever-wider diffu-
sion of molecular radiotracers that can be evaluated by hybrid machines, including
PET-CT, SPECT-CT and, with intriguing perspectives in paediatrics, PET-MRI.
To reach and consolidate a clinical role, NM has to demonstrate its capability to
answer to clinical indications with a cost/effectiveness ratio supporting its utiliza-
tion. In this direction, a further and wider diffusion of nuclear medicine depart-
ments, enriched by technologically advanced tools, acting 24 h a day for 365 days a
year, also in an emergency, has to be stimulated.
Different policies could be actuated for the diagnostic imaging in paediatrics. In
our opinion, although all nuclear medicine departments need to be expert in this
peculiar field, it could be important to individuate and develop centres with a high
workload of paediatric subjects where more easily and reliably can be guaranteed
a reliable and cost-effective approach; the high workload may more easily justify
the acquirement of expensive newest instruments particularly interesting in
younger subjects, as PET-MRI or the most advanced and performing PET-CT and
gamma cameras, allowing a faster and more accurate acquisition at a lower radia-
tion dosage [12].
Waiting for the future, we can give a future to our present favouring the under-
standing of qualities of nuclear medicine by the medical community and, more in
general, by the users. These qualities, strictly linked with our diamond procedures
as PET-FDG, are the essence of all the radionuclide techniques, including those
performed with a planar imaging. We have to demonstrate that for a large number of
clinical indications radionuclide procedures are cost-effective in giving useful and
original responses to the queries made by the prescriber.
Therefore, a crucial part of our future may be found in the aims of this book,
having as main goals the standardization of procedures, the education of nuclear
physicians and the interaction with the clinician, who has to understand how impor-
tant can be the contribution of nuclear medicine to his or her knowledge of the
disease and of the patient.

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toma and paraganglioma model. Eur J Nucl Med Mol Imaging 39(8):1262–1265
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PET/MR in Children
2
Marco Salvatore, Carmela Nappi, and Alberto Cuocolo

Contents
2.1 Introduction 19
2.2 Available Diagnostic Tools in Pediatric Diseases 20
2.3 PET/MR in Pediatric Patients 21
2.3.1 Neurological Disorders 21
2.3.2 Oncological and Hematological Disorders 23
2.3.3 Cardiac Disorders 25
2.3.4 Fever and Inflammation of Unknown Origin 25
Conclusions 26
References 26

2.1 Introduction

The rapid increase in incidence of diagnosed malignant diseases in children over the
last decades, combined with innovations in molecular oncology, neuroimaging, and
hybrid imaging, has encouraged researchers and physicians to make a special effort
in optimizing technological resources to approach pediatric patients using high-
resolution imaging devices with concern about radiation exposure. In this context, a
truly hybrid imaging tool, such as simultaneous positron emission tomography/
magnetic resonance (PET/MR), presents the appealing advantage to combine serial
imaging technology (MR) and a volumetric (PET) method, at the same time under
the same conditions, to define and to assess a pathophysiological pattern for each
disease in every single patient aiming to customize therapeutic strategy, therefore
improving survival rate. Furthermore, a simultaneous approach enables to

M. Salvatore (*)
SDN Foundation, Institute of Diagnostic and Nuclear Development, Naples, Italy
e-mail: marsalva@unina.it
C. Nappi • A. Cuocolo
Department of Advanced Biomedical Sciences, University Federico II, Naples, Italy

© Springer International Publishing Switzerland 2016 19

L. Mansi et al. (eds.), Clinical Nuclear Medicine in Pediatrics,
DOI 10.1007/978-3-319-21371-2_2
20 M. Salvatore et al.

overcome some of the limitations of current PET/computed tomography (CT) scan,

such as misregistration of attenuation (CT) and emission (PET) images due to spa-
tial and temporal mismatch between CT and PET acquisitions, thus reducing arti-
factual false-positive result percentage. In addition, the possibility of matching two
powerful modalities such as MR and PET opens the way for new challenging clini-
cal applications for disease characterization that are currently under investigation,
e.g., multiorgan disorders. In this chapter we will focus on the potential clinical role
of PET/MR in pediatric diseases.

2.2 Available Diagnostic Tools in Pediatric Diseases

Nuclear medicine procedures are able to address several childhood diseases in

the manner of diagnosis, treatment planning, monitoring, and follow-up by using
well-established diagnostic methods. Thanks to advanced single-photon emis-
sion CT (SPECT) and PET systems available and state-of-the art CT and MR
devices combined with a wide range of radiopharmaceuticals and contrast agents
developed, most childhood-specific disorders can be accurately studied. In par-
ticular, radionuclide techniques with the use of gamma camera have been widely
validated and applied to investigate the kidney and urinary tract in children by
using three categories of 99mTc-labeled radiopharmaceuticals: diethylene tri-
amine pentaacetic acid for glomerular filtration rate measurement, mercaptoacet-
yltriglycine for tubular secretion assessment, and dimercaptosuccinic acid for
evaluation of tubular retention. Bone scintigraphy with 99mTc-methylene diphos-
phonate as specific tracer is a valuable tool for identification of alterations of
bone metabolism derived from benign or malignant pathologies. In addition, the
recent introduction of 18F-sodium fluoride as PET tracer allows the achievement
of higher-resolution images with similar dosimetry for pediatric bone malignan-
cies evaluation. Regarding to neuroimaging, brain tumors and epilepsy can be
investigated with MR and the support of SPECT or PET techniques by using
99m
Tc-ethyl cysteinate dimer, 99mTc-hexamethylpropylene amine oxime for
SPECT, and 18F-fluorodeoxyglucose (FDG) for PET. Other brain PET receptor
tracers have also been introduced, such as serotonin markers (5-HT1A, MPPF
(4-(2’-methoxyphenyl)-1-[2’-[N-(2”-pyridinyl)-pfluorobenzamido]ethyl]pipera-
zine), dopamine system receptors [18F]-fluoro-L-dopa, [18F]-fallypride), gluta-
mate/NMD receptors (11C-S-ketamine, 11C-CNS 5161), and opiate receptors
(11C-carfentanil). However some limitations, such as commercial availability,
restrict their use in clinical practice. As regards imaging in oncology, in the last
decades FDG-PET/CT has emerged as valuable method for metabolic character-
ization of hematologic and solid malignancies. Qualitative image evaluation
combined with standardized uptake value assessment is a validated approach for
staging, assessing response to therapy, and detecting disease recurrence. Novel
developed tracers, such as 11C-methionine and 18F-fluorothymidine for gliomas,
18
F-dihydroxyphenylalanine (DOPA), 68Ga-DOTANOC, and other analogues for
neuroendocrine tumor investigation, may increase the accuracy of method.
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 CHAP. XI.

LETTER LXVIII.
From Capt. Sinclair to Capt. Flint.
My Dear Sir, Jamaica.

Our worthy and zealous friend Mr. Paget having spared me the
painful detail of events, which, of late, have rendered this abode of
peace one of sorrow and consternation, I will employ my pen on
subjects of better and renewed hopes. In the first place, Lady
Maclairn will be soothed by hearing, that Philip is the father of a fine
healthy boy; and that the mother is doing well, and already the
nurse. She has been cautiously told of Mr. Flamall’s death; and thus
the suspense and alarm avoided, that would have been occasioned by
her seeing her husband’s dejection, which was but too apparent, in
spite of his endeavours. We must give him credit for more sensibility
on this melancholy occasion, than we feel ourselves. To say the truth,
the termination of a life passed without honour or satisfaction, is, in
my opinion, little entitled to the tear of affection; although the
means, which Flamall employed for the purpose, are appalling to
nature and to the Christian. It is a happy circumstance for my
brother, that he has uniformly conducted himself in respect to his
uncle, so as to have secured his own self acquittal. This, with the
prospect of happiness, before his eyes, will, in time, restore him. We
shall, however, wait with anxiety for news from Farefield. Had not
his wife’s critical situation checked his solicitude for his mother, I
believe we could not have prevented his undertaking the voyage to
England, for the purpose of supporting her, in the trial which nearly
overset himself.
 I beg you to be particular in your account of Lady Maclairn’s
health, as also Miss Flint’s.
Let Miss Cowley be assured, that her concerns will suffer nothing
from the loss of her agent. We have been fortunate in having with us
a Mr. Montrose; this gentleman is the early friend of Philip and
Margaret; and is brother to Mrs. Lindsey, my sister’s first nurse, and
constant companion at present.
Montrose makes a better consoler than myself. I therefore yield up
to him this office; as being his by profession; and no man can better
know, and perform his duty. I have not, however, been idle. The
attested papers you will receive with this, will inform you that all has
been done that could be done. Flamall’s late gloom and the evidence
of the servants, induced the coroner’s inquest to give in a verdict of
lunacy. We have discovered no letters nor papers of consequence, to
his private concerns; and one letter excepted, of a recent date, from
his banker, which mentions his having received the half year’s
interest of five thousand pounds Bank stock: this of course devolves
to his sister. I cannot conclude this letter, without telling you, that I
believe, from the order in which all Flamall’s accounts were, that he
has, for sometime, been meditating how to escape from a world, in
which he knew he was regarded with contempt. You may think me
too harsh; be it so. But believe me sincere and honest, and

Your’s to command,
Francis Sinclair.
 LETTER LXIX.
From Dr. Douglass to Mr. Hardcastle.
Farefield, Dec. 30.

I conjure you, my dear Sir, to rely on my assurances. Miss Cowley

is entirely out of danger. We have a decided intermission, and are
hourly gaining on the enemy. But I will not disguise my fears, for the
consequences which will probably result from you and Miss
Hardcastle’s visit here at this time. The truth is, that as terror and
exertions beyond Miss Cowley’s strength, produced the fever, it is my
opinion, that joy, and a new demand on her feelings, will produce a
return of it. Calmness and repose are necessary to give efficacy to the
medicines which have hitherto been useful, and I entreat of you, to
postpone your journey, till my patient is more able to welcome you.
To say what this young creature’s fortitude has been, is beyond my
abilities! I only know, that I shall in future blush, when I hear
strength of mind called a masculine endowment.
You will easily imagine, how little prepared she was, after the
attention and exertions she had shown to Lady Maclairn, to sustain
the sudden terror, which Miss Flint’s death produced. Every
precaution had been used to prevent the intelligence of Mr. Flamall’s
death, from reaching the dying woman. She was so weak, as to bear
with apathy her sister’s absence from the room; indeed, she noticed
little those who were about her, being for the most part in a lethargic
stupor, and gradually sinking. In the neighbourhood it was, however,
no secret that Mr. Flamall had died suddenly. Warner, Miss Flint’s
woman, had in the morning left her post to a chamber maid, in order
to get some repose. This girl’s mother had been frequently employed
in the sick room, and she, on calling to see her daughter, was
directed where to find her. Miss Flint was heavily dozing, and the
women, though with precaution, as they say, talked of poor Lady
Maclairn’s illness, and the melancholy news from Jamaica. The
visitor had heard the report, which has circulated here, and which a
London newspaper has communicated to the public. Namely, that,
“Mr. Flamall was assassinated by a negro, whom he had too severely
treated.” I suspect the precaution of whispering this tale was
forgotten, in the eagerness of curiosity and the love of the
marvellous. Suddenly, they were alarmed by a faint scream from the
sick woman, who, with convulsive groans and agitations, said, “dead!
murdered! lost! for ever lost! Flamall!” Screams followed this
apostrophe, and the terrified girl ran to Miss Cowley’s room. She was
unfortunately sleeping on the sopha, after having passed the greater
part of the night by Lady Maclairn´s bed side. She rose with
firmness, to perform the duty to which she was summoned; not
permitting Mrs. Allen to be informed of what was passing; because
she was with Lady Maclairn. I found her calm and collected; sitting
by the dying Miss Flint, whose senses were lost before she ceased to
breathe. Let me finish this melancholy detail, by saying, that I did
not quit Miss Cowley’s bed side for the space of six and thirty hours.
Heaven was merciful! and she will be restored to health. But we must
have no beloved friends to greet at present.
I quit you to obey the summons of my precious patient. She insists
upon signing this bulletin. She will soon be well; for she is growing
saucy, and this morning, at four o’clock, when I carried her the
prescribed potion, she told me “that in my night cap and gown, I was
the very image of Blue Beard; and still more savage than he; for, that
his scymitar was nothing in comparison with my glass of poison.”
Judge with what contentment of mind I now sign the name of your
sincere

Archibald Douglass.

P.S. Indeed, my dear Lucy, I am getting well. They tell me, the
wind is still against the Lisbon packet’s sailing. How fortunate I am!
There! the whole junto are rising! and the inkstand has vanished.
Your’s! your own R. Cowley is, indeed, only too weak to mutiny
against this authority.
 LETTER LXX.
From Miss Cowley to Miss Hardcastle.
It is with gratitude to Heaven, that I find my dear friends at
Heathcot, are relieved from their too tender anxieties and
apprehensions on my account, yet wherefore do I say “too tender,” I
recall the words, my Lucy, which my heart does not sanction, and I
will not assume a virtue I have not; I give you joy, that death has
spared to you your Rachel Cowley. I rejoice in your love; and I
participate in your present feelings. Your goodness to Horace has
contributed towards my restoration. I should have died, had you
mentioned your terrors to him.
I have written to him the state of affairs here. He will be satisfied,
that the recent events, in which I have been engaged, occasioned the
brevity of my letter.
Mrs. Heartley sends her love to you with the enclosed: she insists,
that you will be better pleased with it, than with my labours. They
have, amongst them, annihilated the self will of your

Rachel Cowley.
 LETTER LXXI.
From Mr. Serge to Mrs. Heartley.
(Enclosed in the preceding.)

Madam, Putney.

I make no doubt, but that you have heard Mr. Maclairn mention
his friend Jeremiah Serge; and that you are convinced, I mean to
deserve my title. I shall, therefore, enter into the business before us
at once. Herewith you will receive the deeds, which secure to your
daughter and her children the estate called the Wenland Farm, now
occupied by Malcolm Maclairn; the day she becomes that
gentleman’s wife, he is her tenant and his children’s steward.
Counsellor Steadman has managed this affair for me, to my entire
satisfaction, and I trust it will not be less so to my young friend.
I have, for the first time, during many long weeks, felt that the
Almighty has yet the means in his hands with which to heal my
wounds. I never, Mrs. Heartley, had a son; I have not, like Sir
Murdoch, had a son like his Malcolm, to follow me in my feeble
steps, with duty and affection; nor try to perpetuate my name, and
his own virtues to children unborn; but I had a child, who was, whilst
she lived, the joy and the prop of my life! But you know what I have
had to suffer! I am forgetting the object of this letter.
From the first hour I knew Mr. Malcolm Maclairn, I took a liking
to him; this goodwill was, in part, owing to the favourable character I
had of him from my excellent friend, Counsellor Steadman. Some
particulars I learned from this gentleman, led me to think that it was
in my power to serve this worthy young man; and with this intention,
and other thoughts in my mind, I paid my visit to Farefield Hall. I
was in part disappointed in my scheme; but I saw the young man was
all, and more, than I expected, and I gave him my heart, though I
could not give him my daughter’s hand. I thought I had explained
myself to his good father, in regard to my views in assisting the son;
but I perceived, that Sir Murdoch had a little of the infirmity, which
is common to men of high birth; so I consulted the counsellor, and
did what I could without offending the baronet’s high spirit.
Believing that you are a very judicious lady, I request from you the
favour, in case you should see the good baronet’s scruples, to say
what, in truth, you may affirm, that you perceive nothing in my
conduct, that ought either to offend, or surprise him.
Some men, with less wealth than I possess, keep fine houses, fine
madams, and fine horses; buy fine pictures, and plant fine gardens.
Now, Mrs. Heartley, I have no taste nor pleasure in these things;
seeing I was not brought up to like, or understand them; but this is
no reason why my money should be useless to me, and if I can
purchase, by my superfluity, the happiness of having such a friend as
Malcolm Maclairn, I should be a fool not to have done what I have
done. So, heartily wishing the young couple happy, and
recommending to your fair daughter to marry her tenant directly,

I remain, your sincere,

Jeremiah Serge.
 LETTER LXXII.
From Miss Cowley to Miss Hardcastle.
January 12.

My patience is recompensed. “I may write half an hour, seeing that

scribbling is the aliment some girls live upon.” This is my kind
doctor, Lucy; and if you had seen how grateful I was for this
indulgence, you would be of Mrs. Heartley’s opinion, who has
pronounced my fever good for something; for that it has saved Lady
Maclairn’s life; and, as you may perceive, has taught me to submit.
Blessed be God for the renewal of that life, which is so dear to my
friends! and which I may, if it be not my fault, still render a blessing
to them and myself.
We are once more in sight of the harbour of peace; not indeed of
that peace which “this world can neither give nor take away,” but of
that season of tranquillity, which, in mercy, is allotted to man, in
order, as it should seem, to give us time to refit our feeble bark, and
to rectify the chart, to which we have hitherto trusted; to recover by
repose, strength and vigour for the storms and perils we may yet
have to encounter in our passage to eternity; and to leave behind us
traces of that providential power which hath piloted us home.
You will like to have the particulars of Miss Flint’s will. It will
satisfy you, as it has done me, that a death-bed repentance is much
better than none. She specifies, that, in consideration of her brother
Oliver’s donation to Philip Flint, it appears to be an incumbent duty
on her part, to provide for those of her family, who have been too
long neglected, and to the last moment of her mortal life, will she
bless Philip Flint, for having seconded her in this act of justice, by his
advice and concurrence.
The Farefield estate, with the moveables, besides a considerable
sum in money, which will devolve on him as residuary legatee, are
left to Captain Flint for his life; at his decease they go to Philip Flint,
to whom she has only bequeathed five thousand pounds “as a token
of her love.” To her niece Mary the same sum, payable when she is of
age, and five more at her uncle’s decease. To Malcolm Maclairn two
thousand pounds, “as a mark of her esteem for him, and gratitude to
his mother.” By the way, poor Malcolm was nearly overpowered by
this mark, for he had not mourned as one who needed comfort; and I
suspect that his conscience was not quite prepared for the legacy.
To the poor of the parish she has left a liberal peace offering: to her
servants she has been generous and just: to Warner, her woman, she
leaves a thousand pounds.
Flamall’s execrable name does not appear in any paper that is left;
and yet the contents of the cabinet left to Lady Maclairn’s inspection,
clearly prove that Miss Flint had long been engaged by the thoughts
of death. Not a friend has been overlooked but Flamall, and it is
evident to me, that she ceased to regard him even in that point of
view, from the time he declared his marriage. I suspect she was
informed of his baseness in that business. All her little donations
were marked and ticketed by her own hand. To Sir Murdoch she
leaves a very fine seal; its antiquity as well as beauty, make it
valuable. To Mrs. Allen a gold snuff box, containing an hundred
pound bank note, “for mourning;” for Miss Cowley a diamond ring.
To each of Douglass’s boys a hundred guineas for books, and three
hundred pounds in notes, for their worthy father. A small box,
directed “to my niece, Mary Howard, as a token of my too late
repentance and unfeigned love.” The captain, who was present when
her ladyship performed this painful office, was so much affected by
the sight of this box, that he burst into tears, and, with extreme
agitation, tore off the address, and put it in his bosom. Philip Flint
had not been overlooked in this partition of kindness. Her picture in
miniature, taken at the time he was born, with a rich string of pearls
that had been her mother’s, were marked for him and his wife. We
have since examined Mary’s gift. Some fine lace, and a few family
jewels are the principal things. When you have cautiously informed
her, that, from her aunt’s hand, she has restored to her what she will
judge to be invaluable, namely, her father’s and mother’s pictures, so
long lost! so deeply regretted! But I am called to order; and you will
be contented with this four day’s labour of your poor shackled Rachel
Cowley; who is bound, though in silken fetters. You know that the
Heartleys are here. I gain nothing by that; for they are as bad as any
of my arguseyed nurses.
 P. S. My dear Miss Hardcastle, we have now only to fear that our
patient should be too soon well. She has no fever, but that which
arises from her exertions. She cannot vegetate, to use her own word;
and she thinks her body is strong, because her mind is never idle. It
is in vain that we oppose her. She will write; and then who can
wonder that she does not sleep! Use your influence, and give us time
to recruit her strength.

Yours,
A. Heartley.

Mrs. Allen is in good spirits. She has left me nothing to say in

regard to Doctor Douglass. But, I verily believe, his care saved the life
of our precious friend. She was, indeed, for some hours, so ill as to
leave little for hope. I leave Alice to express, to my dear Mary, all that
my full heart feels on her account.
 CHAP. XII.

LETTER LXXIII.
From Miss Cowley to Miss Hardcastle.
January 29.

Although in the calculation of months and weeks, I have contrived to

beguile the lagging hours which are still between me and my
promised bliss, I have not yet been able to find an expedient for the
day, without scribbling to you. It seems to be the aliment necessary
for my existence; and notwithstanding I could match an hungry
school boy, in my appetite for my pudding, I could sooner console
myself for the absence of my dinner, than of the use of my right
hand, as the agent of my fondest, sweetest employment. I have
written a volume to Horace; and he will know as much of the
occurrences at Farefield, as will content him. He will know that I am
in health and in hope. Say not a word of my having been so ill. The
old bard says, “men are deceivers ever.” A woman therefore, may for
once deceive, when in that deceit, she spares to a beloved object the
useless anxiety arising from past danger and past pains.
Yesterday our “busy-heads” went to Wenland place, in order to
give their opinion of certain alterations and improvements projected
by the new tenant Malcolm. I was ordered to stay at home by my
despotical doctor, and Lady Maclairn promised to take good care of
me.
They departed after breakfast, meaning to dine at Mr. Wilson’s,
and left us to a danger, as bad as cold rooms. I soon found it
impossible to evade the topic I so much dreaded for her; she at once
led to the subject by saying, that she had still secrets to communicate
to her only comforter, but that she feared my sensibility. I desired
her to proceed. “Some time before my sister’s death,” continued she,
“I received this sealed parcel from her hands. It is, as you see,
addressed to myself. I hesitated when she offered it to my
acceptance. She observed my reluctance.” “Make yourself perfectly
easy,” said Miss Flint, “it contains nothing but papers essentially
necessary for your future security. I cannot die, without telling you
that they are necessary. You do not know your brother, Harriet, so
well as I do; and I must tell you, what steps I have taken to secure
you from his future tyranical power. I shall die, however, without
bitterness of spirit. I once loved Flamall; I do not accuse him here;
nor will I accuse him hereafter; for my own envy, my own implacable
spirit, my own stubborn and hard heart prepared the way for the
influence of his inordinate purposes, and more deliberate mischiefs.
As a father, he has been equally base and cruel. Philip has informed
me of the measures he pursued, in order to gratify his ambition in
regard to his son’s marriage with Miss Cowley. Let it suffice, that
they were such as did not surprise me. I immediately wrote to Mr.
Flamall. You will find a copy of my letter amongst those papers. He
knows, that I have, by a full and ample confession of my crimes, so
implicated them with those which he has committed, as must ruin
him in this world, if discovered; and as inevitably destroy his hopes
of a better, if he do not repent. Should he ever dare to disturb the
comforts of my son, by a declaration of his real affinity to him;
should he ever dare farther to invade on your peace; he knows what
must be the consequence. Actions, which will be recognisable in a
court of justice, will determine his fate, and crush with ignominy his
worthy and unoffending child. Obdurate as he is in sin, nature is not
extinguished in his bosom. He loves his son, and, I am certain, would
sooner die himself, than see him disgraced in the world: time may
soften to him his present disappointment. I have urged to Philip
every possible measure, in order to effect a reconciliation between
him and his uncle Flamall. He may, if he be wise, live on good terms
with his son, and if he be not lost to conscience, he may find
employment, for his remaining term of grace.” “You weep, my dear
Harriet,” continued my poor Lucretia; I cannot. How many bitter
tears of yours will swell my account; for I was born for your sorrow!
and the ruin of the innocent! Can you give comfort to the broken and
contrite of heart? Can you say you forgive me? “As freely,” answered
I eagerly, “as I hope for mercy and pardon. I have also sinned, I have
also erred.” “Yes,” replied she, with quickness; “but the snare was
laid for you; and you only stumbled. I boldly invited the danger, and
made an acquaintance with guilt and perfidy; see to what purpose?
to languish with a mother’s yearnings, to behold and bless that child,
who would shrink from me as a monster, did he know me; to dread
the future, and to mourn, too late, the wretchedness annexed to a life
of guilt. Promise me,” added she, “to be still my Philip’s mother. Let
me die in the hope, that, you will never forego the title.” “Never,”
answered I, sensible only to her condition, “never, whilst it depends
on me to preserve it; he is mine in affection, and nothing can cancel
his rights to my love.” “May Heaven reward you,” exclaimed she, in
an agony. “May that child’s children bless and revere you——My poor
boy will not be surprised at the tenor of my last will,” continued she
thoughtfully. “He is rich; and I have explained my intentions, in
regard to my brother and Mary. It required very few arguments to
prove, that they had not been justly treated. But let me not think of
their wrongs! I wrote him word, that it was essentially necessary to
my peace to consider them. His last letter was a cordial to my sinking
soul; he urges me even to omit his name, if it interfered with my kind
purposes; that he possessed more than he wanted of the goods of
fortune. Judge, adds he, when I tell you that my brother has
frequently realized fourteen thousand pounds annually from his
estates: Judge whether, my dear, I may say maternal friend and
sister, needs bequeath me more than her blessing and her love.” “I
wear at my heart this precious letter,” added she, taking it from her
bosom; “but you must take it with the papers. His picture may yet
remain, I mean it should moulder into dust with me.”—She paused
—“I think,” pursued she, as though collecting herself, “that I may
hope to stand acquitted before my Maker for the last and only
compensation I can make to some, whom I have injured; perhaps
strict justice would exact more sacrifices. But I am a mother,
Harriet; the guilty mother, of an innocent child, now a worthy
member of society. Something is surely due to him; and thy merciful
Maker will not weigh this consideration in the balance of offended
justice. Such has been my state of mind for some time past, that had
it not been for Philip, I would have fearlessly met every stigma with
which this world could have branded me, for the hopes of meeting
with a reconciled God. It becomes not me to say, that I think, in this
instance of my conduct, I have acted right. But conscience has at
least been my guide; I have done for the best. Will not that prudence,
which will protect the honour of your family, and the happiness of
mine, sanction your secresy in regard to the birth of thy poor——!”
She could not go on. Again I soothed her to composure, I solemnly
repeated my promise, my dear Miss Cowley, that I would preserve
our secret from every danger of a disclosure. “This engagement now
distresses me,” continued Lady Maclairn, “I fear I have been wrong;
but what could I do, in a moment of such difficulty? I was unequal to
the trial; I could not see her die miserable.”—
I placed before Lady Maclairn the wonderful interference of
Providence, which had removed the guilty, to secure the innocent. I
urged to her the purity of her intentions, and the humanity which
pointed out to her the line of conduct she had pursued, and had
engaged to pursue. “Repose on your merciful Maker,” added I, “for
an acquittal, where you mean to do for the best; patiently wait the
end, when this darkness shall be removed; and you will, I trust, find,
that having lived to promote the happiness of others, to have
contributed to the comfort and security of your family has not been
to live in vain. Be assured, my dear friend, that your sufferings will
have their place with a Being “who knoweth what is in man; and with
a Father, who loveth his children, you may reasonably hope for
acceptance and favour.”” “You are my comforter,” replied she,
meekly raising her eyes to Heaven; “I have not outlived this first of
all human hopes. My weakness, not my will, has betrayed me from
the paths of rectitude. But it is difficult for me, to conceal my
feelings. I dare not even break the seal, which confines my
knowledge to what I already know of the wretched life and conduct of
my brother; I sometimes think I shall lose my senses, in reflecting on
his end, and the enormities of his conduct. Oh, it is dreadful, Miss
Cowley, to follow him to that tribunal before which he must appear!
——Leave me for a while,” added she, sobbing, “leave me to my God,
to my Almighty supporter”——I obeyed, too much affected to resist. I
took the papers with me. She has acted prudently in not reading
them. She begs they may be forwarded to you, and that the whole
transaction may remain in your hands. You are allowed to read them.
What will you say to the letter marked No. 4? The one she burned
was the answer to it; but I dare not pursue this horrid subject. My
eyes would betray me, and the doctor would be angry; for he has
made me promise not to harrass my spirits, and to check my friend’s
sorrows. I am going to her! and we will be wise. The return of the
vagrants renders this necessary.

Yours,
Rachel Cowley.

P. S. Sedley will give you this.

 LETTER LXXIV.
From Miss Cowley to Miss Hardcastle.
Again I am permitted to take a better cordial than bark. Mrs.
Heartley has fully explained to us the mystery relative to the portraits
in Miss Flint’s possession. It appears that Mrs. Howard,
apprehending that they would be more pernicious to her brother,
than consolatory, requested Mrs. Heartley to secrete them from his
search. She obeyed her dying friend. “But,” added Mrs. Heartley, “my
feelings at this juncture were nearly as little under the control of my
reason, as poor Percival’s. I wrote a letter to Miss Flint, which was
dictated by my sorrow, and the romantic hope of touching her heart
in favour of a child whom she had contributed to render an orphan
and a beggar. I enclosed these powerful pleaders,” continued Mrs.
Heartley, taking up the miniatures, and surveying them with
emotion, “and my language was not less forcible. Malcolm was
employed to place my packet in her hands. He effected his purpose;
for she found it on her dressing table. The next morning he was
questioned, and he frankly owned, that he had, at my request, placed
the parcel where she had found it. You have been faithful, Sir, in the
performance of your commission, said Miss Flint, trembling and pale
with fury; “be so in delivering my message to your Mrs. Heartley.
Tell her, that her insolent and officious interference has failed, and
that whilst Miss Flint’s family have no better advocates than a kept
mistress, she wants no apology for renouncing it.” Malcolm bluntly
told her, that she must employ some one to deliver such a message
who had never heard of Mrs. Heartley; for himself, he begged leave
to decline insulting his best friend. I heard no more from Miss Flint;
and I concluded that she had destroyed the portraits in a similar
manner as she had that of her mother. Frustrated in my project, I
was forced to conceal this occurrence; and the pictures were
supposed to be irrecoverably and unaccountably lost.”
Although my conscience reproached me frequently when hearing
the captain bewail this loss, it never did so as to the motive from
which I had acted: but it is to be feared, that my zeal in the cause of
the injured, disqualified me for making a convert to justice and
humanity. It is most probable that I irritated where I wished to heal;
and it is certain, that I was from that time the object of Miss Flint’s
implacable resentment. “Poor woman!” continued Mrs. Heartley,
with compassion, “she was then under the miserable yoke of those
passions, which although they govern, cannot blind us. Neither her
spirit of resentment, nor any entrenchment from her prosperous
fortune, could shield her from the voice within her bosom. It spoke
my language with tenfold energy, and she hated me, because she
knew I was in unison with her conscience. She shunned me, as she
would have shunned that, had she been able.” “Is it not
unaccountable,” added Mrs. Heartley, addressing me, “that any
rational being should fear to encounter the eyes of a fellow creature
under the circumstances of guilt, nay, even of folly, without
considering the power of conscience, from whose suggestions this
very dread arises. That Miss Flint was sensible of its power is certain.
Nor do I believe, with some, that it is possible for us to outlive its
authority. When I hear of such, who are said to be hardened by sin,
and become callous by guilt, I no more believe it, than I do those
tales I hear of the elixir for perpetuating our existence here for ever. I
am convinced that God will not be mocked by the creatures of his
power, and I have only to follow the bold and impious offender of his
laws to his hours of privacy, to learn, that he cannot evade that
Being’s presence, whose commands he insults.” I was more disposed
to shorten this conversation, than to dispute the truths it contained.
Lady Maclairn’s conscience wants no stimulants. Douglass entered,
and we became cheerful. You love the doctor, you say, prithee who
does not? but no one shall love him so well as Horace. You have
heard of his gallantry three or four nights he past in my antichamber!

Rachel Cowley.
 LETTER LXXV.
From Miss Cowley to Miss Hardcastle.
I am, my dear friend, so powerfully impressed by the perusal of
Miss Flint’s confession, as her legacy to Lady Maclairn may with
truth be called, that I cannot divert my mind from the subject. What
a scene of iniquity have I sent you! and how rejoiced am I, that I
prevailed on Lady Maclairn not to tear open those wounds afresh by
reading a detailed account of actions and artifices which her brother
employed to defraud Mr. Flint’s children of their rights. Surely, my
Lucy, the death of Flamall was “a consummation devoutly to be
wished.” To be removed from the indignation of the injured, to be
spared from the abhorrence of the virtuous; to be saved from the
constant dread of living an object amenable to the most vigorous
laws of his country; to be freed from the horrors of his dying bed! But
how momentary is this delusion of feeling! My reason and my faith
point out this disembodied spirit in its next state of existence. With
trembling awe I follow it to the tribunal of an all-wise, omnipotent,
and pure Judge. There do I contemplate this forlorn and sullied soul,
as rushing uncalled into the presence of that Being, whose merciful
purposes he has counteracted; and whose laws he has insulted.
Nature stands appalled, at the magnitude of offences like these; and
humanity must deplore the sinner thus cut off in the midst of his
sins.
I cannot however help being of opinion that, useful as the
contemplation of a Flamall’s life may be to beings who fearlessly
follow the impulse of every disorderly passion, we, my beloved Lucy,
shall not be unwise, to direct our thoughts from such shocking
depravity of creatures like ourselves. I wish so to do; and yet not lose
the lesson of wisdom as applicable to myself. In what, I would ask
you, consisted the difference between Miss Flint and Rachel Cowley
at two years of age. The general lineaments of our minds have a near
affinity. What has produced the moral differences which from that
period have discriminated us? Education, and the habits resulting
from our respective situations: in the one instance, the soil was left
uncultured; in the other, it was judiciously cultivated. Lucretia had
been overlooked by her mother in the early period of her life.
Indolence and indulgence were this mother’s faults. She found, in
cultivating the docile and mild Percival, a gratification of her own
taste, and an object of amusement, as well as for exclusive
tenderness. This mother wanted firmness, and the vigilance
necessary for her duty. When passion had taken its root, this
unhappy creature was consigned over to the care and tuition of a
schoolmistress. I mean not to be illiberal; for I believe many women
in that class of life are not only accomplished women, but
conscientiously disposed to be useful to their pupils; but I cannot
think that in a large school, either the temper, or peculiar moral
defects of a girl are likely to meet with that nice and accurate
observation which are necessary for their correction. I will however
admit that in this seminary Miss Flint acquired the outward habits of
decorum, and that knowledge, which, with experience, and a
different temper, might have conducted her, as it does multitudes of
our sex, in the common routine of private and domestic life. She then
returned to her parents, slenderly furnished by the gifts of nature,
with a spirit unsubdued, and a mind without any fixed principle of
action, beyond a confidence in herself. She was next a candidate for
favour in the world; and she proudly conceived that no one would
dare refuse it; but she found a rival, even in the cradle, and under the
parental roof. Is it to be expected, that from such a disposition, and
under such circumstances, envy and malice could be long a stranger
to her? The mother perceived their baneful influence; and she
opposed to their growth, nothing but remedies which relieved herself
from trouble and vexation. She flattered instead of reproving, and
gave to her daughter an authority which she knew she would abuse.
Uncontrouled and domineering over those about her; irritated by the
neglect of those whom she could not subjugate to her imperious will,
she became soured, disappointed, and vindictive; and she finished by
becoming the fit instrument in the hands of a Flamall, for the ruin of
the innocent, and the perpetration of injustice, cruelty, and deceit.
Thus have we seen the fatal torrent of unchecked passions flow!
but suppose this wretched victim of their fury had been in Mrs.
Hardcastle’s hands. Oh Lucy, we want no supposition! We have seen
a torrent, not less impetuous, directed by her wisdom, to the salutary
purposes for which Heaven gave it strength and abundance; and
instead of desolating all within its reach, it has been led to supply
delight, and satisfaction! How often has her patient firmness
subdued my angry passions? How often has she detected them
before I knew their power! With what skill did she temper and mix
the warm affections of my nature with the rougher elements which
composed me. How sweet, how endearing was her notice of every
little triumph I gained over myself; and with what discrimination did
she effect that bond of love, which made her children useful to each
other. Her Lucy’s gentleness was opposed to her Rachel’s courage;
and Horace’s self-command was the only point to which emulation
was recommended. Is it wonderful, that I have escaped the fate of a
Miss Flint? Is it wonderful that I should love virtue, and reverence a
faith thus exemplified? No, Lucy. But I have to fear, lest I should
disgrace Mrs. Hardcastle. We may, and I hope we shall, live to be
wives and mothers. Let us in that case, aim at being something better
than mere teeming animals; and like some in that class, who,
following their instinct, squeeze their offspring to death through
fondness. I am persuaded that we are weak and fallible creatures; but
I cannot for an instant admit, that an all-wise and merciful Being has
exacted any one duty, or enforced any one command, without having
bestowed upon us the faculties and capacity for fulfilling our
obligations. Every mother whose mind is sound, is called upon to
perform the duties of a mother; and without any better guide than
her own reason and attention, she will soon perceive that something
more is required, than merely watching over the preservation of her
children. I am, and I wish to remain, a stranger to that humility
which represses, as beyond me, all that is arduous and praise-
worthy. I believe, that by applying my heart to wisdom, I may
become wise; and the mother who diligently watches over the first
openings of moral existence in the beings entrusted to her, will soon
discover, that she has the necessary talents for governing them
safely. Attention and experience will enlighten her; and should she
never reach to the accomplishment of all she wishes, she will at least
secure to herself the favour of God, and her own peace of mind. It
pleases me, my Lucy, to look forward to that period, when, with the
name of Hardcastle, I may be treading in the same path of duty
which our mother pursued in her road to Heaven. Will you wish me
to suppress my hopes, that I may one day be able, with the pure joy
of an accepted spirit in her abode of bliss, to point to her those
inmates, whom her virtues trained for happiness? Yet why this tear?
I cannot erase the blot it has made. Wherefore is it that my spirit
faints? You must come and chide me; you will find me paler and