Magnetic resonance imaging protocols for paediatric neuroradiology

Increasingly, radiologists are encouraged to have protocols for all imaging studies and to include imaging guidelines in care pathways set up by the referring clinicians. This is particularly advantageous in MRI where magnet time is limited and a radiologist’s review of each patient’s images often results in additional sequences and longer scanning times without the advantage of improvement in diagnostic ability. The difficulties of imaging small children and the challenges presented to the radiologist as the brain develops are discussed. We present our protocols for imaging the brain and spine of children based on 20 years experience of paediatric neurological MRI. The protocols are adapted to suit children under the age of 2 years, small body parts and paediatric clinical scenarios.
Introduction
The use of imaging protocols allows the standardization of procedures and workflow as well as consistency of image quality. With appropriate training, radiographers can select and implement imaging protocols with relatively little requirement for radiological involvement. This use of skill mix provides radiographers with an expanded role and greater responsibility that increases job satisfaction and staff retention.
Imaging protocols can also provide guidance for radiologists and radiographers for patients in shared care between secondary and tertiary care institutions. The use of protocols set up by the referring centre will prevent repeat MR scanning with the additional burden on MR scanner time. These advantages are offset by the minor disadvantage that radiologists’ personal preferences and the intricacies of individual scanners are not taken into consideration.
At Great Ormond Street Hospital (GOSH), MRI protocols have been implemented for nearly 20 years and have been modified as scanners are replaced and new sequences developed. Our success is measured by the minimal number of patients recalled (less than 1%). Increasingly, we are asked about our MR protocols by departments throughout the United Kingdom and have set them out here to make them freely available to those who may find them beneficial to patient care. The protocols provided are confined to conventional imaging techniques and diffusion-weighted imaging (DWI), and do not include the advanced imaging techniques of perfusion imaging, diffusion tensor imaging and MR spectroscopy that remain largely within the research domain.
Practical issues of MRI in children
One of the biggest challenges of paediatric neuroimaging is the acquisition of high-quality diagnostic images, as it requires the infant or child to keep still for a long period of time (sometimes nearly 1 h). Children over the age of 7 years are scanned, where possible, without sedation and with recourse to play specialists and videos. Neonates under 2 months old (corrected age, if premature) are scanned during natural sleep induced by food, comfort and warmth (feed and wrap), often best after a period of sleep deprivation. If this fails then light oral sedation, e.g. chloral hydrate, may be used. The majority of our patients (approximately 70%) require sedation or a general anaesthetic. When sedation is required, it is usually heavy and heavier than that required for CT or nuclear medicine studies. Sedation is applied by specially trained nurses who are trained to decide when and how much to administer and monitor its effects, and who are skilled in the recovery of the child [1]. Details can be found in a review of the management of painless imaging in children [2].
All MR sequences may disturb the sleeping infant or child and ear protection such as earplugs and baby earmuffs should be used. Some motion can be avoided by swaddling infants, keeping them warm, and by placing moulded foam or airbags around the baby’s or child’s head. Cardiorespiratory monitoring with MR-compatible equipment is essential in all infants, whether sedated or not, and all sedated or anaesthetized children [2].
Commercial MR machines are designed for adult practice and few manufacturers make provision for the issues encountered in paediatric practice. Currently, most children are imaged in units that have a wider adult practice with only a handful of institutions throughout the world having dedicated paediatric MR facilities. The structures we need to examine in children are generally small and we aim for a maximum slice thickness of 5 mm in the brain and 3 mm in the spine. The slice thickness is reduced to 3 mm when acquiring images of the pituitary gland and orbits.
We do not recommend ultrafast ‘breath-hold’-type T2-weighted (T2-W) sequences that have reduced contrast to noise as an alternative to sedating a child, as achieving high contrast to noise is of utmost importance given the small size of the paediatric head. Advances in coil design have improved signal-to-noise and we now use multichannel head and spine coils.
Practical consideration of the changing brain with age
Changes in normal values of measured parameters in very young children occur as the brain undergoes very rapid development during the first 2–3 years of life. This necessitates the creative modification of pulse sequence parameters in order to optimize the soft-tissue contrast between anatomical and pathological structures. The two most important physiological changes to take place within the first 2–3 years are reduction in the total brain water content and T1 and T2 shortening largely as a consequence of the maturation of myelin [3].
From birth to 6 months of age the maturation of myelin is best assessed using T1-weighted (T1-W) images. From 6 months until the completion of myelination at around 2 years of age, T2-W images are more useful. During the process of myelination on T1-W images the signal from white matter goes from dark to bright. For a variable period the subcortical white matter becomes isointense with grey matter. This loss of grey/white matter differentiation obscures structural detail and makes identification of subtle abnormalities such as polymicrogyria difficult to detect within the first 6 months of life. The white matter shows maturity later, between 6 months and 2 years, on T2-W images and at this stage T1-W images are essential to evaluate structural abnormalities [4].
To overcome the difficulty of increased brain water in those under 2 years of age, we use a dual-echo short-tau inversion recovery (STIR) sequence that has improved contrast resolution in this age group (Fig. 1) [5]. Typical values for a dual-echo STIR sequence are TE 30/128 ms, TR 5,400 ms and TI 130 ms. We prefer this sequence to the more conventional T2-W fast (or turbo) spin-echo sequences, for reasons of increased lesion conspicuity. However, we recognize that similar tissue contrast may be achieved if such fast spin-echo sequences are modified using increased TR and TE to compensate for the increased water content in this age group. The additional brain water is difficult to suppress and we do not find the fluid-attenuated inversion recovery (FLAIR) technique useful in this age group as lesion conspicuity is poor.
Fig. 1Axial images acquired through the bodies of the lateral ventricles of a 6-month-old child. First (a) and second (b) echo (TE 30/120 ms, TR 5,500 ms, TI 130 ms) of a dual-echo short-tau sequence shows the increased contrast between grey and white matter on the second echo compared to (c) the T2-W (TE 90 ms, TR 3,500 ms) sequence that would be used in those over 2 years of age. The slice thickness (5 mm) and matrix size (512 × 192) were the same for both sequences
Diffusion measurements in the brain of newborns and infants show that there is more movement of water (high apparent diffusion coefficient, ADC) with less directionality (low anisotropy) within the immature and unmyelinated brain than in the mature and myelinated adult brain [6, 7]. The most dramatic decrease in ADC values occurs within the first few months of life and the greatest changes are seen in the frontal and parietal white matter [8]. Failure to appreciate the normal changes with age of the ADC will result in the erroneous reporting of white matter abnormality particularly in the neonatal period.
Factors influencing sequence choice
For any imaging protocol, it is the specific combination of sequences that determines the diagnostic efficacy of the examination. It is clear that imaging protocols vary between institutions. This is largely because rapid advances in imaging technology and variations between manufacturers, applied in the context of investigating relatively rare disorders, precludes an effective evidence-based approach to sequence choice.
The main advantages that MRI offers over alternative imaging modalities is the ability to demonstrate different tissue contrasts (principally T1-W, T2-W and spin density, but also flow and diffusion) in multiple imaging planes (principally sagittal, coronal and axial). The disadvantage of MRI is the artefacts that it generates in almost every image.
The choice of sequence combination should reflect the multicontrast and multiplanar capabilities of MRI. We have found that applying the generic principle of combining T2-W images in two planes, supported by T1-W imaging in two planes, as the basis of our imaging protocols, serves to optimize the benefits of MRI whilst minimizing the impact of artefacts.
Standard MRI studies
Brain
Our standard brain sequence (>2 years of age) is composed of an axial T2-W, coronal FLAIR, and coronal and sagittal T1-W images. Sagittal T1-W images allow the assessment of the midline structures, particularly the corpus callosum and cerebellum, which are frequently abnormal in congenital abnormalities. Coronal T1-W images are valuable in the diagnosis of abnormalities of the anterior visual pathway, schizencephaly and holoprosencephaly. Axial T2-W and coronal FLAIR images provide T2-W images in two different planes and have been shown to be complementary in children [9]. DWI is acquired in all children unless artefacts from, for example, dental braces or a ventriculoperitoneal shunt, preclude it, and an ADC is calculated using automated computer software and provided for reporting.
In those under 2 years of age, the T2-W sequence is replaced by a dual-echo axial STIR sequence (see above). In some cases, a T2*-W gradient-echo (GE) sequence (“susceptibility-weighted” sequence), sensitive to changes in local field inhomogeneity caused by the breakdown products of haemoglobin, is added. The sequence is particularly useful in trauma and vascular malformations such as multiple cavernomas.
Spine
MRI is the modality of choice for imaging the intraspinal components of the paediatric spine. Prior to ossification of the posterior elements of the spinal column, US has been shown to be a valuable screening tool; however, infants with an abnormal sonogram or who have a neurological abnormality in the context of a normal sonogram, still require MR imaging [10].
Our standard spine imaging includes sagittal, fast spin-echo T1- and T2-W sequences (3-mm-thick slices). Both axial T1-W and T2-W images are acquired through any abnormality. Unlike most adult spine imaging protocols, groups of axial images through disc levels are not applied because degenerative disc disease is rare. Children with scoliosis and/or suspected spinal dysraphism routinely have axial T1-W images through the conus and filum terminale to detect lipomas of the filum terminale that may not be visible on sagittal imaging.
Contrast medium
The use of contrast medium is a personal choice and in the majority of units is requested on a case-by-case basis. At GOSH the radiographers or sedation nurses administer MR contrast medium according to guidelines set up by the neuroradiologists (Table 1). In the event of an unexpected finding the radiographers are encouraged to make a decision on contrast administration without discussion with a radiologist.
Table 1Indications for contrast medium administrationVarious indicationsAcute inflammation Acute disseminated encephalomyelitis (ADEM) Optic neuritisAcute infection Abscess Cerebritis Discitis Empyema Encephalitis Meningitis Transverse myelitisNeurocutaneous disorders Congenital melanocytic naevus Neurofibromatosis type IITumours Benign and malignant Intracranial IntraspinalWhite matter disordersaVascular anomalies Cavernomas Developmental venous anomaliesVascular disorders Intraparenchymal haemorrhage Sturge-Weber syndrome VasculitisaAt presentation and at follow-up if necessary
MRI protocols for specific areas
The strategies applied to the brain are also applied to small parts such as the orbits and pituitary gland. The orbit is scanned using a STIR sequence to benefit from the fat saturation properties of the sequence and improve the conspicuity of lesions within the orbit. The slice thickness is reduced to 3 mm and, to increase the signal-to-noise, the matrix size is reduced, thereby slightly reducing the in-plane resolution.
A heavily T2-W 3-D volume sequence of the petrous temporal bones is used to image the membranous labyrinth and is reconstructed in the coronal plane of the petrous temporal bone, and the axial and sagittal plane of the internal auditory meati (IAM). The sagittal plane is used to view the vestibulocochlear nerve in cross section. A constructive interference steady state sequence (CISS), available on Siemens scanners, is acquired and reconstructed at a slice thickness of 0.7 mm. The GE equivalent is the FIESTA sequence and the Philips equivalent is DRIVE.
MRI protocols for specific neurological or neurosurgical presentations
The majority of children undergoing an MRI brain scan will have epilepsy, stroke or a brain tumour and are often referred to specialists with an interest in these areas.
Tumours of the brain and spine
Brain
Imaging of brain tumours is performed using our MRI brain with contrast enhancement protocol. We add contrast-enhanced T1-W imaging of the spine to establish the presence of any distant metastases in accordance with the United Kingdom Children’s Cancer Study Group (UKCCSG) guidelines for the imaging of brain tumours [11]. One of the commonest reasons for repeat scanning of a child with a brain tumour is the acquisition of contrast-enhanced imaging of the spine in a child who has had only a brain scan at the referring centre.
The purpose of preoperative imaging of brain tumours is to assess tumour location and type, establish whether there are single or multiple lesions, define its relationship with vital structures and look for any complications such as hydrocephalus. Contrast-enhanced T1-W volumetric acquisitions are also acquired for image-guided surgery.
Imaging of the spine is performed in all children with intracranial tumours (not only posterior fossa tumours) and although this requires a change of coil and an additional sequence, we find it beneficial as tumour histology is often not certain at the time of the initial imaging. Some tumours unexpectedly metastasize to the spine and assessment of the postoperative spine is made more difficult in the presence of blood products.
Postoperative MRI is acquired using our MRI brain with contrast enhancement protocol to assess the degree of tumour clearance. We aim to do this within 72 h of surgery to reduce enhancement due to postoperative changes that can complicate the assessment of tumour clearance, in accordance with guidelines proposed by the UKCCSG [11]. If preoperative spinal imaging has not been acquired, the spine is imaged with both unenhanced and contrast-enhanced T1-W imaging to enable differentiation between haematoma and tumour metastases.
Surveillance imaging (SI) during adjuvant treatment and follow-up is a major part of the management of childhood tumours and scanning frequency has important implications to anaesthetic and radiology service provision. In children with ependymoma and medulloblastoma, studies at GOSH have shown that SI reveals a substantial number of asymptomatic recurrences and survival appears to be improved in these patients compared with those patients in whom the recurrence is identified by symptoms [12, 13]. Benefits of SI following incomplete resection of posterior fossa low-grade pilocytic astrocytoma have also been shown [14, 15]. SI schedules have been written based on this work (Table 2).
Table 2Proposed protocols for surveillance imaging in children with ependymoma, medulloblastoma and pilocytic astrocytomaTumourTiming of postoperative imagingFrequency of studyMacroscopically complete excisionIncomplete excisionCranial studySpinal studyCranial studySpinal studyEpendymoma24–48 hFirstNoneFirstNone1st year3–6 months6 months3 months3–6 months2nd–5th years6 months6–12 months6 months6–12 monthsMedulloblastomaa24–48 hFirstNoneFirstNone1st year3–4 months3–4 months3–4 months3–4 months2nd–6th year6–8 months6–8 months6–8 months6–8 monthsCerebellar low-grade astrocytomab24–48 hFirstNoneFirstNone1st year6 monthsNone6 monthsNone2nd yearAt 24 monthsNone6 monthsNone3rd yearAt 3.5 yearsNone6 monthsNone4–5th yearAt 5 yearsNone1 yearNone6th year onwardsNoneNone2 yearsNoneaAll imaging studies in children with medulloblastoma should include the entire neuroaxis.bThe surveillance imaging protocol following complete resection should be applied to children who have radiotherapy with the postoperative scan omitted
Spine
Imaging of spinal tumours is performed using our MRI spine with contrast enhancement protocol (Table 3) with dedicated axial imaging through the tumour. We add a standard brain scan with contrast enhancement to the initial or immediate postoperative scan to stage the tumour. If the brain scan is normal, further brain imaging is not acquired as part of SI and acquired only when clinically indicated (Table 4).
Table 3Protocols for specific areasSpecific areasProtocolsOrbits (3-mm slices) Coronal and axial dual-echo STIR Coronal and axial T1-W spin-echoOrbits with contrast enhancement (3-mm slices) Coronal dual-echo STIR Coronal and axial T1-W spin-echo Contrast-enhanced coronal and axial T1-W images with fat saturationPituitary (3-mm slices) Sagittal and coronal T1-W spin-echo Coronal T2-W spin-echoPituitary with contrast enhancement (3-mm slices) Pituitary protocol Contrast-enhanced coronal and sagittal T1-W spin-echoInternal auditory meati 3-D volume axial CISS Brain MRIFace and neck MRI Coronal and axial dual-echo STIR Coronal and axial T1-W spin-echo Fat-saturated contrast-enhanced coronal and axial T1-W spin-echoMidline facial lesions Axial dual-echo STIR from floor of anterior cranial fossa to hard palate Sagittal T1-W and T2-W spin-echo (3-mm slices) Coronal T1-W spin-echo from nose to brainstemTable 4Standard MRI brain and spine protocolsTypes of brain and spine MRIProtocolsMRI brain (under 2 years old) Axial and coronal dual echo STIR Coronal and sagittal T1-W spin-echo DWI in three planes and calculated ADC map Axial “susceptibility-weighted” GE sequenceaMRI brain (over 2 years old) Axial T2-W fast spin-echo Coronal FLAIR Coronal and sagittal T1-W spin-echo DWI in three planes and calculated ADC map Axial “susceptibility-weighted” GE sequenceaMRI brain with contrast enhancement (under 2 years old) Axial and coronal dual-echo STIR Coronal T1-W spin-echo DWI in three planes and calculated ADC map Contrast-enhanced axial, coronal and sagittal T1-W spin-echo with magnetization transfer Axial “susceptibility-weighted” GE sequenceaMRI brain with contrast enhancement (over 2 years old) Axial T2-W fast spin-echo Coronal FLAIR Coronal T1-W spin-echo DWI in three planes and calculated ADC map Contrast-enhanced axial, coronal and sagittal T1-W spin-echo with magnetization transfer Axial “susceptibility-weighted” GE sequenceaMRI spine Sagittal T1-W and T2-W fast spin-echo Axial T1-W and T2-W fast spin-echo through target area and conus (Coronal T1-W spin-echo for scoliosis, if patient compliant)MRI spine with contrast enhancement Sagittal T1-W and T2-W fast spin-echo Contrast-enhanced sagittal T1-W fast spin-echo Axial T1-W spin-echo through target areaaOptional sequence
Epilepsy
UK guidelines for the imaging of epilepsy include children who have either multiple or focal seizures (NICE guidelines) [16]. In children with epilepsy we are aiming to detect focal cortical abnormalities; the majority are extratemporal and in a smaller proportion they are mesial temporal in origin. The majority of cortical abnormalities are easily diagnosed using conventional brain imaging and our standard brain protocol is used to investigate these children. The acquisition of a coronal T2-W sequence (either STIR, T2-W or FLAIR) allows the visualization of the mesial temporal lobe, and is a sequence often not acquired in referring centres.
There are a group of children with intractable epilepsy, i.e. seizures not controlled by three drugs, who are considered for epilepsy surgery. In this subset of children a more rigorous epilepsy protocol is carried out that includes a 3-D volume T1-W acquisition and hippocampal T2 relaxometry (Table 5). To identify mesial temporal abnormalities the coronal studies are planned on a parasagittal scout image to lie perpendicular to the hippocampi. The 3-D, T1-W gradient-echo dataset is acquired isometrically in the sagittal plane (this saves time) and reconstructed in all three planes with the axial and coronal images tilted to follow the plane of the hippocampus. More recently a 3-D FLAIR sequence reconstructed along the same lines has been added. A sequence is acquired that measures the true T2 values of the hippocampi (T2 relaxometry), which is only of value in suspected mesial temporal sclerosis (MTS). It has been shown that T2 values are more sensitive to the presence of MTS than visual inspection and T2 relaxometry is of particular value in bilateral disease [17]. Normal values will vary between scanners, so normative data should be acquired. The radiographers carry out the postprocessing of the 3-D dataset and the T2 relaxometry.
Table 5Protocols for particular clinical indicationsTypes of clinical indicationProtocolsBrain tumours MRI brain with contrast enhancement Contrast-enhanced sagittal T1-W images of whole spine Contrast-enhanced image-guided images when requiredStrokeAcute Axial T2-W fast spin-echoa Coronal FLAIRb Sagittal T1-W spin-echoDWI in three planes and calculated ADC mapIntracerebral 3-D TOF MRAAxial dual-echo STIR and T1-W spin-echo through the neckExtracerebral 2-D TOF MRA of the neck down to the aortic rootNon-acuteAcute stroke protocol without imaging of the neckEpilepsy Axial T2-W fast spin-echoa 3-D T1-W volume acquisition reconstructed in three planes Coronal T2-W fast spin-echob Coronal FLAIR (or 3-D FLAIR if available) Hippocampal T2-relaxometry (see text)Intraparenchymal haemorrhage MRI brain with contrast enhancement Intracerebral 3-D TOF MRA MRVNon-accidental head injury Standard MRI brain Axial GE “susceptibility-weighted” sequence Sagittal T2-W spin-echo and GE “susceptibility-weighted” sequence of the cervical spineMPRAGE magnetization prepared rapid acquisition gradient echo, MRV magnetic resonance venographyaReplaced by dual echo STIR sequence in the under 2 age groupbReplaced by a dual echo STIR coronal in the under 2 year age group.
Non-traumatic intraparenchymal haemorrhage
The aim of imaging children with intraparenchymal haemorrhage (IPH) is to detect the underlying cause and we advocate the use of CT angiography as a matter of urgency in those children who have a depressed level of consciousness or whose clinical condition is deteriorating. MRI is used to investigate clinically stable children, and we perform brain MRI with contrast enhancement and a 3-D, time-of-flight (TOF) intracranial MR angiography (MRA). In our experience nearly two-thirds of children presenting with nontraumatic IPH have an underlying cause diagnosed by MRI and MRA, with aetiologies including tumour, arteriovenous malformation (AVM), venous sinus thrombosis and cavernous angioma [18]. An attempt is made to perform MRI within 72 h of the ictus to overcome the problem of the visibility of blood products (T1 shortening due to methaemoglobin) on 3-D TOF sequences that may obscure the underlying pathology. The value of intravenous contrast agents in identifying underlying vascular causes has not been proven. We have a largely anecdotal view that it is helpful in identifying small AVMs and venous anomalies.
Stroke
The aims of conventional MRI are not only to detect the infarct, but also to provide information to establish the cause of the stroke and to exclude other causes (such as tumour or infection). The majority of children with stroke have a combination of risk factors including sickle cell disease, congenital heart disease, anaemia, prothrombotic disorders and infections such as varicella-zoster [19]. The rationale for the inclusion of intracranial MRA in all children with stroke is that cerebral arteriopathy is found in up to 80% of these children and most commonly affects focal areas of large intracranial arteries [19]. Specific entities such as moyamoya disease may also be diagnosed. The commonest abnormality identified is occlusion or stenosis, of unknown aetiology, affecting the terminal internal carotid artery (ICA) or proximal middle cerebral artery (MCA).
Extracranial MRA and, either a dual-echo STIR or fat-saturated axial T1-W imaging, through the neck can detect arterial dissection, particularly in children with posterior circulation infarcts [20]. The inversion time of the STIR sequence is selected to suppress the fat within the neck. The fat saturation provided by both these sequences improves the conspicuity of the haematoma within the extracranial vessel wall.
A 3-D TOF MRA sequence is used for the imaging of the intracranial vessels and a 2-D TOF MRA sequence for the extracranial vessels. The TOF scan times are shorter than phase-contrast (PC) MRA and there is lack of dependence on the choice of correct velocity encoding with obvious advantages when scanning ill children. Intracranial 3-D TOF MRA is also included in the investigation of children with IPH, although its sensitivity to T1 shortening may obscure the underlying abnormality (see above).
As CT is often the first-line investigation in children with stroke, the potential of DWI to detect hyperacute cerebral infarction prior to changes on T2-W MRI is not realized. However, inpatients (e.g. cardiac patients, patients with recent-onset stroke) can be imaged early, and in these children DWI can be used to detect infarcts of different ages.
Non-accidental head injury
Although CT is the primary imaging tool in the evaluation of nonaccidental head injury (NAHI), we perform MRI in children with an abnormal CT or neurological symptoms and signs on day 3–4 in accordance with the protocol proposed by Jaspan et al. [21]. The rationale for performing MRI is that it is more sensitive than CT to both hypoxic–ischaemic injury, particularly when DWI is used, and subdural haematomas adjacent to the calvarium or in the posterior fossa. MRI is repeated at 2–3 months in those children with parenchymal brain injury or a persistent neurological abnormality.
Children with suspected NAHI are imaged using our standard brain protocol. In addition axial GE (susceptibility-weighted) sequences are acquired, as they are more sensitive to blood products than standard sequences. Sagittal T2-W and GE images are acquired of the cervical cord, including the brainstem, particularly to identify shear injuries within the brainstem that have been proposed as a mechanism of hypoxic–ischaemic injury in children who have been shaken as the mechanism of injury [22, 23]. The aim of the sagittal T2-W sequence of the cervical cord is to look for any evidence of trauma as a result of violent shaking in an attempt to establish the true, albeit rare, incidence of pathology in the upper cervical spine [21].
Neonatal imaging
Conventional imaging can detect patterns of regional brain injury in the neonatal period that can help time the injury, determine underlying mechanisms and ultimately provide some prognostic information. MRI is useful in detecting hypoxic–ischaemic injury, and germinal matrix and intraventricular haemorrhage, and can be useful to distinguish other pathologies that may mimic hypoxic–ischaemic encephalopathy in the neonatal period such as venous infarction, metabolic disease, infection, and congenital developmental abnormalities.
Our neonatal imaging protocol is the same as the under-2-year brain protocol. Achieving high signal-to-noise is of utmost importance given the small size of the infant head and is improved by decreasing the slice thickness to 4 mm whilst decreasing the matrix size from 512 × 512 to 256 × 256 in a field-of-view of 180 mm. Although specific neonatal head coils have been developed, most nonpaediatric centres are unlikely to have access to them and improved results can be obtained by using an adult knee coil.
Developmental delay
Developmental delay, without other clinical features such as epilepsy or dysmorphic features, is not considered an indication for an MRI scan at our institution. This decision was made in conjunction with our neurologists as it was recognized that there is an extremely low yield of clinically relevant abnormalities seen in patients with developmental delay alone.
The future
The future of paediatric neuroimaging lies in the incorporation of research techniques, such as perfusion imaging and diffusion tensor imaging, into standard imaging protocols once they have been demonstrated to be of value within the clinical arena. The use of higher field strength magnets will have the advantage of increasing signal-to-noise and reducing scanning time, which will be of benefit to the child who is both small and liable to move.


Vascular complications of prosthetic inter-vertebral discs

Five consecutive cases of prosthetic inter-vertebral disc displacement with severe vascular complications on revisional surgery are described. The objective of this case report is to warn spinal surgeons that major vascular complications are likely with anterior displacement of inter-vertebral discs. We have not been able to find a previous report on vascular complications associated with anterior displacement of prosthetic inter-vertebral discs. In all five patients the prosthetic disc had eroded into the bifurcation of the inferior vena cava and the left common iliac vein. In three cases the aortic bifurcation was also involved. The fibrosis was so severe that dissecting out the arteries and veins to provide access to the relevant disc proved impossible. Formal division of the left common iliac vein and artery with subsequent repair was our solution. Anterior inter-vertebral disc displacement was associated with severe vascular injury. Preventing anterior disc displacement is essential in disc design. In the event of anterior displacement, disc removal should be planned with a Vascular Surgeon.
Key points
Anterior prosthetic disc displacement frequently involves major arteries and veins.
Removal of an L45 disc prosthesis is associated with vascular injury.
A Vascular Surgeon should be involved in disc removal.
Introduction
Replacement of the inter-vertebral disc is designed to relieve symptomatic back pain secondary to disc degeneration by preserving segmental function. A successful artificial disc replacement would avoid the significant long-term problems associated with spinal fusion [9]. We report five consecutive cases of anterior displacement of prosthetic inter-vertebral discs resulting in erosion into the bifurcation of the vena cava and aorta, from a series of only 13 patients. One patient suffered recurrent back pain. These patients had no preoperative vascular symptoms to warn of this vascular involvement and all of these discs were removed in order to prevent further vascular injury. The complications associated with removal are described together with our suggestions on an approach to this challenging surgical problem.
Prosthetic disc replacements (AcroFlex disc, DePuy Acromed, Raynham, MA, USA) were carried out as part of a clinical trial with ethical approval, regulatory approval and with informed patient consent. All patients had incapacitating back pain. Leg pain was not an exclusion criteria unless directly attributable to a prolapsed inter-vertebral disc. All patients in this study had magnetic resonance imaging evidence of degenerative disc disease. All patients had an Oswestry disability index (ODI) greater than 30% and all had discographically established concordant pain at the target level/s. Inclusion criteria, the follow-up protocol and disc design for this study have been described previously [5].
Case 1
A 33-year-old woman presented with a 5-year history of low back and right leg pain. A two level artificial inter-vertebral disc replacement was performed at L45 and L5S1 without complication through an anterior transperitoneal approach (L45 31.5 × 43 × 9 × 5° AcroFlex disc and L5S1 34 × 46 × 9 × 10° AcroFlex disc) (Fig. 1a–c).
Fig. 1Postoperative X-ray with satisfactory placement of L45 and L5S1 AcroFlex disc, lateral view (a) AP view (b and c) with anterior disc displacement at 6 months (d)
The patient made an uneventful recovery with improved symptoms at 6 weeks. However on X-ray the prosthesis at L45 had moved 5 mm anteriorly. At 6 months there was further L45 prosthesis displacement; however, mobility was preserved with full lumber flexion and extension at video fluoroscopy (Fig. 1d).
The L45 artificial disc was replaced at 15 months with a size 2 SB Charité III disc containing an 8.5-mm spacer (Waldemar Link GmbH & Co., Hamburg, Germany). At surgery the disc had stretched and eroded into the left common iliac vein. The distal vein was occluded with thrombus. An injury to the medial wall of the left common iliac artery was repaired with 5/0 Prolene and the occluded vein was oversewn with 4/0 Prolene. This provided access and permitted removal of the disc. Postoperative recovery was complicated by a paralytic ileus only. The patient has an L5S1 prosthesis which remains in an acceptable position. She has subsequently become pregnant and had a normal delivery without the need for Caesarian section.
Case 2
A 40-year-old woman presented with a 3-year history of lumber back pain. She underwent L45 disc replacement with a 29 × 40 × 9 × 10° AcroFlex disc. This surgery was complicated only by a temporary loss of bladder filling sensation. At 6 week follow-up her back and leg symptoms were significantly improved. Unfortunately at 6 months her back pain had returned and she was now suffering pain and tingling in the left L5 dermatome. On X-ray the prosthesis had moved anteriorly. At 1 year the patient agreed to have the prosthesis removed. At operation the prosthesis was eroding into the left common iliac artery and vein. Both vessels were mobilised with difficulty due to dense scar tissue, the inevitable venous and arterial injuries were repaired with 4/0 Prolene. The disc was replaced with a Stabilis cage (Stryker, UK) containing artificial bone graft which was secured with a 3.2 × 34 mm screw and washer. Postoperatively the patient wore class II compression hosiery and was prescribed 40 mg Clexane twice daily. Unfortunately, despite this prophylaxis, she suffered left common iliac artery and iliofemoral deep vein thrombosis. Full anticoagulation was achieved with Tinzaparin and subsequently Warfarin. Swelling is controlled by class II compression hosiery. Transluminal angioplasty has been performed for a stenosis of the left common iliac artery at the site of repair. Her claudication has improved and is now thought to be venous.
Case 3
A 51-year-old man presented with bilateral leg pain and no motor or sensory loss. He had undergone laminectomy 12 years previously for a disc prolapse. A prosthetic inter-vertebral disc (29 × 40 × 9 × 10° AcroFlex disc) was placed in the L45 inter-vertebral space, without complication, using an anterior transperitoneal approach. The postoperative X-ray showed the prosthesis to be in an acceptable position, i.e. centrally placed in the disc space on antero-posterior projection and posteriorly placed on the lateral view (Fig. 2a, b). The patient’s symptoms were improved but the prosthesis had migrated 2 mm anteriorly at 6 weeks and 5 mm by 12 months (Fig. 2c).
Fig. 2Satisfactory placement of L45 AcroFlex disc, lateral view (a) and AP view (b) with anterior displacement at 12 months (c) and subsequent spinal stabilisation with plate and pedicle screws (d)
At operation the disc had migrated into the left common iliac vein posterior to the aortic bifurcation. A tear was made in the left iliac vein while mobilising these vessels. The left common iliac vein was divided transversely to facilitate removal of the disc. A 14-mm carbon fibre cage filled with iliac crest bone graft was inserted and the iliac vein re-anastomosed with 4/0 Prolene. Postoperative duplex scanning showed the left common iliac vein and artery to be patent. The spine was stabilised with a flat plate and pedicle screws 12 days later (Fig. 2d).
Case 4
A 47-year-old man presented with lumbar back pain radiating to his thigh and buttock. He underwent L45 and L5S1 disc replacement with a 31.5 × 43 × 11° AcroFlex disc and a 31.5 × 43 × 9° AcroFlex disc respectively without postoperative complication. At 1 month follow-up he was well with no pain.
Anterior displacement of the L45 disc was first seen on plain X-ray at 2 years and the disc was removed 11 months later. Having learned from previous bitter experiences, the vascular surgeon formally divided the left common iliac artery and vein so that there was good access to remove the disc and replace it with a Stabilis cage. The left common iliac artery and vein were then re-anastomosed. Despite this approach the right common iliac vein was injured and required repair. Full deep vein thrombosis prophylaxis was undertaken with pneumatic compression in theatre, peri-operative low molecular weight Heparin, postoperative compression stockings in addition to anticoagulation with Warfarin. Both iliac vessels were widely patent with no thrombus and normal blood flow velocity on duplex imaging at 1 month. Postoperatively he has continued to suffer pain after prolonged standing with occasional sleep disturbance. The L5S1 disc was stable on X-ray at 6 months with fusion progressing between L45.
Case 5
A 44-year-old man who had long standing low back pain had a single level degenerate disc at L5S1. The L5S1 disc was replaced with a 29 × 40 × 10° 11 mm AcroFlex disc. Immediately postoperatively he was well with an improvement in his symptoms. Gradual displacement of the prosthesis occurred from 3 months. The prosthesis was removed at 19 months and fusion performed using a Stabilis cage and cancellous bone graft. During surgery a tear of the left common iliac vein occurred during mobilisation this was repaired with 2.0 Prolene. Formal division of the iliac vein and artery was not necessary as the disc was removed from L5S1. Preoperatively the ODI was 48% after fusion it had fallen to 10%.
Discussion
The five patients reported here gained early symptomatic relief from low back and leg pain with an artificial inter-vertebral disc. However, in each case, revision following surgery for benign disc degeneration was associated with a major vascular injury. Anterior displacement of the L45 disc caused pressure on the left common iliac vein and artery with stretching of the vessels and erosion into the vessel wall in three cases. It was impossible to mobilise the stretched vessels from the firmly adherent surrounding dense scar tissue without vascular injury. In one case the left common iliac vein was thrombosed while in the others repairs were necessary after almost impossible mobilisation of the vessels to expose the prosthesis. Damage to the left common iliac vein and artery in one case led to both venous and arterial thrombosis. It is likely that this complication will lead to longstanding symptoms of venous insufficiency.
The only safe solution for adequate exposure of an anteriorly displaced visco-elastic artificial L45 disc is the formal division and subsequent re-anastomosis of the left common iliac vein and if necessary the left iliac artery; this strategy was successfully employed in cases 3 and 4. An anterior transperitoneal approach is essential to allow proximal and distal vessel control before division. A retroperitoneal approach in this type of revision surgery would be extremely hazardous and potentially life threatening due to an inability to control the right common iliac vein or vena cava when there is bleeding from the left common iliac vein. The aortic bifurcation would also be difficult to control.
The Link SB Charité disc is currently the most widely implanted inter-vertebral disc. This articulating disc consists of an ultra high molecular weight polyethylene spacer between two separate cobalt–chromium–molybdenum alloy plates. Griffith et al. reported displacement or dislocation of the prostheses in 6 of 139 implants with an average follow-up of 11 months. There were six reported vein injuries although it is not clear whether these injuries were associated with displacement or revision surgery or at what level the implant was placed [6]. Cinotti et al. reported only one anterior displacement of 46 SB Charité III prostheses and no vascular injury, with a minimum follow-up of 2 years [3]. In a series of 105 patients with 154 SB Charité III discs five vascular problems were reported (two phlebitis, two pulmonary embolism and one acute leg ischaemia) although no information on the rate of revision or anterior displacement was presented in this series [10]. Zeegers et al. reported a prospective study of 50 patients where 75 SB Charité III prosthesis were inserted. None of 38 patients with full 2 year radiographic follow-up had migration of the prosthesis. One patient lost to follow-up had malposition and some slip but was lost to follow-up. Of 12 patients who underwent reoperation only one aortic injury was reported during failed disc re-positioning and subsequent fusion [12]. These reports are all non-randomised series without any control and in one case retrospective. The only published randomised study of inter-vertebral disc replacement compares the Charité disc with spinal fusion. This study showed that pain and disability scores are equivalent at 24 months follow-up. There was a 4.4% incidence of venous injury in the arthroplasty group and device failure in 5.1% compared to 9.1 and 2% respectively in the spinal fusion group [2].
This first design of the AcroFlex disc contained a hexane based polyolefin rubber core vulcanised between two titanium plates. A retrospective review of six patients who had AcroFlex discs, with a mean follow-up was 3.5 years, reported a poor outcome in two patients with fracture of the rubber component and persistent symptoms in a second. There were no reported cases of disc displacement or of vascular injury during one revision although the prosthesis was at L5S1 [4]. Fraser et al. reported a series of 28 patients who had the third generation AcroFlex disc implanted, 17 patients had the same disc design used in this study. Eight of 28 required revision surgery for deterioration of symptoms and failure of the prosthesis. Two of the four patients who had removal of the prosthesis suffered left iliac vein injury during surgery. Fraser et al. inserted the discs through a retroperitoneal approach and suffered one anterior displacement in this case series [5]. It should be noted that there were two pilot studies. In the first series all patients were implanted in Adelaide. Displacement occurred in series 2 at both test centres but only in Manchester was displacement severe enough to warrant removal for the reasons stated. Disc displacement due to placement of the disc too far anteriorly has been reported with the PRODISC [1]. The high incidence of disc displacement in this series (5 of 13) is thought to be associated with an anterior transperitoneal approach and more extensive removal of the annulus rather than malposition. Design is also an important factor in preventing displacement since it occurred in both centres. On revision surgery no osteointegration of these implants was apparent and displacement occurred despite re-design of the endplates, as a result of the series 1 failure, to a domed surface with 4–6 tapered fins on each surface. This redesign was also inadequate.
Van Ooij has described a series of 27 patients with anterior displacement of four Charité discs one of which led to compression of the iliac artery causing symptoms of ischaemia [11]. A systematic review of total disc replacement examined the results from 564 arthroplasties in 411 patients. The majority of the cases considered were the Charité disc and only eight cases of vascular injury were identified [8]. The authors of both papers concluded that removal of artificial discs is potentially dangerous and no reliable strategy for revision surgery exists for a procedure without proven long-term reliability.
The five cases described in this report highlight failure of three design criteria for a disc prosthesis: (i) the rapid fixation to bone, (ii) fail-safe design to prevent damage to surrounding structure in case of failure and (iii) medium-term osteointegration [7]. If a disc does fail and needs to be removed, surgery can be hazardous with associated vascular injury [8]. Consequently, we advise that a Vascular Surgeon should be available to try and mobilise or divide and re-anastomose the left common iliac vessels when needed for adequate exposure of a L45 disc. Furthermore, this revision disc surgery is usually difficult and should be planned to include autologous blood transfusion.

vascular injury
disc design
artificial inter-vertebral disc
inter-vertebral disc replacement
inter-vertebral arthroplasty


Randomized Controlled Trials of Pediatric Massage: A Review

The existing reviews of massage therapy (MT) research are either limited to infants, adults, or were conducted prior to the publication of the most recent studies using pediatric samples. Randomized controlled trials (RCTs) of pediatric MT are reviewed. A literature search yielded 24 RCTs of pediatric MT, defined as the manual manipulation of soft tissue intended to promote health and well-being in recipients between 2 and 19 years of age. Because RCTs of pediatric MT varied considerably in the amount and types of data reported, quantitative and narrative review methods were both used. Single-dose and multiple-dose effects were examined separately. Among single-dose effects, significant reductions of state anxiety were observed at the first session (g = 0.59, P < 0.05) and the last session (g = 1.10, P < 0.01) of a course of treatment. Effects for salivary cortisol (g = 0.28), negative mood (g = 0.52) and behavior (g = 0.37) were non-significant. Three of eleven multiple-dose effects were statistically significant. These were trait anxiety (g = 0.94, P < 0.05), muscle tone (g = 0.90, P < 0.01) and arthritis pain (g = 1.33, P < 0.01). Results of studies not permitting effect size calculation were judged to be generally consistent with quantitative results. MT benefits pediatric recipients, though not as universally as sometimes reported. Numerous weaknesses endemic to MT research (e.g. low statistical power, frequent failure to report basic descriptive statistics) are identified, and recommendations for future pediatric MT research are discussed.
Introduction
Background
Massage therapy (MT) is one of the most widely used complementary and alternative medicine (CAM) therapies in the United States according to National Health Interview Survey data. It is estimated that consumers spend between 2 and 4 billion dollars on 75 million visits to massage therapists annually (1). Studies indicate that parents are making increasing use of CAM therapies, including MT, for their children. One study found that 33% of parents reported using CAM for their child within the past year, with MT being one of the most popular therapies (2). Another study shows that families of children with special health care needs are almost twice as likely to have used CAM for their child (3). CAM use is now prevalent, even in many traditional medical settings [e.g. 49% of university-affiliated pain management centers in the US and Canada offer MT (4)], yet pediatricians and other health care professionals are often not informed about the CAM therapies that are being used by their patients (2). This may be especially true for pediatric CAM, where survey results indicate that 81% of parents currently using CAM for their child wanted to discuss it with their pediatrician, but only 36% did (5). For CAM to truly be integrated into the health care system, it needs to be openly discussed and recognized for its value, particularly in the area of palliative care (6). A scientific understanding of CAM therapies, such as pediatric MT, will permit a greater understanding of the value of this type of therapy.
Numerous studies of MT for children and young adults have been conducted. These include randomized controlled trials (RCTs), evaluation studies, descriptive case studies and reviews. However, the existing reviews of MT research are either limited to adult participants, limited to infants, were conducted prior to the publication of the most recent studies using pediatric samples, or neglected to quantify results. Ottenbacher and colleagues (7) quantitative review of tactile stimulation for infants and young children, published nearly 20 years ago, found statistically significant beneficial outcomes for five of the six categories examined (these were motor/reflex, cognitive/language, social/personal, physiological and overall development; visual/auditory was non-significant). Field (8) conducted a narrative review, including research on persons of all ages, and concluded that MT had a multitude of condition-specific effects in addition to consistently providing reductions of anxiety, depression and levels of stress hormones (most notably cortisol) that were observed across studies. The two most recent reviews are quantitative reviews that focus specifically on either infants or adults. A Cochrane review systematically examines MT for preterm and low birth-weight infants, and reaches the negative conclusion that ‘there is insufficient evidence of effectiveness to warrant wider use of preterm infant massage’ (9). The quantitative review of MT performed on adults confirmed (and quantified) some of Field's conclusions while disputing others (10). Substantial reductions resulting from multiple sessions of MT were noted for depression (g = 0.62, P < 0.01) and trait anxiety (g = 0.75, P < 0.01), while MT's effect on cortisol levels was not statistically significant (g = 0.14). While this review supported the value of MT by quantifying its ability to substantially reduce symptoms of psychological distress in adults, taken together this set of findings called into question some of the theories most often invoked to explain the benefits of MT, especially the theory that MT benefits recipients primarily by activating the parasympathetic nervous system (10).
Current Review
While the latest quantitative reviews increase our understanding of MT and indicate new directions for research, they neglect MT performed on pediatric samples. The current review examines MT's effects in pediatric samples (defined here as studies where the mean age of participants was between 2 and 19 years), with a focus on RCTs. While some have argued against using RCTs to understand CAM modalities such as MT (11), RCTs represent the state-of-the-art for establishing cause and effect relationships in treatment research because they are the most effective study design for ruling out alternate (i.e. non-treatment) explanations for observed effects, including spontaneous recovery, placebo effects and statistical regression (12).
Though there have been some new pediatric MT studies published since the reviews by Ottenbacher et al. (7) and Field (8), the number of RCTs that examine pediatric MT is still quite small. In addition, a weakness of existing MT research is that, more often than not, studies in this area do not include the minimal statistical detail necessary to calculate effect sizes. For these reasons, a full meta-analytic treatment of MT research with pediatric samples is not possible. However, consistent with Rosenthal's observation that a narrative literature review can only be improved by the addition of a simple, descriptive quantitative analysis (13), we quantified results where possible, and include these results in combination with a narrative review of other RCTs. In some cases, the present findings are being compared with analogous findings in the adult literature. When these comparisons are made, we are referring to the adult meta-analysis conducted by Moyer et al., unless otherwise stated (10).
Operational Definition
A notable challenge in reviewing MT studies is that there are many forms of MT in practice. The American Massage Therapy Association (AMTA) defines massage as ‘manual soft tissue manipulation, [including] holding, causing movement, and/or applying pressure to the body’ (14). As written, this very broad definition includes numerous MT approaches commonly used in clinical practice that are relevant to the current review, but could also include rare forms of medical massage (e.g. optic nerve massage (15), light compressive massage for congenital dacryocystocele (16), cardiac massage (17)), that are outside the intended scope of this review. For this reason, we focus on forms of MT that are consistent with traditional Swedish styles of massage. Swedish massage uses five main strokes to stimulate the circulation of blood through the body; petrissage (kneading), effleurage (stroking), friction, tapotement (tapping) and vibration. For the purposes of this review, MT is typified by the manual manipulation of soft tissue, performed by a person other than the recipient, intended to promote health and well-being. This operational definition allows a range of MT styles to be included in this review. Studies vary on many details, including the amount of clothing worn by recipients, whether a massage chair or massage table was used, whether MT took place in a clinical setting or at home, and whether MT was performed by a person with full, partial, or no training as a massage therapist. Studies also vary in which anatomical regions are massaged. Despite all these variations, it is reasonable to expect that there will be some consistent outcomes that result from MT. Eventually, as a scientific understanding of MT grows, studies that examine the importance of these variations will be advisable, but currently the questions of greatest interest are at a more fundamental level.
Types of Effects
MT effects can be divided into single-dose and multiple-dose. Single-dose effects include MT's influence on psychological or physiological states that are transient in nature and that might reasonably be expected to be influenced by a single session of MT. Multiple-dose effects are restricted to MT's influence on variables that are considered to be more enduring, or that would likely be influenced only by a series of MT sessions performed over a period of time, as opposed to a single dose. Frequently, both single- and multiple-dose effects are examined in the same study. One example is a study of MT for autistic children that examined the single-dose effect of MT on salivary cortisol (immediately prior to, and immediately following, an individual session of MT) and the multiple-dose effect of MT on depression (at the beginning of, and at the conclusion of, a sequence of MT sessions over time) (18). A second example is a study that evaluated children's distress during burn treatment, which included the single-dose effect of MT for state anxiety and the multiple-dose effect of MT for depression (19). Typically, studies include the terms ‘short-term effect’ and ‘long-term effect’ to indicate single- and multiple-dose effects, respectively. Our decision to use the single-dose and multiple-dose terminology is motivated by the desire to prevent any confusion that may arise related to how long an effect may last following the termination of treatment. None of the studies in the current review examine whether any MT effects last beyond the final day on which a participant receives treatment, making the use of the term ‘long-term effect’ potentially misleading.
The potential benefits of MT can be further classified according to whether they are primarily affective, physiological or behavioral in nature. Affective refers to effects most closely associated with the recipients' feelings and emotions. Physiological effects are those concerned with recipients' vital organismic processes. Behavioral effects are those related to the recipients' observable responses to their environment. Study results reviewed here will first be separated by the single-dose versus multiple-dose distinction, then further categorized into affective, physiological and behavioral dimensions.
Methods
Literature Search
A literature search was conducted by the first author (S.B.) using the keywords massage, child and pediatric to search the MEDLINE, LexisNexis, CINAHL and PsycInfo databases. We checked the NIH CRISP Database to search for other publicly funded studies currently in progress. MT researchers were also contacted to obtain studies that were unpublished, in press or otherwise not found by means of database searches. With the introduction of the first Massage Therapy Research Conference in Albuquerque, New Mexico (43), leaders in the field of massage research were readily contacted. We used this opportunity to access current unpublished pediatric massage studies. Studies obtained by these methods were inspected to ensure that they examined a form of MT consistent with the present study's operational definition of MT performed on a pediatric sample. Application of these criteria yielded 24 RCTs of MT with a pediatric sample. These studies, along with important details, are listed in Table 1.
Statistical Analysis
For studies that provided sufficient data, between-groups comparisons on variables of interest were converted to Hedges' g effect size by the second author (C.A.M.). Hedges' g, calculated as (Group mean 1 − Group mean 2)/Pooled SD, estimates the number of standard deviations that the average member of a treatment group differs from the average member of a comparison group for a given outcome. Hedges' g was selected over Cohen's d, a similar standardized mean difference effect size. This choice was made for two reasons. First, in some cases the original study data could only be converted to g. Second, using g makes the results of the current review as consistent as possible with the existing meta-analysis of MT effects for adults.
In cases where a study employed more than one measure to examine the same outcome variable, results of multiple measures completed by participants or by blinded observers (but not those completed by non-blind observers) were standardized and then averaged, yielding one effect size per variable for each study. Similarly, if a study examined the immediate effects of more than one application of treatment, the results of the multiple applications or assessments were standardized and, when similar in magnitude, averaged in order to calculate a single effect size for that study. In the single case where these assessments clearly differed in a systematic way (i.e. state anxiety, where the effects of a final session were always larger than the effects of the initial session; paired sample t(3) = 4.46, one-tailed P < 0.02), separate effects were calculated for each timepoint. Effect sizes were coded such that positive values, for any variable, indicate a more desirable outcome (e.g. a reduction in anxiety) for the participants who received MT. Individual study effect sizes were subjected to a correction for small sample bias, then weighted by their inverse variance and averaged to generate a mean effect size for each outcome variable (20). All effect sizes were calculated according to a random effects model of error estimation. Statistical significance of the mean effect sizes was assessed by calculating the 95% confidence interval for the population parameter. A significance level of 0.05 or better is inferred when zero is not contained within the confidence interval.
Results
Of the 24 RCTs, only 9—accounting for a total of 200 participants—provided sufficient data for their results to be systematically quantified. Table 2 lists mean effect sizes for 16 outcome variables (g), as well as the number of studies contributing to each effect size (k), the total number of participants contributing to each effect size (N) and 95% confidence intervals. Five of these sixteen effect sizes were statistically significant. For the single-dose effects category, these included state anxiety at the first session (g = 0.59, P < 0.05) and at the last session (g = 1.10, P < 0.01) of a course of treatment. Effects for salivary cortisol (g = 0.28), negative mood (g = 0.52) and behavior (g = 0.37) were non-significant. Only 3 of the 11 multiple-dose effect sizes were statistically significant. These were trait anxiety (g = 0.94, P < 0.05), arthritis pain (g = 1.33, P < 0.01) and muscle tone (g = 0.90, P < 0.01).
Of the 24 RCTs, 15 (accounting for 458 research participants) do not report sufficient data to permit effect size calculation, a frequent problem in MT research that makes objective interpretation of results difficult. Nevertheless, by judiciously comparing the scant data presented in this subset of studies with the objective data previously summarized, it should be possible to see if there are any dramatic contrasts among the findings. These interpretations, within the context of the more objective findings, appear in the results categories that follow.
Single-Dose Effects
Affective Dimension
State anxiety. Field et al. have conducted several pediatric MT studies where anxiety is an outcome measure. These studies date back to 1992 when MT was applied to a group of pediatric psychiatric patients (21). Four studies with reportable effect sizes (No.'s 6, 14, 17 and 21 in Table 1), using a total of 81 participants, compared MT with either relaxation therapy or a reading comparison group with state anxiety—a momentary emotional reaction consisting of apprehension, tension, worry and heightened autonomic nervous system activity (22)—as a dependent variable. Three of the studies (No.'s 14, 17 and 21) used the State Trait Anxiety Inventory (two specify the child version). One study (No. 6) of MT for children with juvenile rheumatoid arthritis used a behavior observation of the child's anxiety level performed by a blinded rater. MT consistently reduced state anxiety in these studies. This single-dose effect was unique in that it is significantly larger at the second timepoint, so we examined these separately. Results of a first session of MT yield a statistically significant effect, g = 0.59 (95% CI = 0.15, 1.04). The effect at the last session is even greater, g = 1.10 (95% CI = 0.64, 1.57). These results are depicted graphically in Fig. 1. Possibly, the substantially larger effect occurring at the last session of treatment may be the result of participants' increasing comfort with MT (or with the massage therapist) over the course of time, or the effect may be related to MT's potential to reduce trait anxiety over a course of treatment (8). These pediatric results are consistent with the same effect found for adults, where this effect has been estimated as g = 0.37 (95% CI = 0.14, 0.59). Possibly, the larger effect for the pediatric samples examined here reflects a greater treatment aptitude for this population; however, with such wide confidence intervals, this is only speculation.
Studies where state anxiety was a dependent variable but effect sizes could not be calculated include samples of children who experienced Hurricane Andrew (23), depressed adolescent mothers (24), and children and adolescents with a range of illnesses including diabetes (25), atopic dermatitis (26), asthma (27), bulimia (28) and leukemia (29). The most commonly used measures across these studies were the State Trait Anxiety Inventory for Children (STAIC) and the State Trait Anxiety Inventory (STAI) for adolescents. A study of children who experienced Hurricane Andrew assessed both the single-dose effects of state anxiety and the multiple-dose effects of trait anxiety. These studies are consistent with the previously reported effect sizes, in that MT appears to decrease state anxiety. The MT in all of these studies was conducted either daily or twice weekly over a treatment period of 30–45 days. MT sessions generally lasted between 20 and 30 min, the one exception being the leukemia study where MT sessions were 15 min in duration. Four of these studies trained parents to provide MT directly to their child and the remaining three either used trained massage therapists or massage students.
Mood. Mood, which may be defined as ‘transient episodes of feeling or affect’ (30), has frequently been an outcome measure in pediatric MT studies. Study populations have included depressed adolescent mothers, and children and adolescents with cystic fibrosis, leukemia and bulimia. Two studies (No.'s 13 and 14 in Table 1), using a total of 50 participants, compared MT with either a reading or wait-list control to examine MT's effect on mood. One of these studies (No. 14) used the Profile of Mood States (POMS) (31) depressed mood subscale. The second study (No. 13) used a faces scale and a modification of the Children's Pain/Fear Thermometer Rating Scale. Taken together, these studies yield a non-significant effect, g = 0.52 (95% CI = −0.05, 1.10) that is consistent with the results found for adult recipients (g = 0.34, 95% CI = −0.08, 0.76). These positive but non-significant results suggest at least four possibilities. One is that the tools that have been used to measure mood in these studies are not precisely capturing overall mood, but are being affected by correlates of mood such as depression, pain or fear. A second possibility is that MT's modest effect on mood has not been examined with sufficient statistical power, resulting in wide confidence intervals. The third is that MT's positive effect on mood is affected by a moderator variable that has not yet been examined (e.g. recipient's comfort with MT; the existence of a therapeutic bond between the recipient and provider, etc.). Finally, the possibility that MT does not specifically have a positive effect on mood cannot be definitively ruled out.
Physiological Dimension
Salivary cortisol. Two studies (No.'s 6 and 13 in Table 1), using a total of 50 participants, compared MT with either relaxation training or a wait-list control to examine MT's single-dose effect on cortisol—a stress hormone associated with activation of the sympathetic nervous system in response to certain kinds of stressors. In both studies, salivary cortisol [but not urinary cortisol, which less accurately captures short-term stress responses (32) most likely to respond to single-dose MT] was sampled pre- and post-MT session, with a delay of 20–30 min after the session, because salivary cortisol samples reflect responses to stimulation occurring ∼20 min prior to collection. Both studies also took into account the diurnal cortisol cycle, characterized by an increase in secretory activity following awakening and a declining trend over the course of the day (33). Combined, these studies yield a non-significant reduction, g = 0.28 (95% CI = −0.27, 0.84) of salivary cortisol for the participants receiving MT in comparison to controls. This finding contrasts Field's assertion that reductions in cortisol level are one of MT's most reliable effects, but is consistent with meta-analytic findings based on adult samples, where cortisol effects were small and non-significant (g = 0.14, 95% CI = −0.10, 0.38) (10). Based on the available evidence, MT's single-dose effect on cortisol levels appears to be small, and possibly zero.
Behavioral Dimension
Distress behaviors. One study (No. 20 in Table 1) compared MT with standard care for children receiving burn treatment, and examined the children's distress behaviors before and during this painful procedure. The Children's Hospital of Eastern Ontario Pain Scale (34) was used to code distress behaviors before and during a dressing change (35). Six behavior categories were assessed including cry, facial, verbal, torso, touch and legs. The MT group showed only an increase in torso movements during the dressing change, whereas the control group showed an increase in five out of the six distress behaviors. Combined observational ratings made by nurses, who were blind to the group to which the children were assigned, favored MT, g = 0.37 (95% CI = −0.43, 1.17). Though this effect favors MT, the wide confidence interval, which may be partially or wholly attributable to the small sample (n = 24), makes this result difficult to interpret.
In several other studies with behavioral outcomes where effect sizes could not be calculated, researchers reported improvements in fidgetiness, activity, vocalization and cooperation. The most commonly used instrument in these studies is a Behavior Observation Scale that was first used to assess behavior after relaxation therapy classes (36). Using this measure, behavior is observed three times during the 30 min prior to MT, during MT itself and during the 30 min after MT. Because the effect size data are inconclusive and researchers report positive behavioral improvements resulting from MT, further study on distress behaviors may be warranted.
Multiple-Dose Effects
Affective Dimension
Depression. Depression, including motivational and cognitive deficits, vegetative signs, and disruptions in interpersonal relationships beyond those expected from ordinary unhappiness or poor mood (37), has been examined in pediatric MT studies, albeit with small samples. Two studies (No.'s 13 and 17 in Table 1), using a total of 54 participants, examined whether MT would reduce depression in comparison to either a wait-list control or to progressive muscle relaxation. The first study (No. 13) used the Children's Depression Inventory-Short Form, and was the only study reviewed to use that measure. It is an abbreviated version of a widely used self-report measure of depression for children and adolescents. The second study (No. 17) used the Center for Epidemiological Studies-Depression scale, which was also used in several studies that did not permit effect size calculation. Though the mean effect favored MT, g = 0.48, this effect is not statistically significant (95% CI = −0.06, 1.02). This result is inconclusive, but promising given that the confidence interval approaches significance, and also because the estimated effect is not greatly different from statistically significant reductions of depression found in adult samples (g = 0.62, 95% CI = 0.37, 0.88). It is also generally consistent with the conclusions reached by the authors of studies that did not permit effect size calculation. Still, the possibility that MT does not reduce depression for pediatric recipients to the extent it does in adults cannot be ruled out. At this point, further study on MT for pediatric depression is needed.
Trait anxiety. One study (No. 13 in Table 1), using a sample of children and adolescents with attention-deficit hyperactivity disorder, examines MT's effect on trait anxiety, a dispositional, internalized proneness to be anxious (38), with enough detail to permit effect size calculation. This study, which also appears in the adult MT meta-analysis, uses the Revised Children's Manifest Anxiety Scale to compare MT with a wait-list condition and yields a large, statistically significant effect (g = 0.94, 95% CI = 0.20, 1.68) that is consistent MT's anxiolytic effects demonstrated in numerous studies with adult recipients. This result is consistent with author claims in the ‘Hurricane Andrew’ study, where improvements in children's trait anxiety at the end of the MT treatment are reported. Reduction of trait anxiety, resulting from a course of MT sessions, is certainly worthy of further study in pediatric populations.
Pain. Four pediatric studies have been conducted that include pain as an outcome measure. Three of these studies used the Happy Faces Scale while only one study, a study of children with juvenile rheumatoid arthritis (and the only study with sufficient data for calculating effect sizes), used the Varni/Thompson Pediatric Pain Questionnaire. This study (No. 6 in Table 1) assessed pain in three ways—child self report, parent report and physician report. The children and a pediatric rheumatologist, who was blind to group assignment, generated reports of pain reduction that were consistent; parents' ratings were omitted from effect size calculation due to their non-blind status and proneness to bias. In comparison to a relaxation therapy group, MT yielded a large, statistically significant pain reduction (g = 1.33, 95% CI = 0.37, 2.29). This very large effect, in contrast with other studies that have shown mixed results for pain reduction resulting from MT, suggests that MT may be particularly well-suited to pain reduction for children with this condition.
Three RCT's that do not permit effect size calculation looked at MT's impact on pain, and concluded that children experienced reductions of pain resulting from MT. Samples in these studies included children who experienced Hurricane Andrew (23), adolescents with attention-deficit hyperactivity disorder (39) and children with atopic dermatitis (26). These reports, combined with the findings in the juvenile rheumatoid arthritis study, indicate that MT for pain reduction in pediatric recipients is worthy of further examination.
Physiological Dimension
Muscle tone. Two recent studies that assess muscle tone (No.'s 23 and 24 in Table 1) yield g = 0.90 (95% CI = 0.23, 1.57). The first examines MT for children with cerebral palsy who received 30 min of MT 2 times per week for 12 weeks. This study also assesses spasticity, motor functioning, facial expressions and limb activity. The second study, of children with Down syndrome provided 30 min of MT 2 times per week for 8 weeks. Children's development, and fine and gross motor functioning, was evaluated. Both studies used the Arms, Legs and Trunk Muscle Tone Scale (ALT Muscle Tone Scale), which was designed during the pilot phase of the Down syndrome study. There is modest support that MT improves muscle tone, though it must be pointed out that the two studies diverge greatly in their individual results. Study number 23 in Table 1 had virtually no effect, while study number 24 had a huge effect. It must be noted that because these results come from a newly developed measure, the validity of the measure is not yet well-established. This may account for the divergent results across studies.
Range of motion. One study (No. 23 in Table 1), with a sample of children suffering from cerebral palsy, yields non-significant improvements in range of motion, g = 0.31 (95% CI = −0.57, 1.19). The study notes that right and left hip extension, but not abduction, improved. Study authors note that increased muscle tone may have led to an increase in range of motion, but this result, based on a single study with 20 participants, is inconclusive.
Immune measures. Two studies (No.'s 17 and 22 in Table 1) examined markers of immune system functioning in HIV+ adolescents or children. Though study authors are quick to point out that there were some within-group effects for those who received MT, a between-groups analysis that compares MT recipients with controls yields no effect (g = 0.06, 95% CI = −0.52, 0.63). In light of this result, specific MT effects on CD4 count were then examined separately, to account for the fact that the numerous immune system markers reported in those studies, and combined in the process of effect size calculation, might be obscuring this most important measure of disease progression in HIV+ persons. When an effect size for CD4 count only is generated from these two studies, the effect is only marginally larger and still non-significant (g = 0.24, 95% CI = −0.33, 0.82). Though these studies, and another study of MT for children with leukemia (29), make much of within-groups MT effects on immune system markers, the available between-groups data show that MT's effect on immune system function is probably small and possibly zero.
Pulmonary function. One study (No. 14 in Table 1) examined whether MT might generate an improvement in peak air flow for a sample of 20 children with cystic fibrosis. In comparison to a reading control group, the children receiving MT had higher peak air flow, g = 0.47 (95% CI = −0.41, 1.35), indicating MT may be of specific value to children with this condition. Another study (27) that does not permit effect size calculation reports multiple measures of breathing improvement for asthmatic children ages 6–8 years, though older children (ages 9–14 years) showed fewer improvements. Overall, evidence for MT effects on pulmonary function is promising, and further study is warranted.
Skin condition. Two RCT's examine MT's effect on skin condition. Children with atopic dermatitis were studied to determine the effect of MT on redness, scaling, lichenification, excoriation and pruritus (26). Though effect sizes cannot be calculated, study authors indicate some improvement following MT. Pediatric patients with hypertrophic scarring (HTS) were also studied and vascularity, pliability and height of the HTS revealed no appreciable effects. There is some evidence that pruritis decreased in certain patients with mature burn scars following MT. There is insufficient evidence to validate MT effects on skin condition in pediatric recipients.
Glucose level. (No. 7 in Table 1) One study of children with diabetes examined the effect of MT on blood glucose levels (25). The authors conclude that MT lowers mean blood glucose levels and that compliance for insulin and food regulation improved, though data necessary for effect size calculation are not reported.
Behavioral Dimension
Developmentally appropriate functioning. Two studies (No.'s 23 and 24 in Table 1) used the Developmental Programming for Infants and Young Children (DPIYC) scale to assess developmentally appropriate functioning in recipients following MT. The average effect was small and non-significant (g = 0.24, 95% CI = −0.38, 0.86), though it must be pointed out that the studies had divergent results. Study number 24 yields a modest improvement in developmentally appropriate functioning in a sample of children with Down syndrome. Study number 23, with a sample of cerebral palsy sufferers, yields no effect. Possibly, these divergent results are the result of the different populations sampled within the studies. Taken together these results are inconclusive, but the encouraging results of the study with children who have Down syndrome indicate that further studies should be done with children having this or a related condition.
Spasticity. One study (No. 23 in Table 1), with a sample of children suffering from cerebral palsy, examined whether MT had an effect on spasticity by using the Spasticity scale/modified Ashworth scale. The small, non-significant effect (g = 0.26, 95% CI = −0.62, 1.14) does not support an MT effect on spasticity. Because this study was very small (n = 20), further testing in this area may be beneficial.
Hostility. One study (No. 21 in Table 1), with a small sample of aggressive adolescents, examined whether MT might reduce hostility compared with relaxation therapy. This study yields g = −0.85 (95% CI = −1.85, 0.15), a non-significant effect, but one that almost reaches significance in the wrong direction. The most tenable conclusion from this finding, a result based on a very small sample, is that MT has no effect on hostility beyond that provided by relaxation therapy to which it was compared. Though participants were randomly assigned, the MT group was approximately three points higher on the SCL-90R Hostility subscale prior to treatment. While scores decreased in the MT group during the treatment period, they also did in the relaxation therapy group, such that the MT group is still three points higher than the relaxation therapy group at the end of the treatment period. The authors' assertion that ‘by the end of the study [massaged adolescents] reported feeling less hostile’ obfuscates the fact that there was no between-groups effect. Related measures used in this study, such as the Overt Aggression Scale, were completed not by study participants, but by their legal guardians who were not blinded to group assignment, making their ratings prone to bias. Nevertheless, when all such measures included in the study are used to calculate an effect size, regardless of blinding, the result still converges on no effect.
Classroom behavior. One study (No. 13 in Table 1) examined the classroom behavior of students with attention-deficit hyperactivity disorder using the Conners Teacher Rating Scale. Six factors of this scale were used including hyperactivity, conduct, emotional-indulgent, anxious-passive, asocial and daydream/attention problems. In comparison with a wait-list control, MT yielded g = 0.66 (95% CI = −0.07, 1.39), an effect that, while non-significant, is encouraging. Further studies of MT for this population are needed to confirm whether it might be of value in improving behavior, an outcome that seems possible given MT's relatively well-established potential to reduce anxiety. Studies that do not permit effect size calculation also suggest some improvements in classroom behavior following a course of MT. Improved classroom behavior and social relatedness are reported in studies of preschool children (40) and children with autism (41).
Cognitive performance. (No. 11 in Table 1) A study of MT for children in preschool concludes that MT impacts cognitive performance (42). This study used three subtests of the Wechsler Preschool and Primary Scale of Intelligence—Revised, but does not report sufficient data to quantify the effect.
Sleep and relaxation. (No.'s 1, 2 and 18 in Table 1) Though none permit effect size calculation, three studies have examined the effect of MT on sleep and relaxation. In one study, parents of children with autism recorded their children's sleep behavior in sleep diaries that included 5-point Likert scales (41). It is reported that the MT group showed decreases in fussing/restlessness, crying, self-stimulation behavior and getting out of bed. Nighttime sleep recordings were conducted for a previously mentioned study of MT for child and adolescent psychiatric patients (21). A video camera was set up on a tripod in the participant's room. The video tapes were subsequently coded for quiet sleep, active sleep, awake and lying quietly, and awake and active. Percentage of time asleep increased significantly from the first to last day of MT and the percentage of nighttime wakefulness decreased over the same time frame. Finally, children who experienced Hurricane Andrew were rated by an observer on a visual analogue scale (VAS), based on the child's apparent relaxation level (23). The VAS relaxation score increased significantly from the first to the last day of MT for the MT group. Possibly, MT promotes sleep and relaxation, but current studies do not permit this effect to be quantified.
Discussion
Available data reveals that MT provides benefit to pediatric recipients, though not as universally as has sometimes been reported. Benefits from both single-dose and multiple-dose sessions are evident. Most of the statistically significant effect sizes were observed for affective outcomes; findings for the behavioral and physiological dimensions were less consistent. These results parallel known MT effects in adult recipients, where multiple-dose reductions of depression and trait anxiety are the largest effects.
In reviewing MT for pediatric recipients, we encountered several weaknesses endemic to the MT research literature that should be addressed in subsequent studies. These included (i) low statistical power, (ii) frequent failure to report basic descriptive statistics, (iii) descriptions of results that do not logically follow study designs, and (iv) lack of replication. We discuss these in turn.
Low statistical power. Most pediatric MT studies were conducted with fewer than 30 participants. When studies are this small, only the largest effects have any likelihood of being uncovered. As researchers engaged in our own clinical MT studies, we are sensitive to the expense and difficulty involved in recruiting participants, but our empathy, unfortunately, does nothing to change the mathematics of the situation. The statistical power of MT studies must be increased (primarily by conducting studies with larger samples) if we wish to discover anything beyond the largest effects.
Failure to report basic descriptive statistics. Many pediatric MT studies have appeared in journals with lax standards for the reporting of data; there is no other explanation for why studies would fail to report the most basic descriptive statistics. When a report does not include the standard deviations that describe the spread of the data, that report has almost no value as scientific evidence. This must not be allowed to continue in MT research, because it represents an enormous waste of resources. Simply put, researchers who take the time, effort and expense to perform a study should not allow the results of that study to be published without the statistics that permit an understanding of the outcome. If a journal does not require them, then the onus is on the researcher to ensure that the statistics are reported.
Results that do not logically follow study designs. The importance of between-groups designs in MT has been noted (12). Why, then, do so many MT studies that employ a between-groups design emphasize within-group comparisons? The likely answer is that planned between-groups comparisons were non-significant (possibly due to low statistical power), so study authors may given in to the temptation to report the statistically significant, but misleading, within-group effect. This problem is rampant in MT research, and represents a real threat to the way this research will be perceived in the future. Many of the consumers of MT research are committed practitioners who have not had training in statistics and research design (though it must be noted that research literacy among MT practitioners is increasing). As such, they may be inclined to believe that coming across the sacrosanct ‘P < 0.05’ is proof of an MT effect, without realizing that this ‘effect’ may be nothing more than the effect of time, a placebo effect and/or regression to the mean. Knowledgeable consumers of MT research must learn to distinguish within-group effects from between-groups effects, and MT researchers must clearly present between-groups findings when their studies employ a between-groups design.
Lack of replication. All but two of the pediatric MT studies we reviewed were conducted by the Touch Research Institute at the University of Miami. Their contribution to MT research has been considerable; however, scientific understanding is hampered when one laboratory is responsible for almost all of the results in an area of inquiry. Replication of results is a foundation of scientific progress, so it is necessary that other researchers contribute to this field. Given recent interest in CAM modalities, the small number of studies from other laboratories is surprising. We hope that this is about to change, and the success of the recent Highlighting Massage Therapy in CAM Research Conference (43) suggests that it will. Three pediatric MT RCT's from other research groups, currently in progress, support our optimism. Two of these examine MT for children and adolescents with cancer. While the results of a study that will examine pain, mood, stress and relaxation outcomes from MT and heat therapy for terminal children (44) cannot yet be reported, preliminary results of another study examining anxiety, fatigue, pain and nausea outcomes from MT in a sample of children with cancer (45) are promising; in particular, reductions of anxiety are expected to be consistent with what has been reported in this review. The third study, conducted by the first author of this review (S.B.) and researchers at the UCLA Pediatric Exercise Laboratory (46), evaluates pre-exercise MT for children with and without heart disease. Preliminary results show significant improvement in VO2 (oxygen consumption) for children who have an MT session prior to performing an exercise regimen on a stationary bicycle. If these results are validated in final analyses, they will be generally consistent with the finding that MT can improve pulmonary function. There are two other studies worth mentioning that have received IRB approval from Children's Memorial Hospital in Chicago and will be enrolling participants shortly. These studies are an evaluation of MT for reduction of pain, nausea and anxiety in pediatric cancer patients (47) and an evaluation of MT on immune function and heart rate variability in HIV-infected pediatric patients (48). The outcome measures for the first study are self-report ratings of pain, nausea and anxiety, whereas the second study evaluates T-Helper cells (CD4+), T-Suppressor cells (CD8+), Total B cells (CD3, CD19), Natural Killer cells (CD56+), viral load and heart rate variability.
Conclusion
Current research indicates that MT is not a panacea for conditions studied in the pediatric population. In contrast to what has sometimes been claimed, there is little to no evidence to date to support effects such as improved immune system functioning, reduction of spasticity, or amelioration of hostility. In addition, there is currently scant evidence that MT provides benefits by first reducing cortisol, as MT's effect on this stress hormone is seen to be small when analyzed correctly (i.e. in between-groups as opposed to within-group comparisons). There is, however, a set of MT effects that have been shown to have real value to the pediatric population. MT shows a considerable impact on the state and trait anxiety levels of children. Because these effects are strong, and also because they are consistent with the findings in adults, future research on the anxiolytic effects of MT on pediatric recipients does not need to simply replicate previous studies. The greatest progress can now be made by focusing on the mediators and moderators of MT effects on anxiety, and on testing explanatory theories of these outcomes. MT effects on arthritis pain and muscle tone also appear to be strong, but these results do need to be replicated, as they are based on single studies. Other pediatric outcomes that are promising, but in need of further study, include MT's effects on depression, negative mood, certain types of behavior (likely due to reductions of anxiety) and air flow in those suffering from pulmonary disorders such as cystic fibrosis. As increased statistical power in the form of additional studies is brought to bear on these potential benefits, it is likely that some will be quantitatively validated.
Finally, it has been noted that prior MT research has not accounted for the communication that inevitably takes place between massage therapists and their recipients, nor has it examined the likelihood that therapists and recipients develop a therapeutic relationship during the course of MT (10). This is also true in pediatric MT studies. MT has important parallels (in both process and outcomes) to psychotherapy (10), a treatment that relies on communication and therapeutic relationship to provide effects. It seems likely that MT effects, especially those belonging to the affective category, are mediated or moderated by these previously unexamined factors. These should not be neglected in subsequent pediatric MT research.
As adult consumers continue to explore and utilize all of their health care options, children will increasingly be recipients of MT. With this in mind, it is essential that we continue to study the benefits of MT for children, and the explanatory models that underlie them, so children's health and wellness can be maximized. The value of MT has been examined for many specific conditions that afflict children. It is our hope that this review has consolidated those findings, indicated areas that require further study, and led to an increased scientific understanding of pediatric MT.

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Purinergic signaling in the lumen of a normal nephron and in remodeled PKD encapsulated cysts

The nephron is the functional unit of the kidney. Blood and plasma are continually filtered within the glomeruli that begin each nephron. Adenosine 5′ triphosphate (ATP) and its metabolites are freely filtered by each glomerulus and enter the lumen of each nephron beginning at the proximal convoluted tubule (PCT). Flow rate, osmolality, and other mechanical or chemical stimuli for ATP secretion are present in each nephron segment. These ATP-release stimuli are also different in each nephron segment due to water or salt permeability or impermeability along different luminal membranes of the cells that line each nephron segment. Each of the above stimuli can trigger additional ATP release into the lumen of a nephron segment. Each nephron-lining epithelial cell is a potential source of secreted ATP. Together with filtered ATP and its metabolites derived from the glomerulus, secreted ATP and adenosine derived from cells along the nephron are likely the principal two of several nucleotide and nucleoside candidates for renal autocrine and paracrine ligands within the tubular fluid of the nephron. This minireview discusses the first principles of purinergic signaling as they relate to the nephron and the urinary bladder. The review discusses how the lumen of a renal tubule presents an ideal purinergic signaling microenvironment. The review also illustrates how remodeled and encapsulated cysts in autosomal dominant polycystic kidney disease (ADPKD) and remodeled pseudocysts in autosomal recessive PKD (ARPKD) of the renal collecting duct likely create an even more ideal microenvironment for purinergic signaling. Once trapped in these closed microenvironments, purinergic signaling becomes chronic and likely plays a significant epigenetic and detrimental role in the secondary progression of PKD, once the remodeling of the renal tissue has begun. In PKD cystic microenvironments, we argue that normal purinergic signaling within the lumen of the nephron provides detrimental acceleration of ADPKD once remodeling is complete.

signaling
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polycystic kidney disease