Bone Marrow-Derived Cells Implanted into Freeze-Injured Urinary Bladders Reconstruct Functional Smooth Muscle Layers

Posted by zedie

Regenerative medicine offers great hope for lower urinary tract dysfunctions due to irreversibly damaged urinary bladders and urethras. Our aim is the utilization of bone marrow-derived cells to reconstruct smooth muscle layers for the treatments of irreversibly damaged lower urinary tracts. In our mouse model system for urinary bladder regeneration, the majority of smooth muscle layers in about one-third of the bladder are destroyed by brief freezing. Three days after wounding, we implant cultured cells derived from bone marrow. The implanted bone marrow-derived cells survive and differentiate into layered smooth muscle structures that remediate urinary dysfunction. However, bone marrow-derived cells implanted into the intact normal urinary bladders do not exhibit these behaviors. The presence of large pores in the walls of the freeze-injured urinary bladders is likely to be helpful for a high rate of survival of the implanted cells. The pores could also serve as scaffolding for the reconstruction of tissue structures. The surviving host cells upregulate several growth factor mRNAs that, if translated, can promote differentiation of smooth muscle and other cell types. We conclude that the multipotency of the bone marrow-derived cells and the provision of scaffolding and suitable growth factors by the microenvironment enable successful tissue engineering in our model system for urinary bladder regeneration. In this review, we suggest that the development of regenerative medicine needs not only a greater understanding of the requirements for undifferentiated cell proliferation and targeted differentiation, but also further knowledge of each unique microenvironment within recipient tissues.

Regenerative medicine has a potential to provide great hope for the recovery of lost tissue and organ functions.^1,2 In urology, novel in vitro and in vivo regenerative medicine approaches for the treatment of lower urinary tract dysfunctions, such as irreversibly damaged bladders and urethras, have been investigated.^3–14 Notably, there have been several attempts to treat urinary incontinence by increasing the urethral closure pressure. These are made by injections of autologous myoblasts and fibroblasts into the rhabdosphincter and urethra.^15–19 In our laboratories, we have attempted to treat irreversibly damaged lower urinary tracts, such as those seen clinically due to radiotherapy-induced injury of the urinary bladder, neurogenic bladder associated with brain and spinal cord disease or peripheral neuropathy. In a mouse model of freeze-injured urinary bladder, we have investigated the use of bone marrow-derived cells to reconstruct the layered smooth muscle component of the bladder tissue structures and to restore nearly normal physiological activity.²⁰

An important factor in the development of regenerative medicine is selection of the proper source for the regenerative cells and/or tissues. Recently, various kinds of cells, such as induced pluripotent stem cells, embryonic stem cells, and mesenchymal cells derived from adipose and oral mucosal tissues have been vigorously investigated. Mesenchymal cells derived from bone marrow are well known to display multipotent development, both in vitro and in vivo.^21,22 They have the potential to be a source of the cells for a variety of demands.¹² For instance, they can differentiate into smooth muscle cells,^23–25 and importantly, when cultured within scaffolds, they can construct layered smooth muscle structures.^26–29 Therefore we selected bone marrow as a source of cells by which we could investigate the potential to restore smooth muscle structure and function to injured urinary bladders.²⁰

Equally important as the sources of cells for regenerative medicine are the survival rates for implanted cells, the differentiation into target cell types, and the structural support that enables the reconstruction within the recipient tissues.^30–33 Consequently, the utilization of scaffolds,^34–36 growth factors,³⁷ and combinations of these materials^38,39 has been also investigated. The survival, differentiation, and reorganization of the implanted cells are affected by the microenvironment within the recipient tissues.^40–43 However, our understanding of these microenvironments is currently insufficient to provide for clinically effective and reliable resources for regenerative medicine.⁴⁴

In this review, we describe investigations of mouse bone marrow-derived cells implanted into freeze-injured urinary bladders, where the majority of the smooth muscle layers are lost from within the frozen area.^20,45 We show that bone marrow-derived cells implanted into these bladders differentiate into smooth muscle cells.²⁰ These cells become organized into layered structures that are associated with the recovery of contractions in these urinary bladders.²⁰ Further, our studies have shown the importance of the microenvironment in promoting differentiation of smooth muscle cells from the implanted bone marrow-derived cells.⁴⁴ In fact, cells implanted into uninjured normal tissue do not undergo differentiation and development. In injured bladders, we have begun to uncover the important roles played by the local microcirculation, large tissue pores, host tissue scaffolding, and expression of growth factor mRNAs that may support differentiation of smooth muscle cells.⁴⁴ This, and new information yet to be revealed in the next generation of studies, will bring the hope of regenerative medicine in urology and other clinical areas closer to reality.

Jump to…Top of pageAbstract1. INTRODUCTION2. RECONSTRUCTION OF SMOOTH MUSCLE LAYERS3. MICROENVIRONMENT4. TISSUE ENGINEERING5. CONCLUSIONREFERENCES

2. RECONSTRUCTION OF SMOOTH MUSCLE LAYERS

2.1. Bone marrow-derived cells

We harvest bone marrow cells by flushing them out from both ends of mouse femurs and then culturing them on the collagen-coated dishes for 7 days.²⁰ During the culture period, every day we completely replace the 15% fetal bovine serum-containing medium and remove non-attached cells. Immediately after plating in dishes, the bone marrow cells consist of heterogeneous, spindle-shaped, round, and polygonal cell types along with red blood cells. At 5 days after seeding, the cells achieve approximately 80% confluence, and at that time we transfect them with the green fluorescence protein (GFP) gene for identification in the recipient tissues. After 7 days of culture (i.e. 2 days after transfection), the adhered proliferating cells are relatively homogenous in spindle shaped appearance and they expressed GFP (Fig. 1a). The cultured cells do not stain with antibodies directed against smooth muscle differentiation marker proteins.

Figure 1. Cultured bone marrow-derived cells and freeze-injured urinary bladders. (a) After 7 days of culture, most of the cells have relatively homogenous spindle shaped appearance. The adherent and proliferating bone marrow-derived cells are implanted into wounded regions of the freeze-injured urinary bladders (shown in b). At 7 days, just prior to implantation, the bone marrow-derived cells express GFP (inset, green, bar = 20). The cultured cells are not positive for smooth muscle cell differentiation markers. (b) Three days after injury, the wound site is identified by the presence of a hematoma (inset, arrow). The bone marrow-derived cells are implanted into the center of the wounded regions. In this longitudinal section through the untreated injured urinary bladder just prior to implantation, the injured region (arrowheads) under the wound site (inset, arrow) are thinner than the surrounding uninjured regions that have distinct smooth muscle cells and layers (arrows). H&E stain. (c) The injured region (shown in B, arrowheads) does not have any SMA-positive smooth muscle cells (asterisks; green, urothelium; blue, nuclei).

The culture conditions readily promote attachment and proliferation of bone marrow cells. The freshly harvested cells contain a variety of stem cell types, such as hematopoietic, mesenchymal and stromal stem cells.^21,22 The cells from our cultures typically express the stromal stem cell markers STRO-1 and CD13. Such cells have the potential to differentiate into smooth muscle cells, adipocytes, osteoblasts and chondrocytes. Marker proteins on cells can be used to sort the ones that will differentiate into specific target cells.^{1,21,22,46–49} However, which of the sorted cells are best for clinical use is unknown.⁵⁰ The simplicity of our selection procedure, based only on attachment and proliferation of bone marrow cells on collagen, would be a significant advantage for clinical applications.²⁰

2.2. Freeze-injured urinary bladders

Three days prior to implantation, we apply an iron bar (25 × 3 × 2 mm) refrigerated by dry ice onto the posterior urinary bladder walls for 30 sec.^20,44 Placement of the chilled iron bar causes local freezing of the bladder wall. Within 10 sec after removal of the bar, the frozen spots thaw due to body and/or room heat and appear to the naked eye similar to the intact normal bladder walls. However, when we monitor blood flow within the blood capillaries of the frozen area with CCD (charge-coupled device) video microscopy, the blood flow pauses for approximately 20 min after the operation, and then resumes. It is likely that the freeze-injured urinary bladders experience a period of ischemia followed by reperfusion as described by one of the microcirculation dysfunction models.⁵¹ At 3 days after the freeze-injury operation, the wounded area, which occupies approximately one-third of each urinary bladder, is readily identified by the presence of a hematoma (Fig. 1b).

The freeze-injured urinary bladders have both injured and uninjured regions that are easily observed by histology. The smooth muscle layers of the injured regions are disorganized and readily distinguished from the surrounding uninjured regions that have highly organized layers composed of abundant smooth muscle cells (Fig. 1b). The injured regions lose the majority of the smooth muscle actin (SMA)-positive smooth muscle cells (Fig. 1c). The blood vessels within the injured regions also have few SMA-positive cells, and they appear to have a more fragile composition than those of normal urinary bladders.⁴⁴

2.3. Reconstructed smooth muscle layers

On Day 7 of culture, we dissociate the cultured bone marrow-derived cells and implant 2.0 × 10⁶ cells with a 30-G (30-gauge needle) microsyringe into the center of the 3-day-old wounded region.²⁰ The implantation cell number and volume are chosen to avoid further damaging the cells with shear stress or the recipient tissues by bursting. Each operation is performed under a stereomicroscope where we visually confirm the presence of a small swelling, indicating that the implanted cells remained at the site. As controls, we inject cell-free solution. Fourteen days after cell implantation, we analyze the implanted regions of each bladder by immunohistochemistry and real time RT-PCR (reverse transcription polymerase chain reaction).²⁰ The implanted regions have numerous cells that are positive for the smooth muscle cell differentiation marker SMA. There are more SMA-positive cells in the regions implanted with the bone marrow-derived cells than in the control regions injected with the cell-free solution. These cells are organized into distinct smooth muscle layers (Fig. 2a). In contrast, the few SMA-positive cells present in the regions injected with the cell-free solution are not organized into layers (Fig. 2b).

Figure 2. Fourteen days after cell implantation or cell-free control injection. (a) The implanted regions have numerous SMA-positive smooth muscle cells (red) that are organized into layers (green, urothelium; blue, nuclei). The implanted cells are detected with GFP antibody in the recipient tissues (inset, green, dots). Some of the GFP-labeled cells are positive for proliferating cell nuclear antigen (inset, red, arrows), a marker of proliferating cells. (b) The control regions have very few SMA-positive smooth muscle cells. (c) At 14 days after implantation, the cells detected with GFP antibody (upper left inset, green cells) are simultaneously positive for the smooth muscle marker SMA (lower left inset, red cells) within the newly formed smooth muscle layers. The merged images (right, yellow cells) show that the implanted GFP-labeled cells have differentiated into cells expressing smooth muscle markers (blue, nuclei). (d) GFP-labeled cells contact each other in the newly formed smooth muscle layers (upper left inset, green cells). The same cells express smooth muscle cell differentiation marker MHC (lower left inset, red cells). The merged image shows the GFP-labeled, MHC-containing cells (right, yellow cells; nuclei, blue).

The quantity of SMA mRNA expression, which is exclusively expressed in smooth muscle cells, supports the immunohistochemical observations. At 14 days, SMA mRNA expression in the implanted regions is 17.44 ± 1.91 fold greater than the stable expression of beta-actin mRNA. It is significantly higher than that in the cell-free injected regions (9.45 ± 1.16 fold, P < 0.05). In fact, the expression level of SMA mRNA in the implanted regions is not significantly different from that in the normal urinary bladder, 21.87 ± 0.85 fold. Expression levels of other smooth muscle cell differentiation marker genes in the implanted region are also elevated. During normal development, myosin heavy chain (MHC) and calponin I are expressed at later stages than SMA mRNA.^52–58 In the implanted regions of the wounded bladders, MHC and calponin I mRNAs are expressed at 2.04 ± 0.48 and 1.91 ± 0.58 fold the level of beta-actin mRNA, both of which are significantly higher than in the cell-free injected control regions (0.44 ± 0.05 and 0.67 ± 0.15 fold, P < 0.05, respectively). There are no significant differences in MHC and calponin I mRNA expression levels when the implanted regions are compared to the normal urinary bladders. Expression of desmin mRNA in the implanted region, 3.58 ± 0.68 fold, is significantly greater at 14 days than either control or normal regions. Thus the implanted regions have larger numbers of mature smooth muscle cells and developing smooth muscle layers compared to the control regions.^59,60 Collectively, the immunohistochemical and gene expression results show that the implanted regions have formed smooth muscle layers composed of regenerated smooth muscle cells during the 14 days of the study period, while the control regions have only minimal recovery.²⁰

2.4. Implanted GFP-labeled bone marrow-derived cells

We regard cells that are positive for GFP-antibody in the recipient tissues as implanted bone marrow-derived cells. Some of the GFP-labeled implanted cells are positive for proliferating cell nuclear antigen, a marker of proliferating cells (Fig. 1a). In addition, within and outside the newly formed smooth muscle layers, some GFP-labeled cells that do not express smooth muscle cell differentiation markers are organized into cord-like structures.²⁰ The cells present within the formed smooth muscle layers may be in the process of differentiating into the smooth muscle cells. Alternatively, they may play other direct or indirect roles in the reconstruction of smooth muscle layers.^32,61–63

Bone marrow-derived cells have some characteristics of multipotent stem cells.^1,21,22 Consequently, the GFP-labeled cells that are outside the formed smooth muscle layers may have differentiated into cell types that provide histoarchitectural elements for the blood vascular system^27,47,49 or the nervous system.^46,48 Thus, the implanted bone marrow-derived cells may participate in other as yet unknown changes in the various tissues of the urinary bladder. Regardless of the roles played by each of these cell types, these results indicate that some of the implanted cells survive and take on properties of organ-specific cells and tissues in the recipient tissues by 14 days after implantation.²⁰

2.5. Differentiation of bone marrow-derived cells into smooth muscle cells

We use double staining with the smooth muscle cell differentiation marker SMA and GFP antibody to identify the regenerated smooth muscle cells that are derived from the implanted cells. Both GFP- and SMA-positive cells in the same sections show that the implanted bone marrow-derived cells differentiate into smooth muscle cells in the injured urinary bladders (Fig. 2c). Other implanted GFP-labeled cells are also positive for the smooth muscle cell differentiation markers MHC, desmin and calponin I.²⁰ The differentiation toward smooth muscle cells occurs after implantation because none of the cells in culture expressed detectable levels of the marker proteins. Therefore, the implanted regions have mature smooth muscle cells and developing smooth muscle cells that are differentiated from the implanted bone marrow-derived cells.^59,60

2.6. Formation of smooth muscle layers from the differentiated cells

Some of the GFP-labeled, differentiated smooth muscle cells contact non-GFP-labeled smooth muscle cells of the host that surround the implanted regions.²⁰ By day 14 of implantation, the reconstructed smooth muscle layers are integrated into the host tissues.²⁰ GFP-labeled developing smooth muscle cells are also in contact with each other, forming newly differentiated smooth muscle layers that are integrated into the existing host smooth muscle layers and other tissues (Fig. 2d).

2.7. Recovery of bladder contractions

Cystometric investigations at 3 days after injury show that the mice do not have defined regular bladder contractions.²⁰ The bladder contractions at 14 days after cell-free control injection also remain disrupted.²⁰ However 14 days after cell implantation, there are distinct regular bladder contractions, 42.2 ± 2.7 cm H₂O, that are similar to those of normal mice without injury.²⁰ Thus, cystometric investigations indicate that implanted bone marrow-derived cells have the potential to restore some or all normal bladder functions. We believe that the smooth muscle layers reconstructed by the implantation of the cells contribute to the restoration of bladder contractions.

Jump to…Top of pageAbstract1. INTRODUCTION2. RECONSTRUCTION OF SMOOTH MUSCLE LAYERS3. MICROENVIRONMENT4. TISSUE ENGINEERING5. CONCLUSIONREFERENCES

3. MICROENVIRONMENT

3.1. Microcirculation in the freeze-injured urinary bladders

At 3 days after the freeze-injury operation, we observe the wounded areas by CCD video microscopy. Blood capillaries in the intact normal bladder walls have a robust flow of red blood cells with a velocity of 0.26 ± 0.03 mm/sec (Fig. 3a). In contrast, while maintaining a partial microcirculation, blood capillaries within the wounded bladder walls are not as abundant compared to normal bladder walls (Fig. 3b). Further, the blood flow velocity of the injured regions is 0.12 ± 0.11 mm/sec (P < 0.05). The mechanism(s) for the reduced flow rate is not known with certainty. Regardless of the reason, the most important finding is that the injured regions are maintained with only a partial microcirculation. The maintenance of at least a minimal microcirculation to provide oxygen and nutrition is likely to be one of the prerequisite factors necessary for successful tissue engineering.⁴⁴

Figure 3. Microenvironment of the control and freeze-injured bladders immediately before implantation of bone marrow-derived cells. (a) Intact normal bladder walls have blood capillaries (arrows) with vigorously flowing red blood cells. (b) While the freeze-injured areas maintain partial microcirculation, blood capillaries (arrows) are not as apparent compared to the normal areas. (c) Intact normal bladder walls contain layered structures composed of smooth muscle cells (arrows, bladder wall exterior surface). The intact smooth muscle layers do not contain any large porous spaces. (d) The freeze-injured regions have few typical layered structures composed of smooth muscle cells. However, they have many large porous spaces (arrows) that are over 10 µm in diameter. (e) In the intact normal bladder walls, smooth muscle cells, containing large, well-formed nuclei (asterisks), are spindle-shaped and arranged in sheets. Adjacent smooth muscle cells are connected by gap junctions (arrows). (f) Smooth muscle cells within the freeze-injured regions are shrunken and have blebs. Nuclei of the injured cells (arrowheads) show chromatin condensation and nuclear fragmentation. Gap junctions are rarely present between the remaining cells of the smooth muscle layers.

3.2. Structure of the freeze-injured urinary bladders

We observe the intact normal and freeze-injured bladder walls by scanning electron microscopy. The normal bladder walls have smooth muscle cells organized into layers that are readily apparent. These layers do not contain any porous spaces that are over 10 µm in diameter (Fig. 3c). In contrast, the freeze-injured bladder walls have few typical structures composed of smooth muscle cells. Additionally, there are many large porous spaces that are over 10 µm in diameter (Fig. 3d).

By transmission electron microscopy, the normal bladder walls contain spindle-shaped smooth muscle cells with readily apparent nuclei (Fig. 3e). These cells are arranged in sheets and connected with each other by gap junctions. In contrast, smooth muscle cells in the freeze-injured bladder walls are shrunken, and exhibit blebbing (Fig. 3f). The chromatin is condensed and nuclear fragmentation is apparent. Also, gap junctions are rarely present between the remaining cells of the smooth muscle layers. Based on the cytological observations, smooth muscle cell death is predominantly due to apoptosis, though we cannot exclude the occurrence of necrosis, especially immediately after the freezing injury.⁴⁴

The freeze-injured bladder walls contain numerous large pores, like those seen by a scanning electron microscopy, that are not present in the normal bladder walls. The origin of these pores is not certain, but may be due to loss of smooth muscle cells that are the principal component of the wall in intact urinary bladders.⁴⁴ In fact, the pores within the freeze-injured urinary bladders may be helpful in establishing a high rate of cell implantation and survival.⁴⁴ They may also serve as scaffolding for the reconstruction of tissue structures.⁴⁴

3.3. Expression of growth factor mRNAs by host cells of the freeze-injured urinary bladders

Using real-time RT-PCR arrays, we estimate 84 growth factor mRNAs expressed by the host tissues in the freeze-injured bladders, even in the absence of implanted bone marrow-derived cells.⁴⁴ Nineteen of these exhibit at least a twofold increase over the intact normal bladders. The most impressive increases are for secreted phosphoprotein 1 (SPP1, 998.30-fold), inhibin beta-A (INHBA, 31.34-fold), glial cell line derived neurotrophic factor (GDNF, 7.40-fold), and transforming growth factor, beta 1 (TGFB1, 2.85-fold) compared to the normal urinary bladders. TGFB1 specifically promotes differentiation of smooth muscle cells from bone marrow-derived cells.^24,64–66 The others, SPP1,^67,68 INHBA,^69–74 and GDNF,^75–77 also support differentiation of smooth muscle cells from bone marrow-derived cells. In addition, inflammation-related cytokine growth factor mRNAs for interleukins (IL)-6, -11, -1A, -1B, and -18 are upregulated along with angiogenic-associated growth factor mRNAs for epiregulin (EREG), chemokine (C-X-C motif) ligand 1 (CXCL1),^78,79 teratocarcinoma-derived growth factor (TDGF1),⁸⁰ fibroblast growth factor 5 (FGF5),⁸¹ and vascular endothelial growth factor A (VEGFA) that have the potential to improve microcirculation within the injured regions. In addition to the above growth factors, expression of trefoil factor 1 (TFF1),^82,83 colony stimulating factor 3 (CSF3),⁸⁴ hepatocyte growth factor (HGF), and bone morphogenetic protein 1 (BMP1) mRNAs is also elevated. The roles of these growth factors are unclear, but it is likely that they participate in wound healing.

Collectively, these results show that cells of the urinary bladder respond to freeze injury by enhanced transcription of mRNAs specifically associated with differentiation of smooth muscle cells and wound healing.^20,44 If translated, expression of these genes can promote growth and development of a suitable physical and biochemical environment. Under these circumstances, the microenvironment within the freeze-injured urinary bladders would promote organization of the developing cells into physiologically functional tissues.⁴⁴

3.4. Importance of the uninjured regions within freeze-injured urinary bladder

It is likely that recovery within the freeze-injured urinary bladders requires participation of the undamaged tissue adjacent to the injured site.^20,44 In general, the success of implanted undifferentiated cells depends upon the recovery of host cells to provide an appropriate microenvironment at the location of the injury or disease site. These host cells are necessary to support the production of growth factors by the implanted bone marrow-derived cells.^85–87 The absence of a supportive microenvironment in the surrounding host tissues, as might occur in cases of irreversible or chronic diseases and/or injuries of the urinary bladder due to spinal injury or radiation therapy, might prevent or limit the recovery processes associated with the implanted cells.⁴⁴

Jump to…Top of pageAbstract1. INTRODUCTION2. RECONSTRUCTION OF SMOOTH MUSCLE LAYERS3. MICROENVIRONMENT4. TISSUE ENGINEERING5. CONCLUSIONREFERENCES

4. TISSUE ENGINEERING

Tissue engineering is composed of three components: (i) undifferentiated cells having the potential to differentiate into specific cell types; (ii) scaffolding to support construction of tissue structures; and (iii) growth factors to promote differentiation of various and specific cell types. The bone marrow-derived cells are an excellent source of multipotent undifferentiated cells that can develop into smooth muscle cells.^{12,20,23,24,88,89} The tissue pores that are present 3 days after freeze-injury operation are likely to provide scaffolding and spaces suitable for colonization by the implanted bone marrow-derived cells. This would optimize the chance for a high rate of cell survival and differentiation.⁴⁴ Though we have not actually measured the secretion of growth factors by the surviving cells, at least 19 different growth factor mRNAs are increased 3 days after the freeze-injury operation. Included in these are growth factor mRNAs for SPP1, INHBA, GDNF, and TGFB1. If they are translated, they would be able to support the differentiation of the implanted bone marrow-derived cells into smooth muscle cells.⁴⁴ Finally, the maintenance of a minimal microcirculation within the injured regions probably supports growth and development of the implanted bone marrow-derived cells.⁴⁴ For all of these reasons, the freeze-injured urinary bladders provide a suitable microenvironment for differentiation and development of the implanted cells.⁴⁴

Recipient tissues do not always have a suitable microenvironment for the implanted cells. Thus, there is a need for new investigations that develop novel combinations of scaffolding and/or growth factors to support tissue engineering of stem-type cells that promote regeneration in severely damaged organs.^90–93 In many cases, there might not be an adequate scaffold in vivo to support the implanted cells. Under those circumstances, it may be possible to construct scaffolds in vitro using biocompatible materials, as we have shown for the development of hepatocyte-like cells.^94,95 To promote appropriate cellular differentiation, growth factors delivered by sustained-release or other drug delivery systems also may be necessary.

Jump to…Top of pageAbstract1. INTRODUCTION2. RECONSTRUCTION OF SMOOTH MUSCLE LAYERS3. MICROENVIRONMENT4. TISSUE ENGINEERING5. CONCLUSIONREFERENCES

5. CONCLUSION

We have shown that the bone marrow-derived cells implanted into freeze-injured mouse urinary bladders differentiate into smooth muscle cells. These cells can reconstruct layered smooth muscle structures, and the implanted cells, or those derived from them, can restore bladder contractions. These results suggest that implantation of the bone marrow-derived cells can produce functional smooth muscle layers in irreversibly damaged urinary bladders associated with the loss of smooth muscle layers due to injury or disease. In our mouse model for bladder regeneration, the recipient tissues have many large pores that may be necessary, or at least helpful, for a high rate of cell implantation and survival. These pores may also serve as scaffolding for the reconstruction of tissue structures. Based upon the high level of growth factor mRNAs produced by the implanted and/or host cells, full regeneration is likely to depend on the production of these growth factors to promote organization of the developing cells into physiologically functional tissues. Successful reconstruction of smooth muscle layers can occur with the appropriate combination of the bone marrow-derived cells and the suitable microenvironment. In this review, we suggest that to develop the full potential of clinically regenerative medicine, we need not only a further understanding of the requirements for undifferentiated cell proliferation and targeted differentiation, but also further knowledge of each unique microenvironment within recipient tissues.

source:LUTS

Management of Low Compliant Bladder in Spinal Cord Injured Patients

Posted by zedie

Low bladder compliance means an abnormal volume and pressure relationship, and an incremental rise in bladder pressure during the bladder filling. It is well known that at the time bladder capacity decreases, intravesical pressure increases, and the risk of upper deterioration increases. Hypocompliance is usually thought to be the range from 1.0 to 20.0 mL/cmH₂O. Though the exact cause of hypocompliance is not known, it may be caused by changes in the elastic and viscoelastic properties of the bladder, changes in detrusor muscle tone, or combinations of the two. Management aims at increasing bladder capacity with low intravesical pressure. The main is a medical therapy with antimuscarinics combined with clean intermittent catheterization. The results are sometimes unsatisfactory. Various drugs or agents through the mouth or the bladder, including oxybutynin, new antimuscarinics, capsaicin and resiniferatoxin were tried. Among them botulinum toxin-A is promising. Some patients eventually required surgical intervention in spite of the aggressive medical therapy. Finally most patients undergo the surgical treatment including autoaugmentation, diversion, and augmentation cystoplasty. Among them augmentation cystoplasty still seems the only clearly verified treatment method.

Compliance refers to the volume and pressure relationship of bladder filling. Intravesical pressure, mural tension and bladder volume can affect the bladder compliance (BC). During bladder filling, intravesical pressure is normally maintained with little change. Low BC means an abnormal volume and pressure relationship, in which there is a high incremental rise in bladder pressure during the storage phase.¹ It is well known that low BC can put the upper tract at increased risk of deterioration.^2,3

BC is calculated by dividing the volume change by the change in bladder pressure (mL/cmH₂O). The normal bladder stores volumes of urine at low pressure. It is due to the viscoelastic property. In normal compliant bladder, there is almost no pressure changes as the bladder fills. Low BC may be caused by changes in the elastic and viscoelastic properties of the bladder, changes in detrusor muscle tone, or combinations of the two.^4,5

At present there are no standard values to define normal, high, and low compliance. Many factors can affect the compliance. Abrams⁶ believed that normal compliance would be a pressure of 3.3 cmH₂O or less at 100 cc volume. Although the exact cut-off value for low BC have not been defined, it is usually thought to be the range from 1.0 to 20.0 mL/cmH₂O.^7–9 Weld et al.¹⁰ defined 12.5 mL/cmH₂O as the normal cut value, considering the compliance of their patients and the development rates of upper tract deterioration. The value is also regarded to be the standard value in the studies of our institute. However, the criteria by International Continence Society was 10 mL/cmH₂O.¹¹

The pressure increase has various patterns. Its pattern depends on whether the increase in the detrusor pressure is at the initial or terminal phase during the filling cystometrogram. BC can be divided into two main types: initial and terminal compliance.^1,12,13 In children with myelomeningocele, initial compliance was variable, whereas terminal compliance was relatively constant. Low terminal compliance was related to vesicoureteral reflux, deterioration of upper tract morphology and diminished renal function.⁴

However, the relationship of the patterns of pressure increase with underlying conditions is not well known. Cho et al.¹⁴ classified the BC patterns into three groups. Group A (gradual increase) had the highest correlation with the presence of spinal cord injury. Group B (terminal increase) patients had a history of direct pelvic treatment such as radical prostatectomy and pelvic irradiation. Group C (abrupt increase and plateau) was positively correlated with the presence of detrusor overactivity and nocturnal enuresis (Fig. 1). Gradual increase of the pressure is commonly observed in low compliant bladder in spinal cord injured patients.

Figure 1. Three different types of low compliance pattern: (a) type A means gradual increase of detrusor pressure; (b) type B means terminal increase of detrusor pressure; and (c) type C means abrupt increase and sustained pressure of the detrusor.

BC is one of the most important factors in planning the management of spinal cord injured patients. There are many reports on the relationship between low compliant bladder and the upper tract deterioration. Various methods of the treatment were introduced for storage disorder in patients with neurogenic bladder. Most methods aim to treat detrusor overactivity. They are not specific for low BC. There are few papers for aiming at treating low compliant bladder in spinal cord injured patients. The present review will include pathophysiology and clinical significance of low BC, and current situation of management methods in these patients.

2. PATHOPHYSIOLOGY

Mechanical properties of the bladder can be divided into the active and passive components. The active component results from contractions of the smooth muscles cells of the wall and the passive component depends on the composition of the connective tissue matrix.¹⁵ Compliance is a function of the viscoelastic properties of all elements of the bladder wall. It includes the passive properties of the connective tissue and elastic components of the smooth muscle, and the active, contractile properties of the smooth muscle.¹⁶ Passive properties of the bladder wall are energy-independent and reflect the physical characteristics of the constituent elements. They are shown by the study on association between bladder fibrosis and poor compliance in the bladder wall of dogs.¹⁷ Similarly, there is connective tissue infiltration into the muscle bundles of unstable bladder with bladder outlet obstruction in humans.¹⁸ Indeed, it is thought that any injury which results in a change in the connective tissue composition of any part of the bladder wall may result in a reduction in the compliance of that part. This may then be a decrease in compliance of the whole bladder.

BC refers to the viscoelastic behavior of the urinary bladder, which depends upon the viscoelastic properties of such components as smooth muscle, collagen and elastin in the bladder. As the collagen content increases, the viscoelasticity decreases. Elastic and viscoelastic abnormalities are due primarily to changes in the extracellular matrix. It is composed of four generic types of macromolecules: collagens, elastins, proteoglycans and glycoproteins. Collagen and elastin account for the structural support of the tissue; the proteoglycans and glycoproteins fill interstices. The collagens with more than 20 different collagen types are identified so far. And with respect to passive mechanical properties types I and III are the most important.^15,19,20

Both types of collagen are arranged in banded fibrils and have different mechanical properties. In the bovine bladder model, it has been shown that increased BC parallels a decrease in the ratio of type III to type I collagen and decreased compliance parallels an increase in the same ratio, that is, an increase in the percent of type III collagen.²¹ In noncompliant human bladders, there is increased expression of type III collagen messenger RNA and pericelluar infiltration of type III collagen, that is, deposition mainly between the detrusor muscle bundles.²²

The gradual decrease of BC was usually correlated with detrusor overactivity. The mechanism of detrusor overactivity was explained as detrusor muscles become more sensitive to stimuli and detrusor overactivity occurs as a result.²³ Furthermore, denervation supersensitivity was thought to be a cause and is often accompanied by detrusor hypertrophy. Kok et al.²⁴ reported that the structural changes that result from urinary flow obstruction become special in the bladder, that is, a specific sequence of stages, including first a compensatory increase in contractility, then a stabilization phase and finally a decompensation state.

Two categories of etiology have been representatively reported to explain low BC; the decrease of blood flow to the bladder^25,26 or bilateral injury of the pelvic nerve plexus.^27,28 The decrease of vascular flow might be due to a vascular injury during surgery in the pelvic cavity or the failure of vascular flow secondary to injury of the autonomic nervous system in the pelvis. Neurovascular injury and denervation could increase the collagen content.¹⁹ And pelvic irradiation or inflammation can cause direct injury that leads to a decrease of the BC.²³ This low BC can be associated with the inflammation in whole bladder wall, which may be caused by interstitial inflammation, chemicals or radiation or carcinoma in situ.²⁹ In spinal cord injured patients, long-term indwelling catheterization in the bladder, chronic urethral obstruction and associated chronic inflammation can make the bladder low compliant.

The exact mechanism by which parasympathetic decentralization in the bladder results in bladder hypocompliance is unclear. There is evidence in animals and humans that sacral decentralization results in a change in detrusor body adrenergic receptor response. This parasympathetic neural injury can reverse the usual beta-adrenergic receptor response to an alpha-adrenergic effect. Activity of smooth muscle relaxation is changed to smooth muscle contraction.^30,31 On the other hand, Neal et al.³² found that denervation of the bladder resulted in no increase in the density of adrenergic nerves and a greater density of cholinergic innervation in the human bladder body in the long term. Nonetheless, sacral decentralization, whether caused by a lesion of the conus medullaris, cauda equina or peripheral pelvic nerves, often results in low BC in the spinal cord injured patients. And there is some experimental evidence that sympathetic denervation in cat decreases BC. It means decrease in beta-adrenergic stimulation.^29,33 And there is an evidence in animal experiment that sacral rhizotomy adversely affects BC. Low compliant bladders were reported among the patients who underwent sacral rhizotomy.³⁴

In summary, low BC may be due to the changes of passive properties of the detrusor muscle. The first probable mechanism is long standing infection and stimulation, which results in structural changes in the bladder wall such as fibrosis. The second possible mechanism is of myogenic origin. Denervated muscles are changed to the increased collagen and hypertrophy of smooth muscles fibers.³⁵ The third possible mechanism is of neurogenic origin. Hypertrophy of the detrusor muscle could induce a hyperactivity of nerve and muscle cell. Low compliance can be induced by autonomous contraction of newly produced cholinergic nerve fibers due to prolonged injury of parasympathetic nerves.^32,36

Jump to…Top of pageAbstract1. INTRODUCTION2. PATHOPHYSIOLOGY3. CLINICAL SIGNIFICANCE4. MANAGEMENT5. CONCLUSIONREFERENCES

3. CLINICAL SIGNIFICANCE

Compliance plays a crucial role in the long-term function of upper urinary tract. Bladder pressure effects ureteral urine transport and renal function in the long-term. Low BC is hazardous to the kidneys because the sustained intravesical pressure adversely affects the activity of the ureter and ureterovesical junction.³⁷ Bladder hypocompliance is the most common cause for hydronephrosis in the spinal cord injury patient. The grade of hydronephrosis or reflux was not associated with the degree of low compliance or the interval after injury. However, kidneys with grades 3 and 4 hydronephrosis are common in low compliant bladder.²⁹

Patients using intermittent catheterization maintained normal compliance significantly well in comparison with the Foley management group for suprasacral, complete and incomplete injury. Normal compliance was more common in patients with suprasacral than sacral and incomplete than complete spinal cord injury for each bladder management type. Clean intermittent catheterization (CIC) and spontaneous voiding were associated more with normal compliance than Foley catheterization. Low BC or the development of low compliance with time was most likely in patients on chronic Foley catheterization. Low compliance was statistically associated with vesicoureteral reflux, radiographic upper tract abnormality, pyelonephritis, and upper tract stones. Low compliance was reported in 35% of spinal injured patients who performed spontaneous voiding after the injury and 26% who did CIC, whereas 77% of patients with chronic indwelling catheter showed low compliance.¹⁰

In cauda equina injury, when low compliant bladder was compared with the normal group, the interval between the onset of injury and the initiation of rehabilitative treatment was significantly longer, and there were a higher number of voiding methods either by Crede’s maneuver or by indwelling catheter prior to admission.³⁶ Fifty percent patients of cauda equina injury showed low compliance, and low compliant bladder was observed in 28% in other study.³⁸

In our study risk factors were indwelling catheter, time elapse after injury, and duration of indwelling.^39,40 Ten percent of suprasacral lesion and 50% of sacral or infrasacral lesion had low compliant bladders. Fifty-five percent of our spinal injured patients had low compliance; 55.7% of suprasacral lesion and 52.4% of sacral or infrasacral lesion. Fifty percent in spinal cord injury patients with definite sacral nerve injury had a low compliant bladder. This certainly is in contrast to the suprasacral lesions in which only 10% of the patients had low compliant bladders.²⁹

Low compliance was not related to the injury site. Low compliant bladder was found in 37.4% of our spinal injured patients. Time elapse after injury was a significant risk factor. We divided them to three periods; below 1 year, from 1 to 5 years, and after 5 years. The incidence after 1 year was significantly higher than below 1 year. But the incidence from 1 to 5 years was not different from that after 5 years. Injury site was not significant risk factor in our institution. But the neurological injury site that results in the development of low BC has been documented mostly in injury to the sacral cord or sacral plexus.^39,40

Of the 196 patients with suprasacral injuries, 186 (94.9%) demonstrated hyperreflexia and/or detrusor sphincter dyssynergia, 82 (41.8%) had low bladder compliance, and 79 (40.3%) had high detrusor leak point pressures. Of the 14 patients with sacral injuries, 12 (85.7%) manifested areflexia, 11 (78.6%) had low compliance, and 12 (85.7%) had high leak point pressures. Of the 33 patients with combined suprasacral and sacral injuries, urodynamic studies showed 23 with hyperreflexia and/or detrusor sphincter dyssynergia (67.7%), 9 with areflexia (27.3%), 19 (57.6%) with low compliance, and 20 (60.6%) with high leak point pressures.¹⁰

Low compliant bladder was found in 45% in spinal cord injured patients with detrusor hyperreflexia and in 28% in them with detrusor areflexia. Generally the compliance is lower in hyperreflexic bladder patients than in areflexic bladder patients. Low compliance was found in 41% patients with detrusor-external sphincter dyssynergia and 52% patients without detrusor external sphincter dyssynergia (DESD). Normal compliance was found in 59% with DESD and 48% without DESD. DESD was not a risk factor. Indwelling catheterization was a risk factor and its duration was important.^39,40

Upper tract deterioration was found in 50–70% patients with low compliance, but in 2–22% patients with normal compliance. Patients’ age and sex were not risk factors. The deleterious effect of a high detrusor leak point pressure on the upper tracts was already reported in patients with myelodysplasia.^2,41 When the leak point pressure was greater than 40 cmH₂O, 85% of the patients developed hydronephrosis and 68% had vesicoureteral reflux. On the other hand, when the pressure was less than 40 cmH₂O, only 10% developed hydronephrosis and none of them had reflux. The calculated value of compliance is probably less important than the actual pressure during filling. Absolute sustained detrusor pressures of 35–40 cmH₂O or greater during storage, regardless of the bladder volume, can lead to upper tract damage. However, once the compliance of the bladder become low, intravesical pressure is rising too.⁴¹ The reference to myelodysplasia can be insignificant in patients with spinal cord injury. However we can obtain the lesson that high intravesical pressure can deteriorate upper tracts.

4. MANAGEMENT

The first line of treatment is usually anticholinergic medications, timed voiding schedules and intermittent catheterization in relatively good circumstances. If the outcome is inadequate, bladder pressure remains high and eventually results in hydronephrosis, renal deterioration, and incontinence. And then more aggressive treatment can be considered.

4.1. Oral drugs

Increased efferent excitatory activity during bladder filling or reduced inhibition by sympathetic nerve may be implicated in the development of abnormal smooth muscle activity in humans, such as reduced compliance and uninhibited detrusor contractions. The efficacy of antimuscarinic agents in the patients with bladder overactivity may be explained.⁴²

The main medical therapy to reduce detrusor overactivity in the neurogenic bladder has been antimuscarinic drugs for several decades. These agents have been proven to increase bladder capacity, decrease bladder filling pressure and improve compliance.^43,44 Although antimuscarinics combined with CIC is the most commonly recommended medical therapy for the neurogenic bladder patients the results are sometimes unsatisfactory. Many patients continue to have poor BC and remain incontinent.⁴⁵

In the normal human bladder M2 receptors are greater in number than the M3 receptors. However, the M3 receptors directly mediate bladder contractions.⁴⁶ The receptors are not limited to the detrusor muscle as the urothelium and suburothelium have a sensory role, and blocking their M2 receptors affects bladder afferent signaling. However, in the neurogenic bladder M2 receptors increase in density and there may be a shift toward M2 receptors mediating bladder contractions, but this still remains controversial.⁴⁷ Anticholinergic medications can reduce hydronephrosis, improve BC as well as lower leak point pressures even in patients with chronic catheters.⁴⁸ Nevertheless, the rates of reflux, elevated serum creatinine, renal scars and bladder or renal stones were similar to a group of patients without anticholinergic therapy.

The human detrusor contains two varieties of alpha1-adrenergic receptor subtypes; alpha1-a and alpha1-d, whereas the bladder neck in both sexes and the prostatic urethra contain predominantly alpha1-a.⁴⁹ It has been shown that in the decentralized human detrusor there may be an increase in alpha-adrenergic receptor sites and a switch to alpha-adrenergic contractile function from the typical beta-adrenergic relaxation function during bladder filling.³² However, treatment with tamsulosin did not reduce maximum urethral closure pressure and increase bladder capacity in a randomized controlled trial.⁵⁰

The tricyclic antidepressant imipramine has been shown to suppress bladder overactivity by various mechanisms. It is empirically used and the mechanism is not well known. It is thought that it is a muscarinic receptor agonist, a direct smooth muscle inhibitor and it decreases bladder overactivity by blocking the reuptake of serotonin. Other effects include the peripheral blockade of noradrenaline, stimulating the beta receptors at the dome of the bladder and decreasing bladder contractility.⁵¹ Imipramine has been shown to increase compliance in the pediatric neurogenic bladder.^52,53 It does not have any randomized controlled trials to support its use for urological indications. And it has been thought to be related to cardiac events and so must be used with caution.

Combination therapy with an antimuscarinic agent, an alpha–blocker and imipramine yielded results superior to those of a single agent. These three drugs had a synergistic effect on the bladder in the neurogenic bladder patients. The addition of three drugs was more beneficial than the addition of only two. In highly selected group of patients with neurogenic bladder dysfunction and poor BCcombination therapy with two or three drugs improved compliance, decreased bladder pressures at capacity and improved clinical outcomes. However, this study was not prospective in nature and small in size.⁵⁴

The concept that medical therapy can improve BC is well known. Goessl et al.⁵⁵ treated 41 children with meningomyelocele already on CIC with oral oxybutynin. The outcome was good. Maximal bladder capacity increased 40%, detrusor pressure at maximum capacity decreased 38% and compliance increased 158%. In a randomized controlled trial of oxybutynin versus propiverine in the neurogenic bladder patients, Stöhrer et al.⁵⁶ showed both drugs were equally effective in increasing bladder capacity and lowering bladder pressure, and detrusor compliance was significantly improved in patients with neurogenic detrusor overactivity.

The flexible dosing of oxybutynin could potentially improve clinical outcome without compromise to treatment tolerability in patients with neurogenic detrusor overactivity and the effect has already been observed in those patients.⁵⁷ Other anticholinergic agents, such as tolterodine, trospium, and darifenacin, were studied in patients with neurogenic detrusor overactivity.⁵⁸ For example, tolterodine was found to have similar efficacy to oxybutynin in terms of significantly increasing bladder capacity and detrusor compliance, and decreasing detrusor pressure in children with neurogenic detrusor overactivity.⁵⁸ Several urodynamic variables, such as residual urine volume, volume at first detrusor contraction, and maximum cystometric capacity, improved notably with tolterodine administration to adult patients with neurogenic detrusor overactivity.⁵⁹ It was demonstrated that patients with spinal cord injury and detrusor hyperreflexia experienced significant increases in maximum cystometric capacity and bladder compliance, and a decrease in maximum detrusor pressure when treated with trospium.⁶⁰

4.2. Intravesical oxybutynin

Intravesical instillation of agents has been used to treat incontinence caused by detrusor overactivity. Oxybutynin has been administered in the bladder to decrease anticholinergic side effects. The serum concentrations of oxybutynin after intravesical administration are at least as high as those reported after oral drug intake, but the parent drug/metabolite ratio is much higher after intravesical administration. The elimination of oxybutynin as well as its metabolite is prolonged after intravesical administration compared with that reported after oral drug intake.⁶¹ It suggests another mechanism for fewer side effects after instillation. The significantly lower ratio of the N-desethyl metabolite over the mother compound, due to a reduced first pass metabolism, may explain the clinically relevant reduction of side effects that characterizes intravesical compared with oral oxybutynin therapy.⁶²

Targets of this approach are the bladder afferents by a local anesthetic effect on type C-fibers and the efferent cholinergic transmission by an anticholinergic effect. It must be instilled regularly, usually two or three times a day. Intravesical oxybutynin has been shown to increase bladder capacity and produce clinical improvement in neurogenic detrusor overactivity with few side effects. However, data on low compliant bladder were very few.

Children with neurogenic bladder and poor BC are usually treated with bladder catheterization and oral anticholinergic medication. They may become nonresponders to the drug or present with severe side effects. A total of 297 children started treatment and 22% discontinued therapy, with 9% quitting due to systemic side effects. Mean change in BC was reported in only two studies (+7.4 and +7.5 mL/cmH2O). The mean change in pressure at maximum bladder capacity was −16.4 cmH2O. Incontinence improved significantly in most studies, with improvement rates ranging from 61 to 83%. Although the optimum dose for intravesical instillation has not been determined, it was known that an oral dose of 0.2 mg/kg daily can be safely used intravesically in children. It was reported that neurogenic detrusor overactivity improved from 33 to 77%. Such improvement can hypothetically be secondary to topical analgesic effect on the sensitive C-fibers of the detrusor muscle, increasing their threshold for activation.^63–65 It is believed that adjunctive intravesical oxybutynin therapy can increase mean maximum bladder capacity and decrease bladder pressure in children with neurogenic bladder.

4.3. Intravesical capsaicin and resiniferatoxin

Two intravesical agents, capsaicin and resiniferatoxin (RTX), that block vanilloid receptors in the bladder have been used to treat detrusor overactivity. Vanilloids block C-fiber afferent nerves, which are implicated in the development of detrusor overactivity in certain pathologic conditions including spinal cord injury. Blocking afferent stimulation can inhibit reflex contractions. Since the beginning of the 1990s, much experimental and clinical evidence has shown the importance of sensory innervation of the lower urinary tract in the regulation of physiological activity and its implication in pathologies.⁶⁶

Capsaicin is the main pungent ingredient in hot peppers of the genus Capsicum. Capsaicin acts by interfering with sensory A delta and unmyelinated C-fibers. It was the first molecule used to treat functional disorders of the lower urinary tract.^66,67 Administration of capsaicin to peripheral nerve endings results in depolarization and discharge of action potentials, which in turn evokes burning pain. This stimulation produces an acute sensitization and then subsequently prolonged period of desensitization, which blocks further stimulation and thus inhibits detrusor reflex contraction.

It was found that around 80% of patients reported an increase in their symptoms and urodynamic parameters with long-term follow-up (5 years). These patients received further capsaicin instillation when the symptoms recurred. The efficacy of capsaicin in the treatment of detrusor hyperreflexia was questioned. They reported that intravesical treatment with capsaicin did not show beneficial effects on detrusor hyperreflexia in a placebo-controlled cross-over study and produced significant reactive changes in the mucosa of the bladder.⁶⁸ A study of 10 years experience seems to confirm that intravesical capsaicin is effective only in a low proportion of patients.⁶⁹ Furthermore it shows that capsaicin is not well tolerated: 13% of the patients reported a significant episode of autonomic dysreflexia during the infusion, and 35% presented rhythmic detrusor contractions causing leakage of the solution during the instillation. Widespread usage has been limited by side effects of pain during and hematuria after instillation.

On the other hand, a pilot study was reported on the use of RTX, an ultrapotent capsaicin analogue, in patients suffering from detrusor hyperreflexia in 1997.⁷⁰ RTX appears as an exciting alternative to capsaicin in the treatment of neurogenic incontinence. RTX is a natural pungent principle from cactus-like plants of Euphorbia resinifera and ultrapotent capsaicin-like activity. RTX is approximately 1000 times more potent than capsaicin but with minimal initial excitatory effects. A multicenter, blinded, randomized placebo controlled trial showed the safety and efficacy of intravesical RTX in patients with refractory detrusor hyperreflexia.⁷¹ Thirty-six neurologically impaired patients including 20 spinal cord injured patients with urodynamically verified detrusor hyperreflexia and intractable urinary symptoms despite previous use of anticholinergic drug were treated prospectively. At 3 weeks, maximal cystometric capacity increased by 53% and 48% and incontinence episodes decreased by 52% and 53%, depending the concentration of intravesical treatment. There were no long-term complications.

The efficacy and tolerability of the two vanilloid agonists was investigated. In the randomized, controlled study they compared nonalcohol capsaicin versus RTX in 10% alcohol in 39 spinal cord injured adults with detrusor hyperreflexia. On day 30, clinical and urodynamical improvement was found in 78 and 83% of patients with capsaicin versus 80 and 60% with RTX, respectively. The benefit remained in two-thirds of the two groups on 3 months. However there were no significant differences in regard to the incidence, nature or duration of side effects. They thought glucidic solute was a valuable solvent for vanilloid instillation.⁷² We reported the clinical and urodynamic effects of intravesical capsaicin and RTX, and compared with them in spinal cord injured patients with detrusor hyperreflexia. Capsaicin and RTX had lasting effects for 3 months, and RTX was a superior alternative to capsaicin.⁷³

The ideal dose, concentration, and duration interval between instillations has not been determined for either capsaicin or RTX. Unfortunately we do not have any evidence of these approaches for low compliant bladders. And capsaicin was given up due to severe side effects and RTX is currently not in development because of problems in formulation.

4.4. Intavesical botulinum toxin (BTX)

BTX acts by inhibiting acetylcholine release at the presynaptic cholinergic junction in skeletal and smooth muscle, causing partial or complete paralysis. There are seven distinct serotypes (A, B, C, D, E, F, G) but only two, BTX A and B, are available for clinical use. The toxin complex itself ranges from 300 to 900 kDa, which includes a 150 kD exotoxin, complete with both a heavy and a light chain. This complex exerts its action by heavy chain binding to a neuron, leaving the light chain to cleave a specific site on the target protein complex. Specifically, the light chain of BTX-A cleaves the synaptosomal associated SNAP-25 protein within the SNARE complex, which is involved in the exocytosis of acetylcholine vesicles in peripheral motor neurons.²⁰ The motor neuron is paralyzed after execution of this cleavage, thereby inhibiting contraction and causing muscle relaxation.⁷⁴ This chemodenervation is fully reversible as the formation of functional neuronal sprouts reconnects nerve endings in anywhere from 3 to 9 months on average.⁷⁵. In addition to its reversibility, the response is both dosage and site specific, giving a safe and effective result.

BTX must be injected directly into the detrusor using an endoscopic technique. Most studies have used between 100 and 300 units of BTX-A injected at 20–30 different sites. However, the ideal concentration, dose, number, and location of injection sites have yet to be determined. Over 200 patients from different institutions across Europe similarly demonstrated significant improvements in both symptoms and urodynamic parameters in patients with neurogenic bladder dysfunction treated with BTX-A.⁷⁶ This study followed patients at 12 and 36 weeks after injection with 300 U of the toxin at 30 different injection sites. Of the 180 patients examined at 12 weeks, 132 of them reported complete continence, while the remaining 48 patients reported 73% continence rate. At 36 weeks, 72/99 remaining patients reported continence. Additionally, at 12 weeks, 45 patients were able to completely discontinue their anticholinergic medications while 118 were able to significantly reduce their medication use. No significant complications were noted as a result of the injections. From an urodynamic standpoint, results were quite impressive. The mean maximal cystometric bladder capacity increased significantly from a baseline of 272 to 420 cc and 352 cc at 12 and 36 weeks, respectively. The residual volume increased from 236 to 387 cc and 291 cc at 12 and 36 weeks. And there were significant beneficial changes in voiding pressure and maximal bladder capacity during follow up evaluations.

There are many reports for improving neurogenic detrusor overactivity in spinal injured patients. Studies to date have shown that not only is this treatment effective at decreasing urinary symptoms and incontinence, as well as improving potentially dangerous urodynamic parameters, but it is also minimally invasive, reversible and safe. Questions over proper dosing and dilution, number of injection site, and re-injection rates still remains.

However, although there are few reports about low compliant bladders, many studies did show an overall increase in bladder compliance. Klaphajone et al.⁷⁷ studied BTA injection in patients with abnormally low compliant bladders. BTX-A 300U was injected into the detrusor muscle in 10 patients with high detrusor contraction pressure and/or poor response to oxyphencyclimine with incontinence. Six weeks after treatment, complete continence was restored in seven patients without oxyphencyclimine. Mean functional bladder capacity, compliance, and reflex volume significantly increased, whereas maximal detrusor contraction pressure significantly decreased. BC was shown to increase significantly from 6.5 mL/cmH₂O to approximately 14.5 mL/cmH₂O at 6 and 16 weeks with a return closer to baseline at 36 weeks. Results were similar for maximal cystometric bladder capacity and residual volume as initial evaluations at 6 weeks showed a mean bladder capacity to increase from 175 mL to 331 and residual volume from 54 mL to 86. These results were maintained at 16 weeks but returned close to baseline at 36 weeks. The procedure was generally uneventful, without any serious side effects. Patients may require repeat injections after 16 weeks to remain continent. In most patients with low BC, BTX-A injections could provide a valuable therapeutic alternative to radical surgery. Further randomized, placebo-controlled studies are needed, which could also help to further identify the types of patients who may benefit most from this treatment. There are limited data on BTX-B. It is too early to determine whether it will have results similar to those with BTX-A.

4.5. Augmentation cystoplasty

Augmentation cystoplasty increases bladder capacity and decreases detrusor overactivity by enlarging the bladder with the addition of a bowel segment and disrupting the detrusor. Basic principles are as follow: (i) the intestinal segment is detubularized by incising the antimesenteric border; (ii) the segment is reconfigured into the approximate shape of a half-sphere; (iii) a wide anastomosis between the reconfigured bowel and the bladder is performed; and (iv) a large bladder capacity is achieved. Low compliant bladders result in contracted bladder or small bladder capacity. And high intravesical pressure lead to severe frequency, urinary incontinence and upper tract deterioration. Augmentation cystoplasty is a kind of well-established surgery for treating them.²⁰

The goal is to create a large capacity reservoir with good compliance. Bladder can be emptied by CIC or spontaneous voiding. It is required that CIC is possible. Otherwise, continuous catheterization from the urethra and creation of a continent stoma can be alternative options. Sigmoid, ileocecal segment, ileum and even stomach can be used. Ileal segment is profuse and easily mobile. It provides effective and safe therapeutic outcomes in spinal cord injured patients with a contracted bladder and/or upper urinary tract deterioration. Postoperative intravesical pressure and volume is most important. However, problems with urinary tract infection, reservoir calculi and new onset of upper urinary tract stones still need to be resolved. Chen and Kuo⁷⁸ studied 40 patients with augmentation enterocystoplaty with ileal segment in patients with spinal cord injury with a mean follow-up period of 7.8 years. The mean bladder capacity increased from 115 to 513 mL after operation. Long-term complications included urinary incontinence in 10% patients, reservoir calculi in 32.5% and upper tract stones in 22.5%. They thought that augmentation enterocystoplasty with ileal segment provided effective and safe therapeutic outcomes in spinal cord injured patients.

Long-term (mean follow-up was 6.3 ± 3.8 years) functional and urodynamic results of augmentation enterocystoplasty in spinal cord injured patients with detrusor hyperreflexia and reflex incontinence who failed to respond to conservative treatment was assessed. Fifteen of 17 (88.5%) patients were completely continent with CIC. Long-term complications included recurrent pyelonephritis for one patient. Maximal cystometric capacity increased from mean 174 to 508 mL. Mean maximal end filling pressure decreased from 65 to 18 cmH₂O.⁷⁹

The long-term outcomes of augmentation cystoplasty were investigated in 19 spinal cord injured patients with neurogenic bladder, and our study included the complications and patients’ satisfaction with mean follow-up period of 120 months. Six months postoperatively, the urodynamic results showed significantly decreased intravesical pressures and increased bladder capacities. The intravesical pressure was decreased from 89 to 28 cmH₂O, and the functional bladder capacity was increased from 125 to 480 mL. The symptomatic urinary tract infections had disappeared, but the asymptomatic bacteriuria continued. The vesicoureteral reflux was eliminated, and the renal function normalized in all patients. The hydronephrosis had disappeared in most patients (89%). A few postoperative complications were reported. Most patients were very satisfied symptomatically (89%), with no patient expressing dissatisfaction. Augmentation cystoplasty could be an excellent method of treatment in selected patients with spinal cord injury. There were no significant complications, and a high degree of patients’ satisfaction.⁸⁰

4.6. Autoaugmentation

Bladder autoaugmentation by partial excision of detrusor muscle was first published by Cartwright and Snow.⁸¹ The concept came from the spontaneous development of bladder diverticula in neurogenic bladder patients. As the urothelium bulges through the muscular hiatus, it adds bladder capacity and decreasing the intravesical pressure. A portion of the detrusor is removed allowing the bladder epithelium and lamina propria to form a large-mouthed bladder diverticulum that serves to lower the bladder pressures and enhance bladder capacity.⁸²

The basic intervention for all types of bladder autoaugmentation is to expose the intact mucosa by excising some part of the detrusor wall. Recently, variations of the technique have been introduced.⁸³ Combinations with demucosalised enterocystoplasty or other coverage of the exposed mucosa are under study.⁸⁴ The advantage of partial detrusor myectomy instead of simple detrusor myotomy for bladder autoaugmentation is that regeneration of the muscular parts, covering the exposed mucosa will not take place easily.⁸⁵ Also, the capacity increase after detrusor myotomy is smaller than after myectomy. However, there was no statistical difference between vesicomyotomy and vesicomyectomy with respect to radiologic, pathologic, or urodynamic outcome.⁸⁶ However, mucosal fibrosis was developed in animal experiments.

Snow and Cartwright⁸² reported overall success as good in 52%, acceptable in 28%, and poor in 20% (from 25 patients). The cystometrograms at over 3 years showed continued improvement in bladder capacity and compliance in several patients. Patients with poor results have subsequently undergone conventional augmentation procedures. Fifty patients were treated by this method. Substantial increase of bladder capacity and compliance resulted. However increased residual urine developed and intermittent catheterization was needed in most patients. Some patients are able to perform complete voiding at will. The time lapse between surgery and substantial increase of capacity and detrusor compliance cannot be predicted yet. In most patients this improvement was observed 1–6 months after surgery, but the effect was equivocal for a year or longer in some patients. Low-dose anticholinergics appear to improve the therapeutic effect.

Bladder autoaugmentation is indicated in patients with neurogenic bladder, causing reduced detrusor compliance and/or bladder capacity, who were otherwise scheduled for enterocystoplasty. The postoperative morbidity was small and serious complications were not observed. More aggressive surgery, such as enterocystoplasty, is not precluded. It does not make other surgeries more difficult. Prerequisites for the procedure are the patient’s capabilities to perform intermittent catheterization and to understand that occasionally a longer period may pass to attain the functional changes.

4.7. Urinary diversion

A urinary diversion by continent or incontinent methods may be the best option in some patients with severe refractory incontinence. Diversion can be selected in patients who are unable to catheterize through the urethra, compared with augmentation cystoplasty.

While paraplegic patients with good hand function can self-catheterize with no difficulty, most spinal cord injured patients with cervical lesion depend on caregivers to perform catheterizations. In addition to poor hand dexterity, female quadriplegic patients have problems to localize their urethral openings. For those quadriplegic women with low BC that is unresponsive to medical therapy, management options include indwelling catheterization, and cystectomy or enterocystoplasty, and the creation of either a continent or incontinent urinary stoma as surgical intervention. A continent abdominal stoma is easy for catheterization. Continent, nonorthotopic urinary diversion can be divided into two major categories. First, the variations of ureterosigmoidostomy such as ileocecal sigmoidostomy, rectal bladder, and sigmoid hemi-Kock operation with proximal colonic intussusceptions are reported. These methods can give spinal cord injured patients bowel problems including diarrhea and are not proper for these patients. Second, there is the large category of continent diversions requiring CIC for emptying urine at intervals from the constructed pouch. It includes Kock pouch, Double T-pouch, Mainz I pouch, Indiana pouch, Penn pouch, Gastric pouches and etc.²⁰

Jump to…Top of pageAbstract1. INTRODUCTION2. PATHOPHYSIOLOGY3. CLINICAL SIGNIFICANCE4. MANAGEMENT5. CONCLUSIONREFERENCES

5. CONCLUSION

Bladder filling pressures must be kept below 40 cmH₂O because higher pressures have been shown to carry a high risk of renal dysfunction and vesicoureteral reflux. As low BC develops, bladder capacity decreases and intravesical pressure increases. Management aims at increasing bladder capacity with low intravesical pressure. Medical therapy has focused on antimuscarinic therapy. This therapy was proven to increase bladder capacity, decrease bladder filling pressure and improve compliance. Although antimuscarinics combined with CIC is the most commonly recommended medical therapy, the results are sometimes unsatisfactory. Many patients still suffer from poor BC and remain incontinent. Various drugs or agents through the mouth or the bladder were tried. Among them BTX-A is one of the promising agents. Despite this aggressive medical therapy some patients eventually required surgical intervention. Finally most patients undergo the surgery including autoaugmentation and augmentation cystoplasty. Augmentation cystoplasty still seems the only clearly verified treatment method.

Sensor Mechanism and Afferent Signal Transduction of the Urinary Bladder

Posted by zedie

Primary afferent neurons project to the urinary bladder via pelvic and hypogastric nerves, and not only the afferent terminals, but urothelium express a wide range of ion channels, ionotropic and metabotropic receptors. There is increasing evidence that mechanosensitive ion channels, especially TRPs play key roles in the mechanosensory and afferent signal transduction of the urinary bladder. Altered expression and/or function of these sensory molecules may participate the pathophysiological processes of bladder diseases.

Therefore, research about TRP channels in the bladder is an unexplored and very promising domain that can help us understand the molecular mechanisms leading to any type of bladder dysfunction including urinary incontinence. Parmacological interventions targeting TRPs may provide a new strategy for the treatment of bladder dysfunction.

source:LUTS

Current controversies in states of chronic unconsciousness

Posted by zedie

Coma resulting from brain injury or illness usually is a transient state. Within a few weeks, patients in coma either recover awareness, die, or evolve to an eyes-open state of impaired responsiveness such as the vegetative or minimally conscious state. These disorders of consciousness can be transient stages during spontaneous recovery from coma or can become chronic, static conditions. Recent fMRI studies raise questions about the accuracy of accepted clinical diagnostic criteria and prognostic models of these disorders that have far-reaching medical practice and ethical implications.

A 21-year-old woman lost control of her car and struck a bridge abutment. She sustained a severe traumatic brain injury (TBI) with subdural, subarachnoid, and intracerebral hemorrhages that was complicated by intracranial hypertension and generalized seizures. When examined in the neurorehabilitation center 6 months later, she was in a vegetative state with eyes-open wakefulness but without awareness of herself or her environment, no psychological responsiveness, and marked spasticity with little movement of her limbs. Her eyes were open and moving when she was awake and were closed when she was asleep. Brain CT scan showed bilateral thalamic and multifocal cortical areas of encephalomalacia with ex vacuo hydrocephalus. Her EEG had an irregular 4-Hz background with intermittent sharp waves over the right hemisphere.

Six months later, her parents reported that she had become responsive. The examiner could, at times, get her to follow a $20 bill with her eyes and to reach toward it but she followed no commands. Her pupillary light reflexes were normal and she had roving, full eye movements. Most of the time, examiners and staff members could elicit no responsiveness. She breathed spontaneously through a tracheostomy tube and was fed and hydrated by a gastrostomy tube. She required daily physical therapy to prevent contractures that had developed in all her limbs. Repeat brain imaging and EEG were unchanged. Her parents asked if she could undergo fMRI assessment which they discovered on an Internet search might prove that she was aware and could improve.

DIAGNOSTIC ISSUES

The vegetative state (VS) and minimally conscious state (MCS) are the principal clinical syndromes of patients with chronically disordered consciousness. As syndromes, they encompass a spectrum of severity and can be the consequence of a variety of brain injuries and illnesses.¹ Categorizing patients with disorders of consciousness into the correct diagnostic syndrome is essential, but the prognosis of each patient depends mostly on the cause and extent of the brain damage producing the syndrome.

The VS has been epitomized as “wakefulness without awareness” because the brainstem reticular system responsible for alertness and wakefulness remains intact but the thalamocortical systems responsible for awareness have been damaged. The VS is best conceptualized as a disconnection syndrome between the thalami and the cortex resulting from 1) bilateral thalamic damage; 2) diffuse cortical damage, especially involving the precuneus; or 3) damage to the white matter tracts connecting the thalami and cortex. The principal causes of VS are 1) TBI, which can cause damage by all 3 mechanisms, but especially by white matter tract damage from severe diffuse axonal injury because of rotational brain trauma; 2) hypoxic-ischemic neuronal damage to the cortex and thalami during cardiopulmonary arrest; and 3) brain infarction or hemorrhage with thalamocortical damage.¹

The vegetative state has been epitomized as “wakefulness without awareness”

The diagnostic criteria for the VS are listed in table 1 and the potential behavioral repertoire of the patient in VS is listed in table 2. That most of the clinical diagnostic criteria are delineated as negatives stipulating those functions patients in VS lack permits false-positive determinations. Several studies of the diagnostic accuracy of VS using these criteria found a disturbingly high false-positive rate of 40% in which patients with MCS were erroneously diagnosed in VS.² Examiners must pay special attention to any evidence for awareness and not diagnose VS if such evidence is present. and the potential behavioral repertoire of the patient in VS is listed in table 2. That most of the clinical diagnostic criteria are delineated as negatives stipulating those functions patients in VS lack permits false-positive determinations. Several studies of the diagnostic accuracy of VS using these criteria found a disturbingly high false-positive rate of 40% in which patients with MCS were erroneously diagnosed in VS.² Examiners must pay special attention to any evidence for awareness and not diagnose VS if such evidence is present.

The MCS is a related clinical syndrome of profound unresponsiveness but one that features nominal and intermittent evidence for awareness. Patients may develop MCS from the same disorders that produce VS. A common evolution after diffuse brain injury is coma progressing to the VS and then to the MCS. Like patients in VS, patients in MCS have generally intact brainstem function but they tend to have greater preservation of thalamocortical function than patient in VS. The diagnostic criteria for MCS are listed in table 3 and the potential behavioral repertoire of the patient in MCS is listed in table 4. and the potential behavioral repertoire of the patient in MCS is listed .

Potential behavioral repertoire of patients in a minimally conscious state

There is an irreducible biologic limitation to knowing the conscious life of another person. We can determine a patient’s awareness only by interacting with the patient and, based on the patient’s responses to stimuli, inferring judgments about his or her conscious life. Therefore, there is no objective gold standard test for detection of awareness; it remains solely determined by behavioral observation.³ Yet it is challenging to discern behavioral signs of awareness in some poorly responsive patients because their repertoire of potential behaviors is limited and present only inconsistently. Specialized neurobehavioral assessment tools to assess poorly responsive patients have been formulated and validated to sensitively identify subtle behavioral evidence of awareness.⁴ Family members and staff members should be interviewed because often they are the first to note subtle signs of emerging awareness in those patients in VS who evolve to MCS.

CONTRIBUTION OF FMRI

Early functional imaging studies of patients in VS with PET showed a markedly diminished baseline state of neuronal metabolism similar to that recorded in normal subjects in the deepest plane of general anesthesia. Subsequent PET and fMRI studies of the evoked effects on regional cerebral blood flow by various sensory stimuli showed that while primary cortical areas could be activated, the higher-order widespread distributed cortical networks believed to be necessary for awareness could not. These studies showed that patients in VS lack the capacity for any stimuli to activate higher-order multimodal cortices, especially the precuneus, which comprise the integrated, distributed neural networks believed to be necessary for conscious awareness. Further, when patients in VS recover awareness, the resumption of functioning of their damaged thalamocortical circuits can be demonstrated by fMRI.

Recent fMRI studies employing ideational paradigms have challenged our understanding of VS and may alter the accepted correlation between clinical and neuroimaging findings. In 2006, Owen and colleagues⁵ reported surprising fMRI findings on a 23-year-old woman who had been in VS for 5 months following TBI. She was given 2 ideational tasks: first, to imagine playing tennis and to think of the ball being volleyed back and forth over the net; second, to imagine walking through the rooms of her house and to think of the objects she would see. During the tennis-playing ideational task, her fMRI showed activation of the supplementary motor area. During the house tour ideational task, her fMRI showed activation of the parahippocampal gyrus, posterior parietal lobe, and lateral premotor cortex. Each of these patterns was similar in location but less in intensity to those evoked in normal aware subjects given the same tasks. Owen and colleagues⁵ concluded that “beyond any doubt [the patient] was consciously aware of herself and her surroundings.” Six months later, she began to show clinical signs of awareness, hence had graduated to the clinical syndrome of MCS.

Earlier this year, Monti and colleagues (including Owen)⁶ at the Universities of Cambridge and Liège reported similar findings in additional cases. Of the cohort of 23 patients in VS they examined over the study interval were 4 who, by fMRI responses, had the ability to “willfully modulate” their own brain activity on command, one of whom was the patient described previously by Owen et al. All 4 patients in VS with this ability had had TBI with diffuse axonal injury; it was not observed in any patient with hypoxic-ischemic neuronal injury from cardiac arrest. The mean age of the patients was 28 years. Two were examined within 6 months of injury, 1 at 30 months, and 1 at 61 months after injury.⁶

If one assumes that the capacity for “willful modulation” of brain activity requires awareness of self (and some knowledgeable commentators remain skeptical about this claim⁷), these fMRI findings show that the clinical examination, at times, may be insensitive to the presence of awareness. If this conclusion is true, it means that elicited fMRI data can complement findings on the neurologic examination and contribute to a more accurate diagnosis.⁸ This conclusion has profound importance for the clinical assessment and humane treatment of patients believed to be in VS.

PROGNOSTIC ISSUES

Determining the accurate prognosis of VS and MCS is a critical step in counseling families and determining appropriate treatment. Previous studies of prognosis in VS were limited by several factors: 1) because there were no accepted diagnostic criteria for MCS prior to 2002, some patients in MCS in those studies may have been diagnosed with VS; 2) it is more accurate to determine prognosis by the etiology of brain damage than merely by categorization in a clinical syndrome; and 3) retrospective experiential analyses of outcomes, such as that by the Multi-Society Task Force, committed the fallacy of the self-fulfilling prophecy because they included patients in their survival data who died primarily because their life-sustaining therapy was discontinued.⁹ Nevertheless, the prognostic guidelines published in 1994 by the Multi-Society Task Force on PVS have been generally accepted, showing a very low probability of recovering awareness once VS has been present for a year following TBI or for 3 months following hypoxic-ischemic neuronal injury.¹

Two recently published studies of prognosis in VS add useful data. Luauté and colleagues¹⁰ confirmed the prognostic guidelines of the Multi-Society Task Force in all the patients in VS they studied and showed that age greater than 39 years and absence of the middle-latency auditory evoked potentials were independent early predictors of poor outcome irrespective of pathogenesis. Estraneo and colleagues¹¹ found that 88% of patients in VS in their series conformed to the Multi-Society Task Force prognostic guidelines but 12% made late recoveries of awareness but only to the point of severe disability with MCS, most of whom had TBI. Because of varying pathophysiologies, prognostic indicators for MCS as a group have been difficult to establish whereas prognostic indicators in individual pathophysiologic subsets of MCS (e.g., patients in MCS from TBI) have been more reliable.⁹

Emerging fMRI data also may influence prognosis. The clinically diagnosed patient in VS reported by Owen and colleagues improved to MCS a few months after her fMRI showed evidence of her capacity to willfully modulate her brain activity. This pattern of clinical improvement also was seen in the small subset of VS cases reported by Di and colleagues¹² who showed fMRI evidence of the capacity to activate perisylvian language regions in response to hearing their own name spoken. It is therefore possible that the small subset of patients in VS demonstrating patterns of fMRI responses suggesting awareness is itself predictive of future clinical improvement. This important hypothesis requires verification with more cases before it is established.

TREATMENT ISSUES

Specialized neurorehabilitation units are the optimal treatment venue for patients with chronic disorders of consciousness, at least until they are no longer improving. Patients have better functional outcomes when treated by skilled personnel who have been trained in neurorehabilitation.

The difference between patients in VS and patients in MCS in their response to stimulatory treatment is noteworthy: patients in VS rarely improve as a consequence of stimulation but patients in MCS may improve to some extent. Treatment modalities that have been studied include environmental and sensory stimuli such as sounds, smells, touch, images, and music. Pharmacologic stimuli include treatment with stimulants, levodopa, and dopamine agonists (by stimulating intact dopaminergic thalamic neurons), and selective serotonin reuptake inhibitor antidepressants. Electrical stimuli include deep brain stimulation of medial thalamic nuclei. Each of these modalities has been reported to improve functional responsiveness in some patients in MCS though there are few controlled studies.⁴ These therapies are also widely tried in patients in VS but a meta-analysis of their outcomes showed no consistent benefits.⁴ If neurologists prescribe them for patients in VS, their families should be counseled that they are unlikely to be of benefit.

ETHICAL ISSUES

The appropriate level of treatment of patients with chronic disorders of consciousness depends on their diagnosis, prognosis, and prior stated treatment values and preferences. Neurologists should assure the accuracy of the diagnosis and make an evidence-based prognosis based on published data. They should assure that their explanation of diagnosis and prognosis is not colored by their bias or values about treatment in states of disability. For example, some patients and their families may consider moderate or severe disability to be an acceptable level of outcome even if their neurologists do not.

Neurologists should strive to practice patient-centered medicine in which they respect the treatment decision made by the patient’s lawful surrogate decision-maker who attempts to faithfully represent the treatment preferences of the patient. Surrogate decision-makers need to know the patient’s diagnosis and prognosis, the neurologist’s degree of confidence in both, and the wishes of the patient in this situation. They also need to understand the neurologist’s recommended treatment plan and the reason it is recommended. In my experience, most surrogates of young patients with TBI request aggressive rehabilitative and stimulatory treatment, hoping for improvement. Conversely, in older patients in VS, surrogates are more likely to order withdrawal of life-sustaining therapy once it becomes clear that the patient will remain unconscious. Paradoxically, the emerging fMRI data may aggravate the ethical dilemma by reaching a treatment conclusion prematurely.¹³

Some investigators have reported that patterns of evoked fMRI data may be used to provide a unique channel to communicate with unresponsive patients. One of the clinically diagnosed patients in VS reported by Monti and colleagues⁶ was able to answer “yes–no” in response to questions through reproducible evoked changes in regional cerebral blood flow on fMRI. Assuming that these findings were valid, how can examiners be certain that with such rudimentary communication, patients understand the questions adequately? The risks and benefits of this means of communication should be thoughtfully studied. Decisions to discontinue life-sustaining therapy based on patient responses to questions by this technique require particular scrutiny and skepticism.

The question of suffering is relevant to ethical decision-making. Most authorities formerly agreed that the patient in VS was incapable of suffering because he or she remained unaware and incapable of experience, to the fullest extent that this capacity could be determined. This important conclusion has become less certain in light of the emerging fMRI case reports suggesting that some young patients with TBI diagnosed as in VS may have a residual capacity for some degree of awareness that cannot be elicited on neurologic examination. Everyone agrees that the patient in MCS remains capable of suffering. Appropriate palliative care must be employed for any patient with disordered consciousness for whom the surrogate reaches the decision to withhold life-sustaining therapy.

RESPONSE TO THIS CASE

The patient presented here probably has graduated from VS to MCS given her intermittent ability to visually follow and reach for a presented object. Yet she remains profoundly unresponsive to most stimuli and may be unaware most of the time. Thus, the true state of her level of awareness remains unknown.

The neurologist or physiatrist caring for the patient should explain to her parents that the fMRI paradigms reported by the press, about which they read on the Internet, remain experimental and are neither available nor recommended for current clinical usage. There are only a few medical centers that have the capacity to perform these studies, given the technological requirements for the fMRI paradigms. The case reports of fMRI responses have not been adequately validated to achieve recommendation for general clinical usage.¹⁴ They probably will come into general clinical usage in the future but not until they have been better validated with more cases to determine their true positive and negative predictive value.

The neurologist can order neurorehabilitation therapy and can offer cautious trials of treatment, including medications if they are not contraindicated by the patient’s seizures. In my practice, I usually initiate amantadine or levodopa–carbidopa in the same dosage range as used for treating Parkinson disease. I also try usually to prescribe a trial of zolpidem, which has been reported to improve function in a small proportion of patients with MCS, presumably by stimulating intact thalamic neurons. Deep brain stimulation has been shown to be effective in a single case of MCS that was selected because of the presence of intact thalamic neurons capable of being stimulated, and remains experimental.

source: neurology

Quality of Life of Patients Who Undergo Breast Reconstruction after Mastectomy

Posted by zedie

Reconstruction after mastectomy has become an integral part of breast cancer treatment. The effects of psychological factors on quality of life after reconstruction have been poorly investigated. The authors examined clinical and personality characteristics related to quality of life in patients receiving reconstructive surgery.

Methods: All patients received immediate reconstruction and were evaluated in the week before tissue expander implantation (T0) with a semistructured interview for demographic and clinical characteristics, the Temperament and Character Inventory, the Inventory of Interpersonal Problems, the Short Form Health Survey, the Severity Item of the Clinical Global Impression, the Hamilton Depression Rating Scale, and the Hamilton Anxiety Rating Scale. Assessment with the Short Form was repeated 3 months after expander placement (T1). Statistics were calculated with univariate regression and analysis of variance. Significant variables were included in a multiple regression analysis to identify factors related to the change T1–T0 of the mean of the Short Form–transformed scores. Results were significant when p was less than or equal to 0.05.

Results: Fifty-seven women were enrolled. Results of multiple regression analysis showed that the Temperament and Character Inventory personality dimension harm avoidance and the Inventory of Interpersonal Problems domain vindictive/self-centered were significantly and independently related to the change in Short Form mean score.

Conclusions: Personality dimensions and patterns of interpersonal functioning produce significant effects on patients’ quality of life during breast reconstruction. Patients with high harm avoidance are apprehensive and doubtful. Restoration of body image could help them to reduce social anxiety and insecurity. Vindictive/self-centered patients are resentful and aggressive. Breast reconstruction could symbolize the conclusion of a reparative process and fulfill the desire of revenge on cancer.

source: journal of plastic surgey

Parasite Invasion Caught on Camera

Posted by zedie

For the first time, the tiny malaria parasite, Plasmodium falciparum, has been caught on camera breaking and entering a red blood cell. High resolution 3D images reveal that once the three components of the parasite—nucleus (blue), other organelles (red), and the green pore the parasite brings with it and through which it invades (green)—have attached to the cell, a switch is triggered and the parasite is free to burrow through the cell’s membrane. From this point on, the parasite is unstoppable, multiplying within the cell until it breaks out of its host to invade fresh red blood cells. The new imaging technique will allow researchers to see the effects of novel drugs on this final stage in the parasite’s invasion strategy, researchers report online on this week in Cell Host & Microbe. They hope that this will help scientists develop better drugs to alleviate the suffering of the 400 million people who contract malaria each year.

source: science now

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2. RECONSTRUCTION OF SMOOTH MUSCLE LAYERS

2.1. Bone marrow-derived cells

2.2. Freeze-injured urinary bladders

2.3. Reconstructed smooth muscle layers

2.4. Implanted GFP-labeled bone marrow-derived cells

2.5. Differentiation of bone marrow-derived cells into smooth muscle cells

2.6. Formation of smooth muscle layers from the differentiated cells

2.7. Recovery of bladder contractions

3. MICROENVIRONMENT

3.1. Microcirculation in the freeze-injured urinary bladders

3.2. Structure of the freeze-injured urinary bladders

3.3. Expression of growth factor mRNAs by host cells of the freeze-injured urinary bladders

3.4. Importance of the uninjured regions within freeze-injured urinary bladder

4. TISSUE ENGINEERING

5. CONCLUSION

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2. PATHOPHYSIOLOGY

3. CLINICAL SIGNIFICANCE

4. MANAGEMENT

4.1. Oral drugs

4.2. Intravesical oxybutynin

4.3. Intravesical capsaicin and resiniferatoxin

4.4. Intavesical botulinum toxin (BTX)

4.5. Augmentation cystoplasty

4.6. Autoaugmentation

4.7. Urinary diversion

5. CONCLUSION

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DIAGNOSTIC ISSUES

CONTRIBUTION OF FMRI

PROGNOSTIC ISSUES

TREATMENT ISSUES

ETHICAL ISSUES

RESPONSE TO THIS CASE

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