Monthly Archives: July 2019

Hepatic Arterial Communicating Arcades – Cases Series and Review of Literature

DOI: 10.31038/IMCI.2019216

Abstract

This case series describes the hepatic arterial communicating arcades and their importance in the endovascular management of hepatic artery pseudoaneurysm, paediatric post liver transplant lobar arterial occlusion and lobar arterial stenosis due to gall bladder carcinoma. We describe different types of arterial communicating arcades which have not been described earlier.

Keywords

Arterial communicating arcades, hepatic artery, pseudoaneurysm, liver transplantation, embolization, gall bladder carcinoma.

Introduction

Interlobar arterial communication or Communicating Arcades (CA) in the hepatic hilum has been recognized as one of the most important collateral pathways to the liver. CAs plays an important role in the blood supply to the caudate lobe and also have a close relationship with the blood supply to the hilar biliary tract. Hepatic arterial communicating arcades develop in hilum when either right or left hepatic artery is occluded or significantly stenosed [1,2]. If Proper Hepatic Artery (PHA) is occluded, liver perfusion can occur through small collaterals in the hepatic ligaments, collaterals around the common bile duct, inferior phrenic artery, pancreatico-duodenal artery and intercalary ‘de novo’ collaterals [3,4]. We describe 3 cases showing the importance of hepatic arterial CA in endovascular treatment of mycotic Hepatic Artery Pseudoaneurysms (HAPAs), lobar arterial stenosis following paediatric deceased donor liver transplant and locally advanced carcinoma gallbladder infiltrating the Right Hepatic Artery (RHA).

Case Series

Case 1

49 year old lady presented with cholelithiasis and choledo-cholithiasis. After multiple failed attempts of endoscopic management, the patient underwent a Roux-en-Y hepaticojejunostomy. On post-operative day 5, the patient had low grade fever and elevated white cell count (13,000/mm3). Ultrasound examination revealed a small collection anterior to the hepaticojejunostomy site. No biliary dilatation was seen. A contrast enhanced CT (CECT) scan was performed which revealed two extra hepatic pseudoaneurysms in the RHA proximal to its bifurcation (Figure 1a). Interventional radiologist was unavailable on that particular week. Drain was placed by diagnostic radiologist avoiding injury to pseudoaneurysms at least to drain the collection. Initially, bile stained fluid was drained, which was followed by drainage of frank blood through the drain tube and hemodynamic instability of the patient. Immediately patient was resuscitated and taken to angiosuite for embolization. In view of the emergency situation, the in house cardiologists performed the embolization. CHA angiogram confirmed the presence of two irregularly filling extra hepatic RHA pseudoaneurysms. A single coil was placed in the right hepatic artery proximal to the pseudoaneurysms. Post coiling, RHA went in to spasm and no reperfusion of pseudoaneurysm was observed (figure 1b). However, on proper hepatic artery angiogram collateral supply from Middle Hepatic Artery (MHA) to distal RHA branches was observed (Figure 1c). No reperfusion of pseudoaneurysms was observed post coiling, and the procedure was concluded. Post procedure CECT scan done after two days did not reveal reperfusion of pseudoaneurysms, however distal migration of coil in in RHA was noted (Figure 1d). Post embolization, liver enzymes and bilirubin were elevated (AST, ALT and ALP were 1352, 1454 and 584 respectively, bilirubin was 2.3 mg/dl) on day 1 and become near normal on day 7. Patient was discharged on 12thpost embolization day. On 17th post embolization day, the patient suddenly collapsed at home. She was found to be hypotensive and resuscitated at a local hospital before being shifted back to our hospital for management. Reperfusion of pseudoaneurysms and mild hemoperitoneum was observed on repeat CECT scan (Figure 1e). Angioembolization was performed by an interventional radiologist. Selective RHA angiogram was performed (Figure 1f) and pseudoaneurysms were delineated. During embolization, attempt was not made to cross the pseudoaneurysms in view of coil migration and rupture of aneurysms. RHA was embolized with multiple 6mm, 8mm 0.018” micro coils. Middle hepatic artery (MHA) was arising from proximal GDA. MHA angiogram showed faint perfusion of pseudoaneurysms through intrahepatic arterial arcades (Figure 1g).  Intrahepatic arterial arcades were embolized with gelfaom particles and main trunk of MHA was embolized with 5mm 0.018” coils (Figure 1h). Left hepatic artery (LHA) angiogram did not reveal perfusion of pseudoaneurysms, however few tiny CA were seen supplying the segment 4 of liver. Post embolization, the patient recovered well. No significant increase in liver enzymes or bilirubin was noted. No recurrence of pseudoaneurysm or other symptoms were observed on 12 months follow up.

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Figure 1. 49 year old female patient, post hepaticojejunostomy presented with prehepatic collection, fever and elevated total white cell count on day 5. Case describes CAs from both middle and left hepatic arteries.  (a) Arterial phase contrast enhanced CT scan, oblique coronal MIP image showing two small mycotic pseudoaneurysms in (white arrow) right hepatic artery. Small biliary collection was also noted. (b and c) Celiac angiography digital image post embolization of right hepatic artery (by cardiologist because of non-availability of Interventional radiologist) showing single coil (black arrow) in RHA with non opacification of pseudoaneurysms and intrahepatic arterial arcades communicating between right and accessory RHA (Black arrows). Pigtail catheter placed in view to drain the collection caused rupture of pseudoaneurysm. (d) Arterial phase contrast enhanced CT scan done post embolization day 2 revealed thrombosed pseudoaneurysm and distally migrated crumpled coil (arrow) near RHA bifurcation. Arrow head shows HepJ anastomotic bowel staple suture (e) Arterial phase contrast enhanced CT scan done post embolization on post op day 17, MIP image shows reperfusion of pseudoaneurysms (arrows) with increase in size of postero-medial pseudoaneurysm. (f) Digital right hepatic artery angiogram showing migrated coil and two pseudoaneurysms (arrow).  (g) Post RHA coiling digital angiogram of MHA showing multiple intrahepatic arterial arcades (small black arrows) feeding distal right hepatic artery. (h) Post MHA coiling, celiac axis digital angiogram showing patent left HA (black arrow) and GDA.

Case 2

A 9 year old male patient, a known case of Alagille syndrome had undergone Deceased Donor Liver Transplantation (DDLT). During transplant two arterial anastomosis were performed. Right and left hepatic arteries of donor were anastomosed to recipient’s PHA. Intraoperative colour and spectral doppler ultrasound didn’t reveal any significant abnormality in Peak Systolic Velocity (PSV), Resistive Index (RI) and spectral waveform of intrahepatic portions of right, segment 4 and left hepatic arteries. From 2nd post-operative day, ultrasound revealed multiple subcapsular ischemic areas in right lobe of liver and increasing post anastomotic (choledocho-choledochostomy) biliary dilatation. Colour and spectral doppler ultrasound revealed low RI (0.523 in RHA and 0.429 in segment 4 artery) and normal PSV in intraparenchymal portions of both right and left hepatic arteries (Figure2a, b & c). Marginal alterations in liver enzymes were observed with normal INR and serum lactate levels. In view of isolated right lobe subcapsular ischemic areas and biliary dilatation, CECT scan was performed. CECT scan showed, short segment complete stenosis of anastomotic and post anastomotic RHA and reperfusion of distal parenchymal arteries through CA from segment 4 artery. Segment 4 artery and LHA were enhancing normally. Multiple non enhancing subcapsular ischemic areas were seen in right lobe. No focal abnormality seen in left lobe of liver. Mild biliary dilatation was seen (Figure 2d, e and f). ERCP and plastic biliary stent was placed to assist biliary drainage. Routine interval ultrasound follow was done till discharge. The patient is doing well 10months after the transplant.

IMCI 19 - 111_Kundaragi NG_F2

Figure 2. 8 year old male patient, post liver transplant status with mild elevated liver enzymes. (a & b) Spectral Doppler imaging of right and segment 4 hepatic arteries showing elevated peak systolic velocity with low RI. (c) Gray scale and colour Doppler ultrasound image dual window showing biliary dilatation black arrow) with narrowing at anastamotic site. (d & e) Arterial phase contrast enhanced CT scan coronal MIP image showing post anastomotic unopacified proximal right hepatic artery (arrow heads). Coronal and axial MIP image showing intrahepatic arterial arcades (small white arrows) communicating between segment 4 artery and right hepatic artery. (f) Venous phase CECT axial images showing multiple non enhancing subcapsular hypodense areas in right lobe (open arrows) and predominant central biliary dilatation.

Case 3

A 64 year old male presented with progressive jaundice of 3 months duration. Total bilirubin was 13mg/dL. Transabdominal ultrasound revealed Gall Bladder (GB) fossa mass with infiltration of adjacent liver and few hypoechoic lesions seen in right lobe of liver. Hilar biliary confluence was involved with significant dilatation of intra hepatic biliary radicles. Through ERCP, plastic biliary stent was placed in to left side biliary ducts. Total bilirubin level came down to 3.5mg/dL in 3 days. The CECT scan revealed a large enhancing mass in GB fossa with infiltration of adjacent liver. Few peripherally enhancing focal lesions were seen in right lobe of liver (Figure 3a). Tumour was seen encasing the proximal RHA with its significant stenosis. Reperfusion of Intraparenchymal RHA branches were observed through arterial CAs from left hepatic artery both from segment 2/3 and segment 4 hepatic arteries (Figure 3b and c). Portal vein was not involved. Tumour was invading the biliary confluence with significant bilateral intra hepatic biliary dilatation. Plastic biliary stent was seen in left lobe biliary duct. Adenocarcinoma of gall bladder was confirmed on percutaneous biopsy of GB fossa mass. Biopsy of right lobe liver lesions revealed cholangitic abscess. The patient was informed about the prognosis and two self-expandable metallic stents were placed.

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Figure 3. 64 year old male patient, inoperable case of GB fossa mass, presented with progressive jaundice and abdominal pain since 3months. Case describes CAs from both the branches of left hepatic artery (segment 4 artery and segment 2/3 branches). (a) Venous phase CT scan, coronal image showing ill-defined enhancing mass in segment 5 and GB fossa. Rim enhancing lesion in segment VI. (b & c) Arterial phase contrast enhanced CT scan, coronal MIP images showing arterial arcades (small arrows) communicating between LHA (open white arrow) and RHA (Long arrow) and segment 4 artery (thick arrow) and RHA respectively. Significant stenosis of proximal RHA seen (curved arrow). (d & e) Spectral Doppler images showing normal velocity and low RI in intrahepatic branches of RHA and high velocity and normal RI in segment IV artery. (f) Spectral Doppler performed at stenotic proximal RHA showing increased peak systolic velocity (158cm/sec) with normal RI.

Discussion

Inter lobar hepatic arterial communications or Communicating Arcades (CAs) develop depending on the site of stenosis or occlusion of the hepatic artery. Interlobar collateral vessels usually develop in the hepatic hilum in patients with interruption either right or left hepatic artery. These vessels are not visualized on angiograms in patients with intact hepatic arterial supply [5].

The CAs is located extrahepatically in the hepatic hilum or cranial to the portal bifurcation close to the hilar bile duct. Caudate lobe is believed to derive  its blood supply not only from the segment I artery but also from the CA, because of which transarterial chemoembolization for caudate lobe hepatocellular carcinoma is not very effective [1].

Tohma et al classified CAs in to type 1a, 1b and 2 if arising from middle hepatic artery, segment 4 artery and left hepatic artery respectively. Authors have also classified CAs arising from right anterior hepatic artery, right hepatic artery or both as type 1, 2 and 3 respectively. In the present article we have presented all 3 cases with CAs arising from left side. In first case CA was arising from middle hepatic artery (type 1a). However in after embolizing segment 4 artery we were able to see tiny collaterals from left hepatic artery supplying the segment 4 area. So this type of collaterals from both middle and left hepatic artery is not mentioned in literature. In second case of post liver transplant CA was from segment 4 hepatic artery (type 1b). In third case CA was arising from both the branches of left hepatic artery (segment 4 artery and segment 2/3 branches). Our first and third cases described different types to Toham et al classification of CAs arising from left arteries (Diagram 1).

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Diagram 1. Pictorial demonstration of cases.

Hepatic artery is the second most common site for visceral artery pseudoaneurysm after splenic artery. Hepatic Artery Pseudoaneurysms (HAPAs) are usually iatrogenic and can present as life threatening complications of hepatic, biliary, and pancreatic interventions. Hepatic procedures accounts for 65% of these cases. Biliary and pancreatic procedures accounts for 30% and 5% respectively [6]. HAPAs can also be associated with intra-abdominal inflammation, infection, or trauma [6]. In our first case, surgery was uneventful and patient developed an infected biliary collection near hepatico-jejunostomy site on post operation day 5. All the authors felt right HAPAs were likely caused by infection (Klebsiella aerogenes bacteria) rather iatrogenic, as patient recovered well after endovascular reintervention.

Coil embolization or exclusion of the pseudoaneurysms by stent graft is most effective treatment option in an emergency setting, especially when associated with an infection. Both proximal and distal ends of the parent arteries of the aneurysm must be embolized simultaneously to block off the pseudoaneurysm in an extra hepatic HAPA, while proximal embolization alone can be performed for an intrahepatic arterial aneurysm; however, reestablishment of collateral circulation increases the risk of re-rupture of the aneurysms [7]. In our case extra parenchymal right HAPAs were seen, which were initially embolized by proximal solitary coil occlusion; however the coil migrated, pseudo-aneurysms were re-perfused and bled again. Later successful embolization was performed by an interventional radiologist with multiple coils in RHA, gel foam in CAs and coil in middle hepatic artery.

Early (<1 month) arterial complications are associated with graft loss and a high mortality rate after Orthotropic Liver Transplant (OLT).  Hepatic Artery Stenosis (HAS) and Hepatic Artery Thrombosis (HAT) are the most common hepatic arterial complications, with high rates of morbidity and mortality. Untreated significant HA anastomotic strictures can progress to HAT (65% at six months follow up). HAS is less frequently associated biliary complications compared to HAT. Biliary complications can be seen up to 67% in liver transplant recipients with HAS. Reduction of arterial flow during liver transplant is commonly associated with biliary tree complications due to ischemic processes. In some cases, HAS is likely to stimulate the development of arterial collaterals that protect the liver from ischemia at the time of HAT [8].

Doppler Ultrasound (DUS) is the gold standard investigation to assess hepatic artery patency in cases of HAT with sensitivity up to 92% or an increased Resistive Index (RI). Anatomical defects (stenosis or kinking) can be detected by CT angiogram or conventional angiography with a high sensitivity and specificity. Early HAS can be detected by DUS with a sensitivity of 100%, a specificity of 99.5%, a positive predictive value of 95% and a negative predictive value of 100%, and an overall accuracy of 99.5%. However MDCTA and standard angiography are the gold standard for HAS diagnosis [8].

Biliary tract ischemia contributes to biliary strictures and anastomotic leakage in liver transplants and can be seen up to 34% of patients. Division of the CA during graft donation may potentially lead to biliary ischemia and complications. Thus, during graft donation the right or left hepatic artery should not be dissected and separated from the bile duct distally to prevent biliary ischemia [1]. In our second case anastomotic stenosis of RHA has led to development of anastamotic biliary stricture (choledocho-choledochostomy) and visible biliary dilatation from 3rd day.

The third case is an uncommon presentation of gallbladder carcinoma involving the right hepatic artery with development of visible hepatic arterial arcades on CECT scan. Primary gallbladder carcinoma is the most common malignancy of the biliary tract. The most common route of dissemination is direct invasion of the liver. Hepatic invasion or hepatic metastasis has been reported in as many as 30%–80% of cases of gallbladder carcinoma. Gall bladder malignancies with vascular invasion (main portal vein or hepatic artery) are typically not amenable to surgery [9].

In conclusion, first attempt of intervention failed in first case due to hepatic inter arterial communication and incomplete embolization, which was later successfully embolized by an Interventional radiologist. Percutaneous drain must be placed only after treating pseudoaneurysms. In second case of post liver transplantation, arterial complication was precisely detected on CECT and not on Doppler ultrasound. Right lobe of graft survived because of hepatic inter arterial communications and no intervention was required, however patient developed few peripheral subcapsular ischemic changes in right lobe and low grade biliary dilatation which was managed by endoscopic plastic stenting. Our first and third case, show different types of arterial communicating arcades arising from middle hepatic artery (from GDA) and left hepatic artery. Thus knowledge of hepatic inter lobar arterial communication is important while treating and diagnosing arterial diseases of both native and transplant liver.

References

  1. Tohma T, Cho A, Okazumi S, Makino H, Shuto K, et al. (2005) Communicating arcade between the right and left hepatic arteries: evaluation with CT and angiography during temporary balloon occlusion of the right or left hepatic artery. Radiology 237: 361–365.
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  3. Redman HC, Reuter SR (1970) Arterial collaterals in the liver hilus. Radiology 94: 575–579.
  4. Mays ET, Wheeler CS (1974) Demonstration of collateral arterial flow after interruption of hepatic arteries in man. N Engl J Med 290: 993–996.
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  8. Piardi T, Lhuaire M, Bruno O, et al (2016) Vascular complications following liver transplantation: A literature review of advances in 2015. World Journal of Hepatology 8: 36–57.
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Supporting Older Nurses in the Workforce: Intersectional Considerations

DOI: 10.31038/AWHC.2019235

Introduction

In most industrialized countries, the nursing workforce, an overwhelmingly numerically female dominant profession, is aging [1]. Analysis of data suggests that this is due to interrelated social and economic factors pushing nurses towards later retirement. Nurses are choosing to remain in the workforce longer, delaying retirement for reasons that include economic and financial necessity, continued desire to care for others and meet professional goals [2], and positive life-span development that is attributable to increased life expectancy and longevity [1–2]. Apart from intrinsic motivators, there is also a growing drive to increase the labour market participation of older individuals in response to shifting population structures secondary to population aging [2, 3–5]. In occupations such as nursing where skills shortages are already being experienced, population aging threatens to deepen this existing problem [6].

Older nurses represent a pool of untapped human capital. Through their accumulated experience and resulting expertise, older working nurses present a number of benefits for economic growth and social welfare. However, if these benefits are to be derived from the continued participation of older nurses in the labour market, the intersecting challenges that they experience in the workplace must be recognized and addressed. The intersectionality of the physicality of nursing work, its embeddedness in gender-based power relations, the health care consequences of population aging, and the increased risk of disability and other outcomes associated with working when older must be taken into consideration in designing healthy, age-friendly work environments where a diversity of nurses can thrive.

Intersectional Issues of Concern

Older nurses working in the labour market are impacted by multiple and gendered axes of influence that must be understood. Equally importantly, they must be considered as part of employers’ and policy makers’ responses both to the struggles of older nurses in the workforce and to the broader challenges of population aging for health care. Key influences and issues of concern are explored briefly below.

Consequences of Aging on Working

While our bodies change with age (e.g., decreased strength, flexibility, and bone mass) [7] disability and illness are not an inevitable part of aging [8]. This notwithstanding, the probability of work-induced disability and injury increases as workers age [5, 9]. Data support that older workers are less apt to acquire injuries on the job than younger workers; however, aging-related physiological and cognitive changes make older workers susceptible to more severe and permanent injuries [5]. Older workers are more likely to experience soft tissue injuries affecting the back, neck, and feet [5, 9–10]. The probability of older nurses sustaining such injuries and acquiring disability is made even more likely because of the physically strenuous nature of nursing work [9] and the concurrent risk for violence [11]. Recent data reveals a significant positive correlation between age and incidence of nurses working with some form of physical or mental impairment [12]. This finding was consistent with other data indicating that the likelihood of individuals experiencing disability increases with age [12].

Given this context, it is surprising that disability among nurses is a topic rarely discussed within the literature and equally absent from policy and administrative perspectives [9, 13]. Available literature reveals that nurses with disabilities, particularly those who acquire a disability while working, receive very little support to persist within the profession [13–14]. Unsupported nurses with disabilities are left in a difficult situation with very little choice, often leaving direct practice or the profession altogether [13–14].

Gender-based Power Relations and Labour Market Discrimination

The influence of age on working does not happen in a vacuum and is not exclusive of other factors impacting individuals’ lives and their work. Gendered experiences of women in labour markets have a compounding effect on working women who are aging. With a few exceptions, women account for approximately 90–95% of the nursing workforce the world over. As a female dominated profession, deeply embedded within nursing are the gender-based power relations of society. As such, the nursing profession is reflective of the value placed on women and their standing in society [15]. In particular, the erroneous feminization of nursing and gender-based discrimination have resulted in occupational segregation and consequently, the forcing down of wages in the profession. Unfortunately, dominance of females within the profession is not effective against the gender-pay gap. Across practice settings, positions, and specialities, male nurses typically out earn female nurses [16–17]. This gender pay gap is also unaffected by education, a common means by which an individual can increase their earnings [17].

Although not all of the factors contributing to the gender pay gap within nursing are known, workplace discrimination and gender discrimination have been identified as factors limiting women from advancing in the workplace and gaining positions of authority [17]. Additionally, gender expectations of women within society have been identified as contributing factors. Like other working women, female nurses often must balance work and care for children, other dependent family members, or both, often at the expense of career progression and their health [18, 19]. While performing this juggling act can and does fall to men in some circumstances, the societal expectation that women should take care of their loved ones, even when they are working, persists. Many women have reported experiencing the weight of these often-unspoken expectations [18, 20].

Population Aging, Health and Health care

Trends in the health of populations and health care are yet another axis of influence on older nurses’ participation in the workforce. These trends include a diminished and slow-growing nursing supply resulting in inadequate staffing; [1, 21] increasing patient volumes and the requirement for more health services due to increased life expectancy and longevity; [1, 22, 23] and increasing patient acuity and the growing complexity of treatment modalities [1, 22]. The sum total of these pressures is that there are ever-rising professional demands and excessive workloads on nurses. Nurses are faced with increasing psychosocial, physical, and cognitive demands. In some cases, they must also deal with unsafe and unhealthy conditions such as workplace violence. Consequently, there is greater likelihood of fatigue, injury, and disability among today’s nurses, which have been linked to overall measures of the quality of nursing work life and patient safety [1, 20, 24]. Older nurses may be doubly impacted by these pressures associated with aging that are situated within the context of gendered labour market experiences.

Intersectional Considerations for Ways Forward

By and large, efforts to address the challenges faced by older working individuals have focused on the consequences of aging, often in isolation of other factors. Nursing-specific interventions that have been championed include flexible scheduling, shorter work shifts, comprehensive disability management programs with an emphasis on accommodation, and redesign of the work environment to meet ergonomic needs and reduce injuries [9, 25]. While there is no doubt that these initiatives are needed and would be of benefit to all nurses, they do not go far enough to address the multiple axes of influence and oppression structuring the experiences of not only older working nurses, but younger nurses as well.

An intersectional approach is needed whereby aging in the nursing workforce is understood in the context of the other interconnected factors that in some cases may have a far more significant impact on working nurses than the consequences of aging. An intersectional understanding of working, aging women exposes the multiple forces that impact upon the experiences of older nurses. These experiences should be understood in ways in which age, gender, issues of power and domination, and socioeconomics intersect with the work experience. Moreover, an intersectional approach to aging in the workplace provides the opportunity to reflect on and apply a social justice discourse in dealing with the challenges faced by nurses.

Ultimately, the problem of a skills shortage in nursing and the multitude of challenges accompanying an aging nursing workforce cannot be addressed through a sum-of-the-parts approach. An intersectional approach calls upon stakeholders to focus on the complexities of the situation and employ a broader frame to understand these problems. Using a well-informed frame in evaluating aging in the nursing workforce will enable changemakers to accurately recognize the issue of skills shortage and retention of nurses as being layered by structural inequalities along axes of age, gender, ableness, and social status. In this context, solutions should be pursued which are emancipatory and aim to empower the nursing workforce while also interrogating and seeking to remedy structural discrimination and injustices, such as the gender pay gap and visible and invisible barriers to career advancement and fulfillment. Estimates predict that upwards of 7 million skilled health professionals (the majority nurses) are currently needed globally [26]. In this context, failure to recognize the context and experience of work for aging nurses, compounded by the profound lack of incentives for younger nurses to remain in the profession [26] will undoubtedly negatively impact not only nurses, but likely the health of individuals, families, groups, and communities around the world who rely on nurses to provide compassionate, high quality care.

References

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  3. Appannah A, Biggs S (2015) Age-friendly organisations: the role of organisational culture and the participation of older workers. Journal of Social Work Practice 29: 37–51.
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  8. Barlow FK, Walker N (2015) Disability and ageing. In Pachana NA, editor. Encyclopedia of Geropsychology. Gateway East, Singapore: Springer Singapore 2015.
  9. Matt SB, Fleming SE, Maheady DC (2015) Creating disability inclusive work environments for our aging nursing workforce. Journal of Nursing Administration 45: 325–330.
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  15. Wrede S (2010) Nursing: globalization of a female-gendered profession. In Kuhlmann E, Annandale E, editors. The Palgrave handbook of gender and healthcare. London: Palgrave Macmillan 437–453.
  16. Muench U, Sindelar J, Busch SH, Buerhaus PI (2015) Salary differences between male and female registered nurses in the United States. JAMA 31: 1265–1267.
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Correlation between Magnetic Resonance Imaging and Arthroscopy in Meniscal Injuries

DOI: 10.31038/IJOT.2019241

Abstract

Introduction: Meniscal injuries have a very high incidence among professional and amateur athletes. It is estimated that the incidence amounts to 24 every 100 000 each year. The different forms of imaging diagnostics play an important role in the management of knee injuries, particularly in the event of uncertain clinical diagnosis, helping to avoid unnecessary and expensive surgeries. In order to diagnose meniscal pathologies, the most commonly used imaging test is Magnetic Resonance Imaging (MRI). Health Officials from all around the world are becoming increasingly involved in the definition of surgical treatment limits, making an effort to enhance their practice and the patients’ cost-effectiveness.

Our work aims to review evidence about the correspondence between imaging tests -particularly the MRI- and knee arthroscopy as the Gold Standard for the diagnosis of meniscal injuries.

Material and Methods: We performed a systematic search that included Medline (PubMed interphase) and Lilacs databases. The search totaled 607 articles. According to filters and inclusion/exclusion criteria, 23 papers were chosen for our bibliographic review.

Results: The selected papers were prospective studies. Our results are based on data retrieval specifically linked to sensitivity and specificity of the MRI with regards to arthroscopy in meniscal injuries.

Discussion: From the analysis of this information we may consider that there is no consistency in results and opinions in English-published bibliography of a prospective profile. Nevertheless, we must acknowledge that the prevailing results are those that prioritize the relevance of MRI in terms of sensitivity and specificity. We must currently accept that MRI is a very costly study for diagnosing meniscal injuries. There are some variations in its sensitivity and specificity, but they are minor and, therefore, do not invalidate these conclusions.

Introduction

Meniscal injuries have a very high incidence among professional and amateur athletes. This injury is one of the most frequent in sports medicine: 24 in every 100 000 athletes suffer one of this each year. They show a bimodal distribution; the first incidence peak is seen among young athletes and the second is seen in middle-aged patients with degenerative joint disease 1].

Macroscopically, the menisci of the knee are two intra-articular semicircular fibrocartilaginous structure, with a wedge shaped structure, placed between the tibia and the femur, in the medial and lateral compartments. They used to be considered as vestigial remains of muscular structures in the knee. Ever since the middle of the Twentieth Century we have thoroughly known their actual functions and their anatomic, therapeutic and prognostic relevance in knee pathology. The menisci have three main functions: load transmission, cushioning and secondary stabilization [2–4].

In general, the medial meniscus is the one with less movement and therefore it gets injured more frequently than the lateral meniscus [5].

In terms of clinical diagnosis, there are over twenty specific tests described for the assessment of meniscal injuries, with sensitivity and specificity levels that fall between 64 and 97% [6–10]. The sensitivity of these tests decreases when there are other associated injuries, particularly of the anterior cruciate ligament [11–13].

The different forms of imaging diagnostic play an important role in the management of knee injuries, and particularly in the event of uncertain clinical diagnosis; they help to avoid unnecessary surgeries [14].

Since MRI was first introduced in 1984 for clinical usage, its diagnostic role in knee injuries has had a substantial impact [15–17]. MRI is the most commonly used imaging study for the diagnosis of meniscal pathologies, even though there has been an increasing amount of studies that conclude that ultrasonography might be a valid diagnostic technique for meniscal injuries [18]. Notwithstanding, MRI possesses one advantage: it assesses both hard and strong parts of the knee together with the meniscal pathology

Some studies have shown that MRI is not better than physical examination for diagnosis of meniscal injuries [7,8,19]; other studies show that diagnostic failures range between 14 and 47% [20–22] and others showed the value of MRI as an effective and non-invasive diagnostic tool [11,23–30].

MRI and ultrasonography are the two most used screening methods for diagnosing meniscal tears and anterior cruciate ligament (ACL) tears. While there are numerous studies that show that MRI is a reliable and accurate diagnostic tool, it is very hard to establish its true sensitivity and specificity [29]. Ruwe et.al [31]. claim that MRI avoids unnecessary arthroscopies, while Bridgman et.al [32] State it doesn’t.

Currrently we need the highest levels of evidence in order to support the use of diagnostic tests, especially when these are an important part of the definition of therapeutic limits, such as knee arthroscopy, for anterior cruciate ligament and meniscus injuries. In the future, the technological and clinical advances shall, undoubtedly, change the way we use MRI [33].

Objective

This paper aims to review evidence about the correlation between MRI and knee arthroscopy as the Gold Standard for the diagnosis of meniscal injuries.

Material and Methods

In May 2018, we performed a systematic search that included Medline (PubMed interphase) and Lilacs databases. We used similar search methods in both databases, employing the term MESH for Medline-PubMed.

We combined the results using Boolean operators; the synthetic results for said search were ((“Menisci, Tibial” [Mesh]) AND “Magnetic Resonance Imaging”[Mesh]) AND “Arthroscopy”[Mesh].

In Lilacs we applied the same search method.

The filters we used were articles published between 2004 and 2018, articles written in English and articles about human beings.

Inclusion Criteria

The inclusion criteria were:

  • Human, adults, and published in English.
  • Prospective cohort studies
    • Evaluation of MRI for the diagnosis of meniscal injuries
    • Arthroscopy as a diagnostic reference (Gold Standard)
    • Results with sensitivity and specificity (Se.& Sp.)

Exclusion Criteria

Exclusion criteria were: retrospective articles, systematic reviews, children injuries, kinds of meniscal injuries.

Thereafter, we selected the title, made an overview (or full review in case of doubts) and used each work’s bibliography as an additional method.

Even though there are differences among the meniscal injury diagnosis criteria in MRIs, it is widely accepted that the presence of an intra-meniscal signal extending to an articular surface and/or a distortion of the regular shape represent a clinically significant injury [34].

Search Strategies

For the bibliographic selection we used, as a guide, the flow chart from the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) protocols (Figure 1).

IJOT 19 - 121_Andrés Gelink_F1

Figure 1. Systematic Review Flowchart, PRISMA Protocol, 2009.

In Medline-PubMed we obtained 593 results as a total, using MESH terms and Boolean operators. After applying the aforementioned filters, the results were the following:

  • Since 2004 to 2018: 396
  • In humans: 390
  • In English: 360

In the Lilacs platform we found 14 studies, and applying the same filters we found 3 papers, one of which also turned up in the Medline-PubMed search.

From both searches, and excluding the repeated article, we obtained 362 articles that, added to 6 other papers found in the bibliography, gave us a total of 368 studies.

When we applied the aforementioned inclusion and exclusion criteria in both platforms with regards to title and overview, we selected 23 articles in total (this excluded 345 studies); so far the search was conducted by only one author.

Afterwards, these 23 studies were read in full and included in our bibliographic review by 2 authors.

When applicable, we extracted the following data from each work: Author, Year of Publishing, Hospital, Study Design, Amount of Patients, Patients’ Age, Study Period, 1 or both menisci studied, Se. & Sp. (Table 1).

Table 1.

 Author

Year

Hospital

Type of study

N

Age (years)

Period

1 or both menisci

Sensitivity and Specificity (%) – MI: internal menisci, ME: external menisci

1

Muresan et al

2017

 University of Medicine and Pharmacy of Tîrgu Mureş, Tîrgu Mureş, România

Prospective

45

29,4

May 2014 – July 2015

Both menisci

+ S y E: MI: 69,4/76,6 ME: 75,0/80,0

2

Chagas-Neto et al

2016

Division of Radiology, Internal Medicine Department,

Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (FMRPUSP),

Ribeirão Preto, SP, Brazil

Prospective

38

33,5

Both menisci

+ S y E: MI: 83/71 ME: 54/92

3

Nilton Orlando Júnior et al

2015

Fundacão Hospital Adriano Jorge, Manaus, AM, Brazil

Prospective

72

33,54

June 2012 – December 2013

Both menisci

+ S y E: MI: 92,50/74,19 ME: 65/88,46

4

Khan et al

2015

Department of Orthopedics of the Holy Family Hospital,

 New Delhi, India

Prospective

26

13–50

March 2011- May 2012

Both menisci

+ S y E: MI: 100/50 ME: 50/86

5

James L. Cook et al

2014

Missouri Orthopaedic Institute, Department of Orthopaedic Surgery,

University of Missouri.

Prospective

71

37.2

Both menisci

+ S y E: 91, 7/66,7

6

H.N Chen et al

2014

The Second Affiliated Hospital of Soochow University, China.

Prospective

171

45.8

October 2009 – December 2011

Both menisci

+ S y E: MI: 95.60/96.25 ME: 96.47/95.25

7

Wei Chen et al

2014

Department of Radiology, Southwest Hospital, The Third

Military Medical University, Chongqing 400038, China

Prospective

94

40,5

December 2011 – October 2012

Both menisci

 + S y E: MI: 93,5/66,7 ME: 92,2/100

8

Bari et al

2014

Department of Radiodiagnosis, JNMC, DMIMS, Sawangi (Meghe) Wardha, Maharashtra, India

Prospective

71

June 2012 – July 2014

Both menisci

+ S y E: MI: 93,54/87,50 ME: 77,77/81,81

9

Timotijevic Sladjan et al

2014

Hospital – KBC

Prospective

107

29.7

****

External menisci

+ S y E: 68/87 (acute) S y E: 75/95 (cronic)

10

Navali et al

2013

The Orthopedic Ward at Tabriz Shohada Hospital,Tabriz, Iran

Prospective

120

29,13

October 2008 – October 2009

Both menisci

+ S y E: MI: 84,2/71.4 ME: 56,5/92,8

11

Roza Dzoleva-Tolevska et al

2013

University Orthopaedic Surgery Clinic, Ss. Cyril and Methodius University, Skopje, R. Macedonia

Prospective

70

Both menisci

+ S y E: MI: 79,5/38,1 ME: 40/92,7

12

Sharifah et al

2013

Department of Radiology, University Kebangsaan Malaysia,

Kuala Lumpur, Malaysia

Prospective

65

28

2009 – 2012

Both menisci

+ S y E: MI: 82/92 ME: 83/97

13

Pieter Van Dyck et al

2013

University Hospital and the University of Antwerp, Antwerp (Edegem), Belgium

Prospective

200

45

2010 – 2012

Both menisci

+ S y E: MI: 93/90 ME: 77/99 (1,5 T) MI: 96/88 ME: 82/98 (3 T)

14

Ersin Eercin et al

2011

Ankara Mevki Military Hospital,Orthopedics and Traumatology

Clinic,Istanbul, Turkey

Prospective

30

38

5 months

Both menisci

+ S y E: MI: 95/60 ME: 67/88

15

F. Rayan et al

2009

Kettering General hospital

Prospective

131

36 months

Both menisci

+ S y E: MI: 76/52 ME: 61/92

16

Gul-e-khanda et al

2008

Radiology Department, Aga Khan University Hospital, Karachi

Prospective

50

2006–2007

Both menisci

+ S y E: MI: 100/69.27 ME: 87.5/88.23

17

M.J. Sampson et al

2008

Departments of Radiology and Orthopaedics, Sports Surgery Clinic, Santry Demesne, Dublin.

Prospective

61

29,6

Both menisci

+ S y E: MI: 91/93 ME: 77/93

18

Naranje et al

2008

Departments of OrthopaedicsAll India Institute of Medical Sciences, New

Delhi, India

Prospective

50

27

Both menisci

+ S y E: MI: 96/89 ME: 84/90

19

Noha H. Behairy et al

2008

Cairo University, Cairo, Egypt

Prospective

70

22–59

Both menisci

+ S y E: MI: 47/95 ME: 100/75

20

F.K.W Schafer et al

2006

Department of Diagnostic Radiology, Christian-Albrechts-

Universitaet Kiel, Kiel, Germany

Prospective

31

40.5

18 months

Both menisci

+ S y E: MI: 88,6/98,3 ME: 90/95,9

21

Keith Winters et al

2005

Wellington Public Hospital

Prospective

67

37

1999 -2003

Both menisci

+ S y E: MI: 87/92 ME: 46/ 91

22

Sanchez Vaz et al

2005

Orthopaedics and Traumatology Department, Hospital Regional do Paraná,

State University of Londrina – Londrina/PA, Brazil.

Prospective

300

August 1998 – March 2002

Both menisci

+ S y E: MI: 97,5/92,9 ME: 91,9/93,6

23

Kocabey et al

2004

Division of Orthopedics (D.L.J.), Section of Sports

Medicine (Y.K., W.M.I., Ö.A.A.), University of Kentucky, Lexington,

Kentucky, U.S.A

Prospective

50

22

August 2001 – December 2001

Both menisci

+ S y E: MI: 80/79 ME: 85/97

Results

All 23 articles were diagnostic prospective studies with Arthroscopy as Gold Standard as diagnostic reference (Table 1).

Among these studies we found 22 that analyzed the correlation between imaging studies and arthroscopy (Se. & Sp.) in both menisci [35–56] and one paper in a single meniscus [18]. About the correlation between imagenology and arthroscopy in ACL we found 13 papers, [35–37,39,41–43,46–48,52,54,55] and 8 studies regarding the correlation between clinical examination and arthroscopy in meniscal injuries [18,35,43–46,52,53].

We found one work that compared the intensity of the MRI scanner’s field (1.5 T vs. 3T) for the assessment of meniscal and ligamentary disorders in the knee [47]. There were three studies that compared the diagnostic power of different sequences of the MRI scanner for meniscal injuries [38,51,55].

Finally, we found three papers that compared ultrasonography with MRI for the detection of meniscal injuries [18,50,56].

Regarding the description of the studies, we found the following: a) 14 [35,36,39,40,43–48,51–53,55] that showed a higher level of sensitivity than specificity in the medial meniscus and a higher level of specificity than sensitivity in the lateral meniscus; b) five [37,38,41,54,56] that showed a higher level of specificity than of sensitivity in the medial and lateral menisci; c) two [42,49] that showed a higher level of specificity than sensitivity in the medial meniscus and a higher level of sensitivity than specificity in the lateral meniscus (it is relevant to highlight that low-intensity scanners were used in said works); d) one [18] showing a higher level of specificity than sensitivity in the medial meniscus in acute and chronic injuries; and finally e) one study[50] that showed a higher level of sensitivity than of specificity globally in both menisci.

Discussion

The results of our review are shown within the context of other two previous reviews related to meniscal injuries [29,57]. Unlike the previous reviews, our investigation only included prospective studies with the aim of finding the most accurate results.

It is worth highlighting that, even though it is not the main focus of our work, the clinical examination is of utmost relevance with regards to the diagnosis of meniscal injuries. Several studies show that a correct and thorough clinical examination, preferably performed by an expert surgeon, is more sensitive and specific than MRI in order to diagnose medial meniscus injuries but has similar results in lateral meniscus issues [8,43–45,58].

Conceptually, it is customary to request an MRI in the event of diagnostic doubts [35,43,46,52] or when another therapeutic procedure is to be performed, e. g.: anterior cruciate ligament (ACL) surgery [42,45,59].

Another diagnostic element with good results, comparable with MRI, is ultrasonography [50,56]. Cook et al. state that in their series they found the same level of sensitivity but a better level of specificity than MRI for the diagnosis of meniscal injuries, thusly encouraging its usage, firstly due to its efficacy and secondly due to its low cost and quickness regarding the performance logistics [50].

Focusing on MRI, there are studies that substantially support its usage for diagnosing injuries within the context of a traumatic knee and, specifically, for meniscal injuries [60,61]. The vast majority of the studies analyzed in this review affirm that this test has great potential in comparison with other diagnostic tools (such as the clinical examination or the ultrasonography). They show that MRI has a better sensitivity level for the medial meniscus and a better specificity level for the lateral meniscus [35,36,39, 40, 43–48,51–53,55], and, also as previously stated, we compared similar results with other reviews contemporary to ours.(29, 57) There were studies in our review that did not show what most of the bibliography affirms [38,42,49]. Some, such as the one published by Behairy et al., showed opposite results: a higher sensitivity level for the lateral meniscus and a higher specificity level for the medial meniscus. Said authors say that this result might be the consequence of including anterior cruciate ligament injuries, which would decrease the sensitivity of the medial meniscus [11].

Other authors like Magee et. al., said that the MRI scanner’s power might be another element that modifies results [62]. The magnetic field’s intensity is a commonly reported study variable that might have some impact over the precision in meniscal injury cases. However, after analyzing different studies, we found no significant difference among different magnetic fields’ intensities, higher or lower (3.0 T and 1.5 T) [18,41,47,63]. Moreover, there are descriptions stating that 0.2 T scanners are equally effective and have lower costs than the conventional ones used nowadays [64,65]. Furthermore, given the current technological progress, it is necessary to develop new studies.

Some authors limited their revisions to the most current studies; they wanted to use those with modern technology and more experienced imagenology specialists [29]. This isn’t the case of other authors who disagree with the aforesaid, who claim that the previous studies have a higher quality and better methodology and that there might be a selection mistake [57]. In other words, all studies should be included regardless of its publishing year. This also avoids the bias that may happen when authors select a specific year for exclusion.

From the analysis of the collected information, and as a consequence of the preceding discussion, we may consider that there is no consistency of results and opinions in English-published bibliography of a prospective profile. Nevertheless, we must acknowledge that the prevailing results are those that prioritize the relevance of MRI in terms of sensitivity and specificity. We must currently accept that MRI is a very costly study for diagnosing meniscal injuries. There are some variations in its sensitivity and specificity, but they are minor and, therefore, do not invalidate these conclusions. There is no doubt that, in future years, technological progress shall provide more accurate devices that will allow us to reach safer diagnostic levels.

Likewise we shouldn’t forget that clinical examination, when combined with MRI, offers the most accurate non-invasive method to obtain the available information about meniscal pathological findings [53, 66].

A thorough search throughout medical literature, including PubMed and Lilacs databases, provided us with 23 studies that informed about the correlation between imaging screening and arthroscopy in both menisci and only one work about the lateral meniscus, all of them published between 2004 and 2018, and they constitute the strength of our study. The limitations are the reduced amount of cases in some studies and the inability of access to final conclusions due to the lack of uniformity in the results of the analyzed studies.

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  66. Glashow JL, Katz R, Schneider M, Scott WN (1989) Double-blind assessment of the value of magnetic resonance imaging in the diagnosis of anterior cruciate and meniscal lesions. J Bone Joint Surg Am 71: 113–9.

Impact of Drug-Based Treatment for Osteoporosis on Pain and Parameters of Physical Fitness – A Clinical Pilot Study

DOI: 10.31038/IJOT.2019235

Abstract

Background: The origin of osteoporosis is attributed to several factors and its prevalence is on the increase. It is one of the principal causes of fractures, morbidity, and chronic pain. Muscle and coordination exercises may help to improve physical performance in everyday life, alleviate pain, and prevent falls. On the other hand, the effect of targeted drug therapy on these parameters is not known yet.

Methods: Twenty-five patients with osteoporosis were observed prospectively for 18 months. During this time the patients received targeted drug therapy for the disease. The results of treatment (pre/post) in regard of parameters of physical fitness and pain were analysed.

Results: No changes were noted in respect of torso strength, mobility, and coordination (p>0.05). The patients’ body height was reduced to a significant extent (p<0.001), their hand grip strength on the right side was significantly reduced (p=0.006), and their pain levels were significantly reduced (p=0.001). Factors influencing the success of treatment were body weight, height, the administration of teriparatide, and sports.

Conclusions: While pain can be influenced by medication for the treatment of osteoporosis, no effect or even a decline was noted in parameters of physical fitness.

Keywords

Hand grip strength, mobility, osteoporosis, torso strength, pain treatment

Introduction

Osteoporosis is a systemic disease of bone, marked by reduced bone mass and a disrupted microarchitecture of bone. The result is a greater propensity for fractures and the frequent occurrence of fractures. The latter are associated with pain, limited mobility and quality of life, as well as greater morbidity and mortality [1]. Furthermore, the patient experiences a loss of conditional resources such as muscle strength, endurance, and coordination.

A number of therapy options in terms of drugs and physiotherapy are available for the treatment of this disease. Regular physical exercise alleviates pain, prevents falls, and improves mobility and quality of life [2–4]. Specific medications for osteoporosis, such as bisphosphonates, reduce fracture rates by adhering firmly to bone surfaces and inhibiting the enzyme known as farnesyl pyrophosphate synthase, which is needed in osteoclasts for the formation of the cytoskeleton [5,6]. Monoclonal antibodies also contribute significantly to reducing the risk of fractures [7]. The impact of long-term specific drug therapy on the development of motor and coordination skills in the course of the disease has been poorly investigated so far. Especially pain caused by osteoporosis is of paramount importance for many patients. Alleviating such pain by drug therapy would be subjectively interpreted as successful treatment and an improvement in quality of life for many patients; this was the subject of the current prospective study.

Material and Methods

The aim of the present study is to evaluate the impact of targeted drug therapy on parameters of physical fitness and pain experienced by patients with osteoporosis. Statements about the factors influencing the success of treatment will also be evaluated.

Study Design and Recruitment

We conducted a prospective single-centre clinical investigation of a treatment group. All probands were informed in detail about the methods, purposes, and risks of the study protocol. Furthermore, they were handed out a copy of their written informed consent. The probands were recruited during the outpatient consultation hours for osteoporosis at the Südstadt Klinikum in Rostock. The recruitment of patients takes 2 years. This made it difficult to predict the required number of patients with regard to the significance of the clinical examination.

Inclusion and Exclusion Criteria

Inclusion criteria for the clinical study were the presence of proven osteoporosis requiring treatment in patients with pathological bone densitometry values and the availability of X-rays of the thoracic and lumbar spine. At the start of the study, all patients underwent a physical investigation to determine their orthopaedic status, which included the Chair-Rising test (CR test), walking speed (WS), Tandem Stand (TS), Tandem Gait (TG), Hand Grip Strength (HGS), and a guideline-oriented laboratory screening.

Exclusion criteria were all forms of severe heart failure, uncontrolled hypertension, relevant neurological deficits, vestibulopathy, and the need for external care.

Clinical Tests

Short Physical Performance Battery (SPPB)

It consists of three tests: tandem stand, walking for 4 meters, and the CR test [8,9]. For each task the patient may achieve a maximum of 4 points. The scores of the three tests are then added. A person may achieve a minimum score of 0 and a maximum score of 12 points. We used the SPPB to measure the function of the lower extremities when performing tasks similar to the activities of daily living. Based on the total score, one can estimate how severely the patient is limited in his/her daily life. Patients with a final score of 0 to 3 points are strongly impaired, especially when walking a few hundred meters, ascending stairs, and in self-care [10,8]. Patients with a final score of 4 to 6 points are moderately impaired, and those with a score from 7 to 9 points are mildly impaired. A patient who achieves a score of 10 to 12 points is minimally impaired or not impaired in his/her daily life.

The patient’s balance and coordination were tested with the aid of the tandem stand. Three positions were retained for 10 seconds each: standing with closed feet, semi-tandem stand (the heel of one foot is at the mid-portion of the inside of the other foot), and tandem stand (one foot behind the other). The patient is free to decide which foot is placed in the front.

The walking test measures the time taken to walk 4 meters at normal speed. This task combines the patient’s strength and coordination in walking and is therefore a good parameter to assess physical performance capacity [11]. The threshold value for limited mobility is a walking speed of ≤0.8 meters per second [12].

The CR test measures five consecutive cycles of standing up from, and sitting on a chair without armrests, with the patient’s arms folded across his/her chest. In general the SPPB is a frequently used instrument that has proved its value not only for the identification and description of probands at the disabled end of the functional spectrum, but also for non-disabled elderly persons [9].

The results constitute a part of the SPPB on the one hand, and provide information about a normal or elevated risk of falls on the other: a score ≤10 s is normal, whereas a score >10 s signifies an elevated risk of falling [13].

Figure 1 (Figure 1) shows an example of the CR test (a), the TS (b), and the test of WS (c).

IJOT 19 - 120_Guido Schröder_F1

Figure 1. Exemplary tests of strength, coordination and mobility
CR test (a), TS (b), WS (c)

Hand Grip Strength (HGS)

In addition to the SPPB we measured HGS in kilograms (kg) with a traditional hand grip strength dynamometer. A score of <27 kg is considered to indicate limited physical capacity for men, while the cut-off value for women is 16 kg [12]. The HGS is an efficient and simple method to test overall strength in elderly persons, and has a high and independent predictive power in regard of functional limitations and disabilities [14,15].

Tandem Gait (TG)

TG: The patient is asked to walk 8 steps in a straight line. The outcome provides additional information about the risk of falling, to the extent that 8 walked steps are considered synonymous with a halved risk of falling in a comparison of age [13].

Pain

In the present clinical trial we used the Numerical Rating Scale (NRS). The latter is a unidimensional pain scale with 11 grades, with 0 indicating no pain and 10 the most severe imaginable pain. The probands selected the grade that described their perception of pain. The advantages of the NRS are the low error rate of its results and its high acceptance by test persons [16].

Non-Pharmacological Treatment for Osteoporosis

Calcium

Many postmenopausal women consume too little calcium. Supplementation is therefore useful, also to reduce fracture rates [17]. In the present investigation we tried to achieve a calcium supplementation level of 800 mg daily in order to achieve optimum absorption. After an initial laboratory investigation of retention parameters the patients were given nutritional counselling and advised to consume natural sources of calcium such as milk and cheese instead of food supplements (500 mg). The latter was only used in cases of marked deficiency, because the undesirable gastrointestinal effects of taking calcium could reduce the patients’ compliance. Furthermore, it has been found that higher doses of calcium may cause kidney stones or myocardial infarction [18].

Cholecalciferol

The probands were advised to take 20000 IU of vitamin D3 every week. The aim of the treatment was to achieve a serum 25-hydroxyvitamin-D level above 55 nmol/l.

Additionally all probands were given information about a balanced diet with a protein content of 1 g/kg daily [5].

Pharmacological Treatment for Osteoporosis

Bisphosphonates

A variety of bisphosphonates are currently approved for the treatment of postmenopausal osteoporosis. We used the following substances among others:

  • Alendronate 10 mg daily or 70 mg weekly taken orally; men with osteoporosis were given 10 mg daily.
  • Zolendronate 5 mg intravenously once every year in postmenopausal women and men with an elevated risk of fractures, including those with a recent fracture due to mild trauma, and for the treatment of osteoporosis in association with long-term systemic glucocorticoid therapy in both genders.
  • Ibandronate 150 mg a month taken orally, or 3 mg as an intravenous injection every 3 months in postmenopausal women with an elevated risk of fractures [19].

Denosumab

This is a monoclonal antibody against the receptor activator of the nuclear factor-kappa B ligand (RANKL), an important regulator of the development and activity of osteoclasts. It is also approved for the treatment of postmenopausal osteoporosis and for men with an elevated risk of fractures. In the present study denosumab was administered – in persons with the appropriate indication – as a subcutaneous injection at a dose of 60 mg every 6 months [19].

Teriparatide

Several cell pathways in the osteoblast are activated by teriparatide, which in turn leads to greater osteoblast recruitment [5]. In patients with an appropriate indication, teriparatide was administered at a dose of 20 to 40 mg daily.

Strontiumranelate

The distrontium saltknown as strontiumranelateconsists of two atoms of stable strontium and the organic portion, which is ranelic acid. It improves osteoblastic cell replication and enhances collagen synthesis. Simultaneously it reduces the differentiation of osteoclasts and the bone resorption activity of mature osteoclasts in vitro [20]. In patients with the appropriate indication it was given at a dose of 2 g daily.

Testosterone

Hypogonadism is the most frequent cause of osteoporosis in men. In this setting it may be useful to administer the male sexual hormone testosterone as a gel.

Statistics

The collected data were analysed using the statistical software packet SPSS, Version 23.0 (SPSS Inc., Chicago, USA). In a first step we performed a descriptive evaluation. The quantitative characteristics were described using means [MW], Standard Deviation (SD), minimum and maximum values, and the number of available observations; these were shown with the interval of means ± standard deviation. For the qualitative characteristics we mentioned absolute and percentage frequencies of the individual grades of severity.

Depending on the result of the Shapiro-Wilk tests on normal distribution, we used the dependent t-test to evaluate changes in the respective parameters between the various time points of measurement, and Wilcoxon’s rank sum test. To test qualitative characteristics and analyse categorical frequencies we used the Chi2 test. We then calculated the effect size from the quotient of the test value (z) and the square root of the number of probands (n). A resulting value below 0.3 was rated as a weak effect, a value between 0.3 and 0.5 as a moderately strong effect, and a value higher than 0.5 as a strong effect. The effect size of Cohen’s D was determined from the quotient of the mean value difference and the standard deviation (SD). A resulting value from 0.2 onward was rated weak, a value from 0.5 onward as moderate, and a value beyond 0.8 as a strong effect.

All p-values are the result of two-sided statistical tests; the level of significance was set to p≤0.05.

Results

Probands and Baseline Characteristics of the Study Population

Twenty-five patients with osteoporosis participated in the clinical trial. The patients’ age at the start of the investigation was between 48 and 78 years (65.0 ± 8.3). Twenty-three of 25 probands (92 %) concluded the clinical investigation. NRS values could not be determined for two patients because of the absence of appropriate documentation. Table 1 summarizes the baseline characteristics of the study population.

Table 1. Baseline characteristics of the study population (n = 25)

General medical history

M ± SD (Min-Max)

Gender m/f

3/22

Age (years)

65.0 ± 8.3 (48 – 78)

Height (cm)

167.2 ± 7.7 (154 – 181)

Weight (kg)

66.4 ± 11.6 (48 – 95)

BMI (kg/m2)

23.7 ± 3.4 (18.7 – 33.3)

Bone density (SD)

-2.7 ± 0.9

Fractures yes/no (%)

  • Central (%)
  • Peripheral (%)
  • Both (%)

76/24

60

4

12

School education 12 years/< 12 years (%)

24/76

Smokers / Non-smokers (%)

28/72

Drugs for osteoporosis

Bisphosphonates (%)

Monoclonal antibodies (%)

Recombinant human parathyroid hormone fragment (%)

Strontiumranelate (%)

Cholecalciferol (%)

Calcidiol (%)

Calcium 500mg (%)

68

16

8

4

72

4

4

Food rich in calcium prior to nutritional counselling

yes/no (%)

16/84

History of pain

Back pain yes/no (%)

88/12

Frequency of pain

  • Daily (%)
  • Occasionally (%)
  • Never (%)

28

60

12

Intensity of pain

  • NRS 0–10(n=23)

4.4 ± 2.9 (0 – 9)

Type of pain

  • Burning (%)
  • Stabbing (%)
  • Dull (%)
  • Different types (%)
  • No pain (%)

8

12

56

12

12

Location

  • Cervical spine (%)
  • Thoracic spine (%)
  • Lumbar spine (%)
  • Entire spine (%)
  • No pain (%)

0

4

56

28

12

Time of maximum pain

  • Morning (%)
  • Noon (%)
  • Evening (%)
  • Night (%)
  • Whole day (%)
  • No pain (%)

12

4

32

8

32

12

Regular use of analgesics yes/no (%)

28/72

Musculoskeletal diseases

  • Rheumatic disease (%)
  • Orthopae dicdisease (%)
  • None (%)

20

32

48

Work situation

  • Labourer (%)
  • Seeking employment/work (%)
  • Pensioner (%)

28

0

72

Activities that challenge the back muscles yes/no (%)

32/68

Activity profile

  • Sedentary (%)
  • Standing (%)
  • Mixed (%)

32

8

60

Sports yes/no (%)

76/24

Data presented as means ± SD and percentages

Height, Body Weight, BMI

The patients’ height at the time point T0 was on average 167.2 ± 7.7 cm. In the observation period we registered a mean value of 164.5 ± 8.1 cm, which amounted to a highly significant difference (p<0.001) between the two time points. The change in the patients’ BMI was also very significant (p=0.008). On the other hand, weight did not differ significantly between T0 und T1 (p>0.05).

CR test

With regard to the CR test, at the start of the investigation we noted a mean value of 9.7 ± 2.3 seconds. After the conclusion of treatment there was a statistical trend in terms of a deterioration of torso strength (10.7 ± 2.7 s, p=0.086).

Walking Speed

WS at the time point T0 was on average 0.9 ± 0.1 m/s. At T1 the mean value was 0.9 ± 0.2 m/s. The pairwise comparison of means revealed no significant difference (p=0.573).

Table 2 provides an overview of the above mentioned parameters.

Table 2. Results of parametric tests as percentage changes (n=25)

Parameter

Observation period vs. Baseline

p-value

Effect size, Cohens d

Height

-1.6 ± 1.8

<0.001

0.869***

Weight

0.9 ± 6.0

0.616

——-

BMI

4.1 ± 7.3

0.008

0.579**

Chair-rising test

12.3 ± 27.1

0.086

——-

Walking test

3.7 ± 21.2

0.573

——-

Data presented as means ± SD, t test against 0, *weak, **moderate, ***strong

Hand Grip Strength

HGS on the right side was reduced after drug therapy from 29.6 ± 9.9 kg to 27.2 ± 8.6 kg; the difference was highly significant (p=0.006). On the left side there was no significant difference (p>0.05). On the left side HGS was 28.0 ± 9.8 kg at the start of treatment and then reduced to 26.5 ± 8.4 kg.

Figure 2 shows the relative changes in the CR test, WS, and HGS.

IJOT 19 - 120_Guido Schröder_F2

Figure 2. Relative changes in selected parameters of strength and mobility

Tandem Gait

On tandem gait the patients were able to walk a minimum of 4 steps and a maximum of 8 steps at the start of treatment. At time point T1 we observed no significant difference in this regard (p>0.05).

SPPB

The SPPB values were between 8 and 11 points at the start of the investigation, and 10.2 ± 1.0 points on average. A comparison of values at the start of the investigation (T0) and after 18 months of drug treatment for osteoporosis (T1) revealed no significant difference (10.2 ± 1.0 points, p=0.776).

Pain

Sixty percent of the study participants said they had occasional pain and 28% had pain every day. The intensity of pain was moderate (NRS 4.4 ± 2.9) at the start of the investigation. Pain was primarily described as dulland was mainly experienced in the lumbar spine. Thirty-two percent of patients had persistent pain throughout the day or in the evening. Twenty-eight percent of the patients used painkillers of the WHO category I regularly while 8% used NSAID. Four percent of patients used phytopharmaceuticals or painkillers of the WHO category II, and 12% used a combination of treatments. After 18 months of drug treatment for osteoporosis the patients’ pain levels on the NRS were reduced on average to 2.6 ± 2.0 points; the result was highly significant (p=0.001), and the effect was strong (r=0.508).

Table 3 provides a summary of the results in regard of the above mentioned parameters.

Table 3. Results of the non-parametricsigned rank test (n=25)

Parameter

p-valueƟ

Effect size, r

Hand grip strength on the right side

0.006

0.391***

Hand grip strength on the left side

0.136

——-

Tandem gait

0.443

——-

SPPB

0.776

——-

NRS (n=23)

0.001

0.508***

ƟWilcoxon test, *weak, **moderate, ***strong

Success of Treatment

We rated the success of treatment (SOT) on a numerical rating scale from 0 to 10. An improvement by at least 2 points on the NRS was rated as successful treatment. Eight patients concluded the treatment successfully, whereas 15 patients experienced no success of treatment (NTS). We also determined the corresponding factors that influenced the success of treatment.

The two groups differed very significantly in terms of body weight at the start of the investigation [57.4 ± 6.8 kg (SOT) vs. 70.3 ± 11.2 kg (NTS), p=0.007], and still differed significantly after the intervention [59.6 ± 9.0 kg (SOT) vs. 69.3 ± 10.0 kg (NTS), p=0.033]. With regard to height, a statistically significant difference was noted between the two groups [161.9 ± 6.8 cm (SOT) vs. 169.0 ± 6.6 cm (NTS), p=0.023], which remained significant in the observation period [158.8 ±  4.4 cm (SOT) vs. 166.5 ± 7.9 cm (NTS), p=0.019]. With regard to BMI, at baseline the difference between the two groups revealed a trend towards significance (p=0.073), which was no longer present after the conclusion of treatment (p>0.05). With regard to the prescribed drugs, a difference was only noted between the SOT and NTS groups when they took teriparatide (p=0.043). As regards sports, a significant difference was noted between the SOT and NTS groups (p=0.021).

In contrast, for the CR test, walking speed, new fractures, and food rich in calcium, we registered no significant differences between the individual time points of measurement (p>0.05) (Table 4). The factors influencing the success of treatment are summarized in Table 4.

Table 4. Success of treatment

Parameter

Successful treatment*

(n=8)

No successful treatment

(n=15)

p-value

Age (years)

63.3 ± 8.5

65.1 ± 8.3

0.625π

Weight (kg)

Before the intervention

After the intervention

57.4 ± 6.8

59.6 ± 9.0

70.3 ± 11.2

69.3 ± 10.0

0.007π

0.033π

Height (cm)

Before the intervention

After the intervention

161.9 ± 6.8

158.8 ± 4.4

169.0 ± 6.6

166.5 ± 7.9

0.023π

0.019π

BMI (kg/m2)

Before the intervention

After the intervention

21.9 ± 2.0

23.5 ± 2.9

24.6 ± 3.8

25.0 ± 4.1

0.073π

0.355π

Chair rising test (s)

Before the intervention

After the intervention

8.9 ± 2.3

10.1 ± 1.8

10.2 ± 2.2

10.9 ± 3.1

0.105π

0.496π

Walking speed (m/s)

Before the intervention

After the intervention

0.9 ± 0.1

0.9 ± 0.1

0.9 ± 0.1

0.9 ± 0.2

0.413π

0.469π

Smokers yes/no

3/5

4/11

0.591c

Bisphosphonates yes/no

7/1

8/7

0.101c

Monoclonal antibodies yes/no

1/7

3/12

0.651c

Recombinant human parathyroid hormone fragment

2/6

0/15

0.043c

Strontiumranelate

1/7

0/15

0.161c

New fractures yes/no

3/5

3/12

0.363c

Sports yes/no

8/0

8/7

0.021c

*defined as a reduction on the NRS by 2 points. Data expressed as means ± SD, πindependent t test, cChi-square test

Discussion

The present investigation is the first to provide comprehensive data on the effects of 18 months of drug treatment for osteoporosis on parameters of physical fitness and pain. The level of pain could be reduced significantly in the entire group, whereas the parameters of physical fitness remained unchanged or even deteriorated. While the reasons for this change are manifold, we presume that the drug treatment could have influenced the patients’ perception of pain. In our investigation, especially teriparatide was found to exert favourable effects. Soen et al. [21] achieved similar results in their investigation of about 2000 patients who took 20 μg of teriparatide daily. The mode of action of this drug is not fully investigated yet and calls for further research. One potential mechanism of reducing back pain is reducing the severity as well as the number of new vertebral fractures [22]. New fractures played a subsidiary role in the present study, especially with regard to the success of treatment. The other drugs that we administered also had an effect on the patients’ perception of pain, regardless of the success of treatment. In the present study 68 % of the probands were given bisphosphonates, which enhance bone density by inhibiting osteoclast activity, and thus markedly suppress bone turnover when used for a long period of time [23]. However, these drugs may also cause an accumulation of micro injuries and thus impair the healing of stress fractures [24]. Despite an increasing quantity of bone, the quality of bone may deteriorate, which may favour bisphosphonate-related proximal femoral fractures among other conditions [25]. However, an animal experiment performed by Naito et al. [26] showed that treatment with alendronate may halt bone resorption and reduce levels of pain mediators. Compared to other bisphosphonates, the unique mechanism of action of minodronate on the inhibition of the P2X(2/3) receptor is advantageous, especially in reducing back pain among patients with osteoporosis [27]. However, in the present investigation we did not use minodronate. It should be noted that patients with osteoporosis benefit from the alleviation of pain in terms of an improvement of their quality of life.

Worthy of note was the significant change in hand grip strength on the right side. Simultaneously, pain levels were reduced in patients who did the sports program regularly. We attribute this effect to the specificity of the component of strength; in other words, only those patients who perform specific exercises for muscle strength are able to increase their muscle strength. Some participants performed the muscle strengthening exercises regularly while others swam or biked.

The results of the present study reveal that, in addition to drug treatment for osteoporosis, consistent muscle exercises may be useful. In a meta-analysis of the impact of various physical activities on osteoporosis, many studies revealed an increase in bone density under regular physical activity. Moderately intensive exercises performed twice to four times a week, in short intervals and at a high frequency, appeared to be especially effective [28]. In the present study only five patients performed regular sports at baseline by way of intensive muscle exercises. Based on these results, patients should be advised to perform regular exercise. Sling therapy is a suitable option; among our patients this exercise led to a significant reduction of pain, improvement of physical fitness, and a positive perception of their subjective health [4].

Independent of drug therapy, a lower body weight with a normal BMI does appear to exert a positive effect on pain levels. In the group that achieved successful treatment, the probands were on average about 12.5 kg lighter and their BMI was markedly lower than the corresponding values in patients who did not achieve successful treatment. Segar et al. [29] showed that a high BMI is associated with pain, especially in the lower extremity; the authors also noted back pain in these patients.

Conclusion

  • Teriparatide has – more than other drugs – a positive effect on the pain experienced by patients with osteoporosis.
  • Independent of the perception of pain, drugs for osteoporosis have no impact on muscle strength.
  • Physical activity or exercise in a sufficient dose does contribute to the reduction of pain in the long term among patients with osteoporosis.
  • A normal BMI may influence the perception of pain in patients with osteoporosis.
  • Supplementary muscle exercises aligned to the patient’s level of fitness appear meaningful in addition to drug therapy.

Limitations

The prospective design and the limited size of the group are limitations of the present study. More complex statistical procedures could not be used. Thus, no general conclusions can be drawn on the basis of the present data. The absence of the blinding of patients and investigators is a further limitation. This is a single pilot study, so a misinterpretation of the findings is possible. Our results may not be generalizable. In general the investigation period of 18 months is short. Bisphosphonates partly unfold their effect up to 3 years. This permits limited statements about the long-term effects of the treatment. In future investigations we intend to evaluate the data of a longer period of intervention and thus achieve a better level of evidence.

Declaration

Ethical Approval

We declare that this study with human subjects is in accordance with the Helsinki Declaration of 1975 as amended in 2000 and that it has been approved by the competent institutional ethics committee of the University of Rostock (Trial registration No. A 2018–0247).

Consent to participate

All  subjects  were  informed  comprehensively  about  the  methods,  purposes and risks of the study protocol and also received a written declaration of informed consent.

Consent for publication

BF agreed in writing to the publication of the illustration.

Availability of data and material

The vote of the Ethics Committee can be found at the following address (https: //www.ethik.med.uni-rostock.de/ A 2018–0247). The consent to the publication of the photographic material has been given to the journal.

Authors’ contribution

HCS led the investigation and is co-responsible for the clinical trial concept. He also participated in the recruitment of the test subjects. GS designed the data preparation concept. UV carried out the survey, measurement and documentation of the data. RB participated in the data preparation and correction of the typesetting. VB was responsible for the translation of the journal article. AH carried out the statistical data evaluation.

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  9. Guralnik JM, Ferrucci L, Pieper CF, et al. (2000) Lower extremity function and subsequent disability. Consistency across studies, predictive models, and value of gait speed alone compared with the short physical performance battery. The journals of gerontology. Series A, Biological sciences and medical sciences 55: M221–31.
  10. Guralnik JM, Simonsick EM, Ferrucci L, et al. (1994) A short physical performance battery assessing lower extremity function. Association with self-reported disability and prediction of mortality and nursing home admission. Journal of gerontology 49: M85–94.
  11. Seefried L, Genest F (2017) Functional diagnostics of sarcopenia. Osteology 26: 13–17.
  12. Cruz-Jentoft AJ, Bahat G, Bauer J, et al. (2018) Sarcopenia. Revised European consensus on definition and diagnosis. Age and ageing.
  13. Runge M (2009) Fünf Esslinger. Ein Bewegungsprogramm für Muskel-Knochen- Fitness.
  14. Rantanen T (2003) Muscle strength, disability and mortality. Scandinavian journal of medicine & science in sports 13: 3–8.
  15. Rantanen T, Volpato S, Ferrucci L, et al. (2003) Handgrip strength and cause-specific and total mortality in older disabled women. Exploring the mechanism. Journal of the American Geriatrics Society 51: 636–641.
  16. Basler HD (2011) Akutschmerztherapie in Pädiatrie und Geriatrie – Schmerzmessung: Welche Schmerzskala bei welchen Patienten? Anästhesiol Intensivmed Notfallmed Schmerzther: 334–342.
  17. Prince RL, Devine A, Dhaliwal SS, Dick IM (2006) Effects of calcium supplementation on clinical fracture and bone structure. Results of a 5-year, double-blind, placebo-controlled trial in elderly women. Archives of internal medicine 166: 869–875.
  18. Bolland MJ, Avenell A, Baron JA, et al. (2010) Effect of calcium supplements on risk of myocardial infarction and cardiovascular events.Meta-analysis. BMJ (Clinical research ed.) 341: 3691.
  19. Compston J, Cooper A, Cooper C, et al. (2017) UK clinical guideline for the prevention and treatment of osteoporosis. Archives of osteoporosis 12: 43.
  20. Dimai HP (2005) Strontium ranelate. A novel concept for the treatment of osteoporosis. Wiener klinische Wochenschrift 117: 728–738.
  21. Soen S, Fujiwara S, Takayanagi R, et al. (2017). Real-world effectiveness of daily teriparatide in Japanese patients with osteoporosis at high risk for fracture. Final results from the 24-month Japan Fracture Observational Study (JFOS). Current medical research and opinion 33: 2049–2056.
  22. Genant HK, Halse J, Briney WG, et al. (2005) The effects of teriparatide on the incidence of back pain in postmenopausal women with osteoporosis. Current medical research and opinion 21: 1027–1034.
  23. Odvina CV, Zerwekh JE, Rao DS, et al. 2005. Severely suppressed bone turnover. A potential complication of alendronate therapy. The Journal of clinical endocrinology and metabolism 90: 1294–1301.
  24. Unnanuntana A, Saleh A, Mensah KA, et al. (2013) Atypical femoral fractures. What do we know about them?: AAOS Exhibit Selection. The Journal of bone and joint surgery 95: 1–13.
  25. Ma C-M, Cheung M-H, Wong W-B (2015) Surgical Difficulties and Complications in the Treatment of Bisphosphonate-related Proximal Femur Fractures. 非典型股骨近端骨折外科手術的困難和併發症. Journal of Orthopaedics, Trauma and Rehabilitation 19: 83–88.
  26. Naito Y, Wakabayashi H, Kato S, et al. 2017. Alendronate inhibits hyperalgesia and suppresses neuropeptide markers of pain in a mouse model of osteoporosis. Journal of orthopaedic science 22: 771–777.
  27. Ohishi T, Matsuyama Y (2018) Minodronate for the treatment of osteoporosis. Therapeutics and clinical risk management 14: 729–739.
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  29. Segar AH, Urban JPG, Fairbank JCT, Judge A. 2016. The Association between Body Mass Index (BMI) and Back or Leg Pain in Patients with Spinal Conditions. Results from the Genodisc Study. Spine 41: 1237–E1243.

Juvenile Tillaux Fractures: A Comparison of Direct and Indirect Fixation

DOI: 10.31038/IJOT.2019234

Abstract

Background: Two different screw configurations for the fixation of juvenile Tillaux fractures have been reported. One technique, direct fixation involves placement of one or two screws directly through the fragment, into the medial epiphysis or across the physis and into the metaphysis. The second technique involves placement of one or two screws through the medial epiphysis and into the fragment. The purpose of the study was to retrospectively study both techniques with regard to their effectiveness in maintaining an open anatomic reduction.

Methods: A review of all juvenile Tillaux fractures that had been operatively treated at our institution over a 5 year period was performed. A total of thirty-eight fractures were identified with twenty-three fractures (61%) treated utilizing a direct fixation technique and fifteen fractures (39%) treated utilizing an indirect fixation technique. All fractures were followed to union with a mean follow-up of twenty-one weeks.

Results: Thirty-four of the thirty-eight fractures were anatomically reduced on intraoperative radiographs with elimination of joint step-off on all radiographs and a residual one-millimeter fracture gap noted in four fractures. No fracture displaced between the time of internal fixation and healing. The mean healed fracture gap was 0mm and the mean healed joint step-off was 0mm. Four of the fifteen fractures stabilized with indirect fixation required hardware removal. One of the twenty-three fractures stabilized using direct fixation required hardware removal.

Conclusion: Either direct or indirect fixation of juvenile Tillaux fractures is effective in maintaining an anatomic open reduction of the joint surface.

Introduction

The juvenile Tillaux fracture was first recognized by Paul Jules Tillaux [1] but was not extensively described until the report of Kleiger and Mankin [2]. The fracture occurs primarily in older adolescents in whom closure of the distal tibial physis has begun [3–7]. Early descriptions of the fracture reported successful treatment with closed reduction and casting [2,8,9]. However, reports of early degenerative changes in patients with displaced intraarticular distal tibia fractures have led to recommendations for open reduction and internal fixation in displaced intraarticular distal tibia fractures [10]. Some authors have advocated closed reduction with percutaneous fixation [11] or arthroscopic reduction [12,13] but open reduction is the standard of care [14–22]. The literature describes two different fixation techniques. The first involves placement of one or two pins or screws through the epiphyseal fragment and into the distal tibial metaphysis [18,20,21,23–25] (figure 1). The second technique involves placement of one or two screws through the medial malleolus and into the Tillaux fragment [17] (figure 2). Both techniques have been used at our institution. This study was performed to evaluate the effectiveness of each technique at maintaining the anatomic reduction obtained at the time of open reduction.

Materials and Methods

After obtaining institutional review board approval, a review of all distal tibial Tillaux fractures treated operatively at our institution between over a five year period was performed. Patients successfully treated with cast immobilization and without surgical intervention were excluded. Charts were reviewed for demographic information, operative details and postoperative complications and follow-up. Radiographs were reviewed for confirmation of the fracture pattern, the screw configuration used and intraoperative measurement of the displacement after fixation. Follow-up radiographs were reviewed to assess healing and measure displacement in both a transverse direction (fracture gap) and a vertical direction (joint step off).

A total of forty-five patients with forty-five fractures were identified. Seven patients had radiographs that could not be located or inadequate follow-up for inclusion in the study. A total of thirty-eight patients with thirty-eight fractures were identified that were followed to union. A total of sixteen males and twenty-two females were included. The mean age of the patients was thirteen years and eight months (range eleven years and one month to sixteen years and two months). The right ankle was involved in twenty-two fractures (58%) and the left in sixteen (42%). A total of twenty-three fractures (61%) were stabilized using direct fixation while fifteen fractures (39%) underwent indirect fixation. All patients were followed to fracture union, which occurred in all fractures within six weeks after the injury. The mean follow up was twenty-one weeks (range six to 124 weeks)

Surgical Technique

After the patient had been placed in the supine position with a bump under the ipsilateral hip, the involved extremity was prepared and draped free. Under tourniquet, in all patients, an anterior longitudinal incision was made over the ankle and dissection was performed down to the level of the anterior tibial tendon. Dissecting either medial to the anterior tibial tendon or between the anterior tibial tendon and the extensor hallicus longus tendon an arthrotomy was then performed. The Tillaux fragment was then identified and distracted by inserting a freer elevator into the fracture site. Hematoma was then curetted from the fracture site and the ankle joint thoroughly irrigated. The articular surface was then reduced under direct vision using the elevator and held reduced using a large bone reduction clamp. One of two fixation configurations was then used after open reduction at the surgeon’s discretion. The first technique, designated direct fixation, involved the placement of one or two cannulated 4.0mm, partially threaded, interfragmentary screws (Smith-Nephew-Richards, Memphis, Tennessee, USA) angled proximally, medially and posteriorly through the Tillaux fragment and into either the distal tibial epiphysis or across the physis and into the metaphysis (Fig. 1a-f). The second technique, designated indirect fixation17, involved making a small (3mm) incision over the medial aspect of the epiphysis and placement of one or two cannulated interfragmentary screws through the medial epiphysis between the physis and the joint surface using image intensification (Fig. 2a-e). Closure of the incisions was carried out after confirming anatomic reduction both visually by inspecting the joint surface and by using image intensification. Regardless of the screw configuration utilized, the ankle was immobilized in a short leg cast or orthotic walker boot and the patient was requested to be non-weight bearing for six weeks. Hardware removal was not routinely performed after fracture healing but was performed if the patent experienced significant discomfort with activity over the area of screws.

IJOT-119_Gordon JE_F1a

Figure 1a. Anteroposterior radiograph of the left ankle in a 13+0 year old female after a twisting injury sustained after stepping into a hole showing a displaced Tillaux fracture.

IJOT-119_Gordon JE_F1b

Figure 1b. Lateral radiograph of the left ankle in the same patient.

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Figure 1c. Coronal reconstruction of computed tomography of the distal tibia following closed reduction showing significant gapping of the Tillaux fragment.

IJOT-119_Gordon JE_F1d

Figure 1d. Coronal reconstruction of computed tomography of the distal tibia in the mid tibia following closed reduction showing mild displacement of the Tillaux fragment.

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Figure 1e. Anteroposterior intraoperative image of the ankle in the same patient obtained using an image intensifier intraoperatively after open anatomic reduction and internal fixation using direct fixation with one screw

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Figure 1f. Lateral image of the ankle in the same patient.

IJOT-119_Gordon JE_F2a

Figure 2a. Anteroposterior radiograph of the left ankle in a 12+6 year old female after an injury sustained while playing soccer. A displaced Tillaux fracture is present

IJOT-119_Gordon JE_F2b

Figure 2b. Lateral radiograph of the left ankle in the same patient.

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Figure 2c. Computed axial tomographic image of the left distal tibia showing displacement of the Tillaux fragment.

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Figure 2d. Intraoperative anteroposterior image of the ankle in the same patient obtained using an image intensifier intraoperatively after open anatomic reduction and internal fixation using indirect fixation with two screws.

IJOT-119_Gordon JE_F2e

Figure 2e. Intraoperative lateral image of the ankle in the same patient obtained using an image intensifier intraoperatively after open anatomic reduction and internal fixation using indirect fixation with two screws.

Results

Anatomic reduction was obtained in thirty-four of the thirty-eight fractures at the time of operative fixation. Joint step off was eliminated in all patients. Three of the twenty-three fractures treated by direct fixation (13%) and one of the fifteen fractures treated by indirect fixation (7%) were noted to have a residual one-millimeter fracture gap intraoperatively that was felt to be acceptable. Measurements at the time of bony union revealed that no fracture had displaced joint step off (mean 0 mm). At the time of union, no patient had a measurable fracture gap (mean 0 mm). One of the twenty-three patients who had direct fixation (4%) requested hardware removal. Four of the fifteen patients who had indirect fixation (29%) requested hardware removal. No intraoperative or postoperative complications occurred although transient tingling in the distribution of the superficial peroneal nerve was noted postoperatively in a few patients. This had resolved by the time of final follow-up in all patients. No patient developed other neurovascular complications, wound problems or infection. Hardware removal was uncomplicated in all patients who requested removal of the screws.

Discussion

Juvenile Tillaux fractures are uncommon and most reports consist of small series or case reports with the largest series in the literature representing 10 patients [26,27] Here we report the operative experience at our institution over an extended period of time with this uncommon fracture. Our routine during this time has been to perform antero-posterior, lateral, and mortise radiographs as the initial radiographic evaluation. Fractures that were displaced were splinted and operative treatment recommended. Fractures that were not clearly displaced were placed into long leg casts with the knee bent 45–90°. After cast placement, computed tomography with coronal and sagittal reconstruction was performed to evaluate the joint surface [19, 28–33]. Displacement with fracture gap or joint step-off of more than 1mm was considered to be significant and operative treatment recommended. Operative treatment in each instance involved open reduction with internal fixation using 4.0mm cannulated screws. Closed reduction of these fractures, if attempted was performed prior to definitive imaging and in our experience rarely achieved the anatomic reduction of the joint surface that we believe is essential to good long-term results.

The advantage of direct fixation is that it is technically slightly easier, not requiring joint space visualization and image intensification needed for indirect fixation. In addition, direct fixation does not require additional incisions to be made in the area of the medial malleolus. Crossing the physis typically involves little risk of late growth problems because these fractures typically occur after closure of the posterior and medial aspects of the distal tibial physis2, 7. Indirect fixation has the advantage of requiring a slightly smaller anterior incision because drilling and screw placement is not performed through this incision. Indirect fixation also has the advantage of simplified screw removal in the event of painful hardware. Hardware removal was more frequently requested in the patients who had been stabilized using indirect fixation, possibly due to prominence of the screws at the medial malleolus causing problems with shoe wear. Either technique seems to be effective in maintaining an anatomic reduction that has been achieved by open reduction.

In conclusion, both direct and indirect fixation of juvenile Tillaux fractures are effective in maintaining an anatomic reduction of the fracture when the limb is immobilized in a short leg, below knee cast or orthotic walker boot when the patient is kept non-weight bearing.

Acknowledgement

Study conducted at Washington University School of Medicine, St. Louis Shriners Hospital for Children, and St. Louis Children’s Hospital, St. Louis, Missouri, USA.

References

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  2. Kleiger B, Mankin HJ (1964) Fracture of the lateral portion of the distal tibial epiphysis. J Bone Joint Surg [Am] 46: 25–32.
  3. Protas JM, Kornblatt BA (1981) Fractures of the lateral margin of the distal tibia. The Tillaux fracture. Radiology 138: 55–7.
  4. Letts RM (1982) The hidden adolescent ankle fracture. J Pediatr Orthop 2: 161–4.
  5. Love SM, Ganey T, Ogden JA (1990) Postnatal epiphyseal development: the distal tibia and fibula. J Pediatr Orthop. 10: 298–305.
  6. Ogden JA, McCarthy SM (1983) Radiology of postnatal skeletal development. VIII. Distal tibia and fibula. Skeletal Radiol 10: 209–20.
  7. Spinella AJ, Turco VJ (1988) Avulsion fracture of the distal tibial epiphysis in skeletally immature athletes (juvenile Tillaux fracture). Orthop Rev 17: 1245–9.
  8. Kleiger B (1956) The mechanism of ankle injuries. J Bone Joint Surg [Am] 38: 59–70.
  9. Spiegel PG, Cooperman DR, Laros GS (1978) Epiphyseal fractures of the distal ends of the tibia and fibula. J Bone Joint Surg [Am] 60: 1046–50.
  10. Ertl JP, Barrack RL, Alexander AH, VanBuecken K (1988) Triplane fracture of the distal tibial epiphysis. J Bone Joint Surg [Am] 70: 967–76.
  11. Schlesinger I, Wedge JH (1993) Percutaneous reduction and fixation of displaced juvenile Tillaux fractures: a new surgical technique. J Pediatr Orthop 13: 389–91.
  12. Leetun DT, Ireland ML (2002) Arthroscopically assisted reduction and fixation of a juvenile Tillaux fracture. Arthroscopy 18: 427–9.
  13. Ogawa T, Shimizu S (2017) Arthroscopically assisted surgical fixation of a juvenile Tillaux fracture and implant removal: A case report. J Clin Orthop Trauma 8: 32–7.
  14. Dailiana ZH, Malizos KN, Zacharis K, Mavrodontidis AN, Shiamishis GA, et al (1999) Distal tibial epiphyseal fractures in adolescents. Am J Orthop 28: 309–12.
  15. de Sanctis N, Della Corte S, Pempinello C (2000) Distal tibial and fibular epiphyseal fractures in children: prognostic criteria and long-term results in 158 patients. J Pediatr Orthop B 9: 40–4.
  16. Koury SI, Stone CK, Harrell G, La Charite DD (1999) Recognition and management of Tillaux fractures in adolescents. Pediatr Emerg Care 15: 37–9.
  17. Lintecum N, Blasier RD (1996) Direct reduction with indirect fixation of distal tibial physeal fractures: a report of a technique. J Pediatr Orthop 16: 107–112.
  18. Kling TF Jr (1990) Operative treatment of ankle fractures in children. Orthop Clin North Am. 21: 381–92.
  19. von Laer L (1985) Classification, diagnosis, and treatment of transitional fractures of the distal part of the tibia. J Bone Joint Surg [Am]. 67: 687–98.
  20. Kling TF, Jr., Bright RW, Hensinger RN (1984) Distal tibial physeal fractures in children that may require open reduction. J Bone Joint Surg [Am] 66: 647–57.
  21. Dias LS, Giegerich CR (1983) Fractures of the distal tibial epiphysis in adolescence. J Bone Joint Surg [Am] 65: 438–444.
  22. Britton PD (1988) Adolescent-type Tillaux fracture of the ankle: two case reports. Arch Emerg Med 5: 180–3.
  23. Dingeman RD, Shaver GB (1978) Operative treatment of displaced Salter-Harris III distal tibial fractures. Clin Orthop 135: 101–103.
  24. Salter RB (1974) Injuries of the ankle in children. Orthop Clin North Am 1974;5: 147–152.
  25. Dias LS, Tachdjian MO (1978) Physeal injuries of the ankle in children. Clin Orthop 136: 230–3.
  26. Tiefenboeck TM, Binder H, Joestl J, et al. (2017) Displaced juvenile Tillaux fractures : Surgical treatment and outcome. Wien Klin Wochenschr 129: 169–75.
  27. Kaya A, Altay T, Ozturk H, Karapinar L (2007) Open reduction and internal fixation in displaced juvenile Tillaux fractures. Injury 38: 201–5.
  28. Yao J, Huurman WW (1986) Tomography in a juvenile Tillaux fracture. J Pediatr Orthop 6: 349–51.
  29. Felman AH (1989) Tillaux fractures of the tibia (in adolescents). Pediatr Radiol 20: 87–9.
  30. Horn BD, Crisci K, Krug M, Pizzutillo PD, MacEwen GD (2001) Radiologic evaluation of juvenile Tillaux fractures of the distal tibia. J Pediatr Orthop 21: 162–4.
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  33. Karrholm J (1997) The triplane fracture: four years of follow-up of 21 cases and review of the literature. J Pediatr Orthop B 6: 91–102.

Extraction of Remaining Teeth and Same Day Loading of Neoss Proactive Dental Implants with a Full-arch Fixed Provisional Bridge. A Survival Analysis

DOI: 10.31038/JDMR.2019224

Abstract

Removal of remaining teeth and same day loading of an implant-supported full-arch bridge may be a sensible treatment modality for many patients presenting with a severely diseased partial dentition. The aim of the present study was to retrospectively analyse 30 consecutive patients (21 female/ 9 male, mean age 61.9 + 11.1 years) subjected to removal of all remaining teeth, placement of four to six implants and loading of a full-arch provisional bridge the same day.  A total of 156 dental implants (Proactive Straight, Neoss Ltd, Harrogate, UK) 3.5 to 5 mm in diameter and 9 to 13 mm in lengths were placed in 21 maxillae and 14 mandibles. Provisional acrylic bridges were fabricated in the in-house dental laboratory and fitted after a few hours from the surgical procedures using screw retention. The fabrication of the definitive prostheses was initiated between three to six months from the implant placement. A total of four implants failed in three patients during the initial healing period with provisional bridges in place, giving a cumulative survival rate of 97.3 % during a mean follow-up period of 3.5 + 1.0 years (range 2–5 years). Two failures occurred in the maxilla as a result of fracture of the provisional bridge and two in the mandible due to infection. These three patients had new implants placed and could maintain the repaired or a new provisional bridge during the additional healing period. A total of seven provisional acrylic bridges fractured. No implant failures were observed after placement of the permanent fixed bridges. Few minor other complications occurred during the follow-up. It is concluded that the evaluated treatment concept resulted in a high implant survival rate and few complications after a follow-up of 2 to 5 years.  Although not quantified, the positive effects on self-esteem and psychosocial wellbeing was obvious.

Keyword

Dental Implants, Full-Arch Bridge, Follow-Up Study, Extraction Sockets, Immediate Loading, Screw-Retained Prosthesis

Introduction

Today, most patients can be offered replacement of lost teeth with fixed implant-supported prostheses using swift and safe procedures irrespective of the conditions of the edentulous areas 1]. This is thanks to developments of the original strict osseointegration protocol [2], which was thoroughly evaluated in clinical studies and proven to be highly successful, initially in totally edentulous jaws [3] and later in partially dentate patients [4, 5] Long healing periods were originally advocated after tooth extraction as well as after implant placement in order to assure osseointegration of the implants prior to loading [6]. Further development and evaluation of improved implant surfaces, regenerative techniques and treatment protocols have resulted in the possibility to dramatically reduce treatment times without jeopardizing the outcomes [1]. For instance, implants can be placed immediately in extraction sockets [7, 8] and loaded the same day or a few days after installation [9, 10]. However, although immediate/early loading of dental implants has evident benefits for the patient, it is a resource demanding procedure, as it requires a well-planned collaboration between the clinical team and the dental technician. In fact, it is a logistic challenge to offer immediate/early loading to all implant patients in a busy dental practice. Since the majority of implant patients are missing one or a few teeth [11–13], fixed or removable provisional prostheses can be made and used during the implant healing period.

The present authors have identified one group of patients in whom immediate loading is justified and highly effective. These patients typically presents with a severely diseased partial dentition in one or both jaws. Apart from the functional aspects with impaired chewing comfort, the aesthetic appearance may have led to low self-esteem, depression and a decline in psychosocial wellbeing [14].  Moreover, the patients may not have seen a dentist for a long time due to severe dental fear.  It is our experience that these patients can be motivated to go through one surgical procedure including removal of remaining teeth and placement of implants followed by the manufacturing and loading of a provisional bridge the same day as reported by other authors [15–17]. Systematic reviews have concluded that immediate/early loading is a straightforward approach in the mandible [18], while treatment of the maxilla is less well documented [19–21], particularly when implants are placed in extraction sockets [21]. However, numerous studies have reported survival rates from 98% to 99% when placing implants in extraction and healed sites for immediate loading of maxillary full-arch constructions [22–25], while other studies have shown less good outcomes with increased failure rates in the maxilla [26, 27] and for implants in extraction sockets [28].

The aim of the present study was to retrospectively analyse implant survival and technical complications in 30 consecutive patients treated with same day loading of full-arch implant-supported temporary bridges in conjunction with tooth extractions.

Materials & Methods

Patients and data collection

This retrospective study includes consecutive patients treated with an immediately loaded fixed full-arch bridge on Neoss implants (Proactive Straight, Neoss Ltd, Harrogate, UK) in conjunction with extraction of remaining teeth in the maxilla and/or mandible at the Edinburgh Dental Specialist referral clinic, Edinburgh, Scotland and with at least two years of follow-up.

Patient data were collected from the charts and entered into spreadsheets.  Gender, age, diagnosis of the failing dentition, surgical date, number of teeth extracted, implant location, insertion torque, implant dimensions, abutment type and angulation, implant and restorative complications or failures were recorded. The study was made in accordance with the World Medical Association Declaration of Helsinki.

At the initial consultation, the patients signed a general consent form for data collection. A comprehensive medical history assessment was made. The clinical examination included an oral cancer screen, intraoral radiographs, comprehensive dental and periodontal examinations. Photographs were taken as well as impressions for diagnostic models (Figure 1). An initial treatment plan was outlined by the prosthodontist (PC) and presented and discussed with the patient. The presurgical patient evaluation with the implant surgeon (LS) consisted of a comprehensive oral examination and the use of orthopantomographic and/or cone beam computed tomographic (CBCT) scans. The only exclusion criteria applied was the insufficient bone availability for implant placement as evaluated initially on orthopantomographic assessment and confirmed by CBCT imaging.

JDMR-19-120- Lars Sennerby_-Sweden_F1

Figure 1. 48 year old female patient at initial consultation for treatment of both jaws. a. Orthopanthomogram, b. Extraoral appearance. c. Intraoral view. d. Left and e. right side. f. Occlusal view of upper and g. lower jaw.

Clinical procedures

The treatment consisted in the extraction of the remaining dentition in the dental arch and the immediate placement of four to six dental implants in the maxilla and four to five in the mandible (Figure 2). (Neoss Proactive Straight, Neoss Ltd, Harrogate, UK). The final number of implants to be placed in the particular case was decided by the surgeon during the surgical procedures, depending on the bone quantity and quality, on the implant distribution in the dental arch and on the initial implant stability. The implants were placed both in healed and extracted sites in order to achieve a good distribution of the implants within the jaw. The implants were typically placed between the maxillary sinuses and the mental foramina.

JDMR-19-120- Lars Sennerby_-Sweden_F2

Figure 2. Intraoral view after extractions of remaining teeth (see Figure 1a) and implant surgery, which was made at two different occasions with 6 weeks in between. a. Upper jaw with six implants and prosthetic abutments. b. Lower jaw with five implants and abutments.

Screw-retained transmucosal abutments (Access, Neoss Ltd, Harrogate, UK or Multi Unit Abutments, Nobel Biocare UK Ltd, Uxbridge, UK) were placed on the implants. Most of the abutments were straight, whereas angulated abutments were used to compensate for the intentionally tilted posterior implants (to avoid maxillary sinuses or mandibular nerve infringements) or to correct the angulation of forward positioned anterior implants. Resorbable sutures were used for soft tissue closure.

Directly after the placement of the transmucosal abutments, working impressions of the implant positions were taken with Impregum (3M Ltd, London, UK). The occlusal vertical dimension was registered in different ways. By using one remaining tooth to be extracted (or refitting the extracted tooth in the extraction socket) in case the original vertical dimension was acceptable. When there was the need of an increase in the vertical dimension, temporary cylinders sectioned at the wished length and fitted onto the transmucosal abutments were used to provide a stable bite registration. The provisional acrylic bridges were fabricated in the in-house dental laboratory and fitted after a few hours from the surgical procedures using screw retention (Figure 3). The distal extension of the temporary bridges was limited to the most distal implant position to prevent acrylic fractures and maintain the occlusal load to the minimum. The fit and occlusion were checked and adjusted as needed. Provisional fillings were placed in the access holes and the patient was discharged with instructions to follow a soft food diet for the time the temporary bridge was in use.

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Figure 3. a. Provisional acrylic bridge for the upper and b. lower jaw. c. Occlusal views of upper and d. lower bridge. e. Extraoral  and f. intraoral appearance with both provisional bridges fitted on the implants.

Post-operative protocol

Post-surgical prescriptions consisted of analgetic drugs in case of pain (brufen 400mg x4 or paracetamol 1gr x4) and a five-day course of antibiotics (amoxicillin 750 mg x2 or clindamycin 150 mg x2). Patients were seen 1–2 weeks following surgery to assess the healing process and the functionality of the temporary bridge (aesthetics, occlusion, vertical dimension) as well as to address any potential concerns regarding swelling and bruising. Patients were encouraged to contact the clinic in case any mobility of the bridge or portions of the bridge were experienced. In such a case, the bridge was carefully removed and the implant conditions assessed. In case of bridge fractures, the bridge was repaired in the dental laboratory and refitted after a few hours. In case of implant mobility, the implant was removed and later replaced with a new one.

Final bridges

The fabrication of the definitive prostheses was initiated between three to six months from the implant placement, depending on the amount of soft and hard tissue recession expected after surgery, on the jaw (maxilla or mandible), on the time availability from the patient’s and the prosthodontist’s sides.

At the removal of the temporary bridge, the stability of the implant/transmucosal abutment complex was verified and the conditions of the peri-implant soft tissues assessed. In the absence of mobility, pain, suppuration at palpation/pressure, the implants were considered ready to support a definitive restoration, which was fabricated during three to four appointments. This would include (i) final impressions, (ii) articulation of the working models in the laboratory using the provisional prostheses as guidance and (iii) insertion of the definitive bridge or (i) final impressions, (ii) bite registration, (iii) wax trial and (4) insertion of the definitive bridge. At the time of the final impressions, the proper fit of the impression copings onto the transmucosal abutments or onto the implants as well as the peri-implant bone level were checked with intraoral radiographs.

Three different types of definitive bridges could be provided:

  1. A titanium framework and acrylic resin denture base material with denture teeth around it,
  2. A monolithic zirconia framework with porcelain bonded on it
  3. A chrome-cobalt framework with porcelain bonded on it.

The bridges were screw-retained onto the transmucosal abutments or directly onto the implants after the removal of the transmucosal abutments (Figure 4, 5), depending on the amount of soft tissue recession that had occurred during healing and on the aesthetic demands. The fit of the bridge to the transmucosal abutments/implants was verified with intraoral radiographs that would also provide for baseline peri-implant bone levels.

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Figure 4. a. Soft tissue situation at the time of fitting the final bridges in the upper  and b. lower jaw.

JDMR-19-120- Lars Sennerby_-Sweden_F5

Figure 5. a-d. Showing the final bridge in the upper  and e-f. the lower jaw.

JDMR-19-120- Lars Sennerby_-Sweden_F6

Figure 6. a. Extraoral view with final bridges fitted. b Intraoral frontal view, c. Right and d. left side. e. Occlusal view of the upper and f. lower bridges. g. Oblique extraoral view of final bridges.

Follow-ups

A follow-up appointment was carried out after 3–4 weeks from the provision of the definitive bridge for a control tightening of the screws and the provision of permanent fillings onto the access holes. Patients were thereafter scheduled for recalls once a year the first two years, thereafter at the fifth, seventh, 10th anniversary and every 2–3 years thereafter. At these appointments, assessments of the integrity of the prostheses and of the soft and hard peri-implant tissues conditions by clinical and radiographic examinations were carried out.

Results

A total of 30 patients (21 female/ 9 male, mean age 61.9 + 11.1 years) were included in the study. Five patients had been treated in both jaws at two different occasions. On average, seven teeth (7.7 + 2.8) were extracted in each jaw and treated with 156 implants (Neoss Ltd, Harrogate, UK), where 93 had been placed in the maxilla (21 jaws) and 63 in the mandible (14 jaws) (Table 1). In five cases, previously placed implants were included in the bridge.

Table 1. Number and type of implants placed. Failed implants within brackets.

 Diameter

Length

3.5 mm

4.0 mm

4.5 mm

5.0 mm

Sa

9 mm

2

1

1

4

11 mm

3

14

1

18

13 mm

10

116 (4)

8

134

Sa

13

132

10

1

156

A total of four implants failed in three patients during the follow-up period giving a cumulative survival rate of 97.4% after a mean follow-up of 3.5 + 1.0 years (range 2–5 years) (Table 2). All implant failures occurred during the initial healing period with temporary bridges in place. Two failures occurred in the maxilla (2.2 %) in two patients as a result of fracture of the temporary bridge and two in the mandible (3.2 %) in one patient due to infection. These three patients had new implants placed and could maintain the repaired bridge (n=2) or got a newly made temporary bridge including the newly placed implants (n=1) during the additional healing period. No implant failures were observed after placement of the permanent fixed bridges.

Table 2. Implant survival. Life table analysis.

Interval

Implants

Failed

Not yet due

CSR

Insertion to final bridge

156

4

0

97.4 %

Final bridge to 1 year

152

0

0

97.4 %

1 to 2 years

152

0

31

97.4 %

2 to 3 years

121

0

31

97.4 %

3 to 4 years

90

0

68

97.4 %

4 to 5 years

22

Although not quantified in the present study, the peri-implant marginal bone levels were maintained throughout the observation period with the exception of one anterior mandibular fixture showing a bone loss of 2mm mesially and distally at the 1-y recall compared to the bone levels observed at the time of the fit of the permanent bridge. The fixture did not show any further bone loss at the subsequent recall appointments. From a prosthetic point of view, in seven patients the provisional acrylic prostheses fractured during the healing time. Two of these patients experienced two fractures and one patient three fractures of the same prosthesis. In two cases the fractures of the provisional restorations corresponded to the osseointegration failure of the implant supporting the fractured portion.

The lower jaws were all but one restored with titanium/acrylic prostheses. Fifteen upper jaws were restored with titanium/acrylic prostheses, five with metal/ceramic prostheses and one with a zirconia restoration.

During the follow-up period, four patients experienced the fracture of an acrylic tooth from the permanent restoration (one patient had three fractures of one acrylic tooth). In all cases, the prostheses were repaired in the laboratory within few hours and refitted the same day.

Discussion

In the present retrospective study, 30 patients received a total of 35 immediately loaded fixed implant-supported provisional bridges in conjunction with extraction of remaining teeth and were evaluated after 2 to 5 years. All provisional bridges could be maintained as planned during the initial period of 3 to 6 months in spite of four implant osseointegration failures, although the involved bridges had to be repaired and adjusted. No additional failures occurred after connection of the final bridges, giving an implant survival rate of 97.4 % with small differences between the maxilla and mandible after a mean follow-up of 3.5 years. The four failures in the present study were due to fracture of the provisional bridge and subsequent overload in two maxillary cases and infection in one mandible.

The same treatment modality has been evaluated by other authors in previous publications, which have shown varying clinical results and especially in the maxilla [23–28]. The reasons for the different outcomes may be attributed to differences in patient selection, inclusion criteria and the type/number of implants that were used. For instance, Balshi et al [23] placed a mean of 10 implants per patient and reported a survival rate of 99%, while studies with lower survival rates in general used fewer implants [29]. It is also known that implant surface topography has an impact on implant healing [30–31] and clinical outcome [32], which may explain differences between studies. For instance, Andersson et al [33] used a similar concept as in the present study in 55 patients but where the Neoss implants were loaded 1–3 days after extractions and implant placement. They reported a survival rate of 93.7 % after a mean follow-up of 2.9 years, which is lower than in the present study. Although utilising the same implant design as in our study, they used two different surfaces (Bimodal vs Proactive) and observed better results with the Proactive surface, 96.4 % vs 89.7 % for the Bimodal surface. They speculated that this could be explained by differences in surface topography as well as chemical properties of the two surfaces, as the Proactive surface is rougher and hydrophilic compared to the smoother and hydrophobic Bimodal surface. Experimental and clinical studies have shown a stronger bone tissue response to the Proactive surface, which showed more bone contacts and higher stability as measured with removal torque tests and resonance frequency analysis (RFA) measurements [34, 35]. In addition, clinical studies have also demonstrated higher stability [36] and better clinical outcomes [37] with Neoss Proactive than with Bimodal implants.  However, like in our study, all patients received and maintained a fixed bridge in spite of the implant failures in the Andersson et al study.

From a prosthetic point of view, the maintenance of the implant-retained prosthesis can be viewed as the primary objective of the treatment. In such a case, the survival rate of the restorations described in this study was 100%, with very few minor prosthetic complications that could be amended within few hours. These data are very similar to the data presented by Tealdo and co-workers who reported of a 100% fixed prostheses survival and minor fractures, easily adjusted, in a 6-year prospective study on immediate or delayed implant load on maxillary edentulous patients [38].

The immediate effect of the provision of an immediate fixed restoration on the patient’s life quality should not be underestimated. It is well documented that insertion of an implant-supported bridge in the edentulous patient results in marked psychological and social improvement when using the original and lengthy protocol [39]. Many of the patients in this investigation had a history of poor functioning removable prostheses, constant discomfort and often pain due to failing dentition, low self-esteem and limited social life. The one-day treatment approach had a dramatic effect as it clearly improved the subject life quality and self-esteem almost immediately.

It is concluded that extraction of remaining teeth and same day loading of a provisional full-arch bridge resulted in a high implant survival rate and few complications in both the mandible and maxilla after a follow-up of 2 to 5 years.  Although not quantified, the positive effects on self-esteem and psychosocial wellbeing was obvious.

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  12. Mack F, Samietz SA, Mundt T, Proff P, Gedrange T, et al. (2006) Prevalence of single-tooth gaps in a population-based study and the potential for dental implants–data from the Study of Health in Pomerania (SHIP-0). J Craniomaxillofac Surg 34 Suppl 2: 82–85. [crossref]
  13. O¨sterberg T, Carlsson GE (2007) Dental state, prosthodontic treatment and chewing ability – a study of five cohorts of 70-year-old subjects. J Oral Rehabil 34: 553–559.
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  17. Olsson M, Urde G, Andersen JB, Sennerby L (2003) Early loading of maxillary fixed cross-arch dental prostheses supported by six or eight oxidized titanium implants: results after 1 year of loading, case series. Clin Implant Dent Relat Res 5 Suppl 1: 81–87
  18. Papaspyridakos P, Mokti M, Chen CJ, Benic GI, Gallucci GO, et al. (2014) Implant and prosthodontic survival rates with implant fixed complete dental prostheses in the edentulous mandible after at least 5 years: a systematic review. Clin Implant Dent Relat Res 16: 705–717. [crossref]
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  33. Andersson P, Degasperi W, Verrocchi D, Sennerby L (2015) A Retrospective Study on Immediate Placement of Neoss Implants with Early Loading of Full-Arch Bridges. Clin Implant Dent Relat Res 17: 646–657. [crossref]
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Asymmetrical Naproxen-Conjugated Dendrimer for Targeted- Drug Delivery to Human Prostatic Adenocarcinoma Cancer Cells

DOI: 10.31038/JPPR.2019235

Abstract

Naproxen was directly conjugated to NH2-terminated dendrimers by an amide bond and OH-terminated dendrimers by an ester bond. The drug-conjugated polyamidoamine dendrimers showed better cellular uptake than free naproxen. Free naproxen and conjugates in vitro cytotoxicity studies were performed in U251, PC3, K-562, HCT-15, MCF-7 and SKLU-1 cancer cells using different cytotoxicity assays. Naproxen-conjugates of first and second generation showed significant cytotoxic effects in human prostatic adenocarcinoma PC-3 and human mammary adenocarcinoma MCF-7. Moreover, the naproxen-conjugates improved cytotoxicity compared to free naproxen. The increased therapeutic efficacy was observed in specific naproxen conjugates of first generation using low doses, demonstrating that the conjugate was as potent as the antiproliferative agent cisplatin.

Keywords

Polyamidoamine-dendrimers, Naproxen-conjugates, Anti-cancer activity.

Introduction

Dendrimers are homogeneous structures from their nucleus to their terminal group, and also in their internal branching moieties. Dendrimers have unique properties, such as monomolecular weight and good biocompatibility. Dendrimers are spherical three-dimensional structures with exchanged surface functionalities [1–3]. Dendrimers have a great potential for applications in many fields, including drug/gene delivery, as catalysts, and in bioimaging. Among these, applications have been a key focus of research in nanotechnology and nanobiology [4,5]. Bioactive compounds could be joined with the dendrimers and can act as efficient nanocarriers of the bioactive compounds [6]. Naproxen (Nap, see Scheme 2) is a member of the class of Non-steroidal Anti-Inflammatory Drugs (NSAIDs). As one of the most commonly-used cyclooxygenase (COX) inhibitors, it has been used for the treatment of many inflammation-associated conditions, e.g. arthritis, gout, tendinitis, and bursitis [7,8]. Although some COX-2 inhibitors were demonstrated to be related to increases in the risk of cardiovascular events and gastrointestinal adverse effects [9–11], an emerging body of data suggests that Nap rarely increases the risk of adverse cardiovascular events compared to other NSAIDs. In the literature, the synthesis of dendrimers with naproxen as conjugates or complexes has been reported, improving the solubility and the permeability of the drug. It was also was found that the conjugates of naproxen showed anticancer activity [7–13]. Recently, we designed and synthesized several types of NSAIDs-modified dendrimers with good drug-delivery properties [12,13]. Herein we have further designed and developed naproxen and poly-amidoamine-modified dendrimers as possible targeted drug carriers towards human prostatic adenocarcinoma and human mammary adenocarcinoma cancer cells.

Materials and Methods

1H and 13C NMR spectra were recorded on a Varian Unity-300 MHz with Tetramethylsilane (TMS) as an internal reference.  Infrared (IR) spectra were measured on a Nicolet FT-SSX spectrophotometer. Elemental analysis was determined by Galbraith Laboratories, INC Knoxville. FAB+ mass spectra were taken on a JEOL JMS AX505 HA instrument. Electrospray mass spectra were taken on a Bruker Daltonic, Esquire 6000. MALDI-TOF mass spectra were taken on a Bruker Omni FLEX using 9-nitroanthracene (9NA) as a matrix. The UV-vis absorption spectra were obtained at room temperature with a Shimadzu 2401 PC spectrophotometer.

Characterization of the Conjugates

1H and 13C NMR spectra were recorded on a Varian Unity-300 MHz with tetramethylsilane (TMS) as an internal reference.  Infrared (IR) spectra were measured on a Nicolet FT-SSX spectrophotometer. Elemental analysis was determined by Galbraith Laboratories, INC Knoxville. FAB+ mass spectra were taken on a JEOL JMS AX505 HA instrument. Electrospray mass spectra were taken on a Bruker Daltonic, Esquire 6000.  MALDI-TOF mass spectra were taken on a Bruker Omni FLEX using 9-nitroanthracene (9NA) as a matrix. The UV-vis absorption spectra were obtained at room temperature with a Shimadzu 2401 PC spectrophotometer.

Anticancer Screening

U-251 (human glioblastoma), PC-3 (human prostatic adenocarcinoma), K-562 (human chronic myelogenous leukemia cells), HCT-15 (human colorectal adenocarcinoma), MCF-7 (human mammary adenocarcinoma), SKLU-1 (human lung adenocarcinoma) cell lines were supplied by the National Cancer Institute (USA). COS 7 Monkey African green kidney, SV40 transformed cells were supplied by National Cancer Institute (USA). Cytotoxicity assays were determined using the protein-binding dye sulforhodamine B (SRB) in microculture to measure cell growth, as described [12,13]. Conjugates of naproxen and polyamidoamine dendrimers were prepared in 2 % DMSO and added into the culture medium immediately before use. Control cells were treated with 2 % DMSO. For the assay with COS 7 Monkey African green kidney, SV40 transformed, the tested compounds were dissolved in fresh culture medium with 2% DMSO to afford different concentrations (1, 10, 50, 100 μmol/L).

Results and Discussion

Synthesis of Ethanolamine Polyaminoamide Dendritic Arms Dendrimers

The PAMAM dendrimers were synthesized by a divergent approach using ethanolamine as the core. This methodology involves typical stepwise and iterative two-step reaction sequences, consisting of the Michael addition of primary amines with methyl acrylate and the amidation of methyl ester groups with ethylendiamine to produce amine terminations (Scheme 1).

JPPR 19 - 119 - Martínez-García M_F1

Scheme 1. Synthesis of the ethanolamine PAMAM-dendrimers

JPPR 19 - 119 - Martínez-García M_F2

Scheme 2. Synthesis of the naproxen chloride 13.

The dendrons of first and second generation were characterized by 1H, 13C NMR, FTIR, UV-Vis spectroscopy and mass spectrometry.

Synthesis of Naproxen Chloride

After that, from the naproxen acid, the naproxen chloride with thionyl chloride in CH2Cl2 at reflux for 3h was obtained (Scheme 2) and characterized by 1H, 13C NMR and mass spectrometry.

Synthesis of Naproxen Dendrimers

The naproxen chloride was coupled to the dendrons with ethanolamine and amine terminal groups (Chart 1). For the NMR spectra of compounds 7 and 8, methanol deuterated was used as solvent. Their peaks were similar to those of compounds 2 and 4. The high-resolution mass spectra results of compounds 7 and 8 were 926.4 and 1806.8 m/z, respectively.

JPPR 19 - 119 - Martínez-García M_F3

Chart 1. Naproxen derivatives of first 7 and second 8 generation.

In the 1H NMR spectra, the following signals were observed: at δH 8.26 one broad signal due to the NH groups, three broad signals at δH 7.73–7.12 assigned to the Ar protons from naproxen, one singlet at δH 3.83 for the OCH3 groups, one broad signal at δH 3.75 for the CH protons due from the naproxen moiety, three broad signals at δH 3.38–2.24 due to the dendritic branches and finally at δH 1.39, one broad signal for the CH3 from the naproxen moiety.

Cytotoxicity of Naproxen conjugates

The cytotoxic activity of the synthesized PAMAM-ethanol derivatives 3, 4 and the conjugate compounds of naproxen 7 and 8 were chosen for evaluation of their biological activity against cancer cell lines. We screened in vitro against seven human cancer cell lines: U251 (human glioblastoma), PC-3 (human prostatic adenocarcinoma), K-562 (human chronic myelogenous leukemia cells), HCT-15 (human colorectal adenocarcinoma), MCF-7 (human mammary adenocarcinoma), SKLU-1 (human lung adenocarcinoma). As a control, we also tested against the COS-7 African green monkey kidney cell line. The free naproxen and cisplatin were used to compare the antiproliferative activity of the dendrimers 3, 4 and 7, 8. The dendrimers 3 and 4 with two and four NH2 terminal groups at 10 µM showed low anticancer activity against all the cells used. In the case of the conjugates 7 and 8, the concentration of the conjugate was diluted in 3 and 5 times to have the anticancer activity for one molecule of naproxen and compare it to the free naproxen. Table 1 shows the normalized percentage of inhibition of the growth that allows comparing the activity of the same amount of naproxen in its free state and when it is contained in the conjugates of compounds 7 and 8.

Table 1. Cytotoxic activity of the compounds 3, 4, 7 and 8 at 10 mM.

% of  inhibitión

Sample

U251

PC-3

K562

HCT-15

MCF-7

SKLU-1

COS7

3

NC

1.8±2.2

1.6±1.1

NC

1.8±1.2

NC

NC

4

NC

1.2±1.7

1.9±1.2

0.6±0.6

1.1±1.3

NC

NC

7

4.5±1.4

53.0±2.2

6±1.5

7.5±0.8

33.0±1.0

11.1±1.3

NC

8

5.1±1.1

59.4±1.1

7.1±1.4

8.1±1.3

38.5±1.9

15.3±0.8

NC

Naproxen

NC

NC

1.76

2.23

6.43

NC

NC

Cisplatin

87.49

42.65

79.15

32.42

32.42

81.35

42.39

NC = non cytotoxic.

Cisplatin was tested at the same concentration of 10 µM. The initially obtained cytotoxic screening data (Table 1) showed that at 10 µM, the conjugate 7 showed good inhibition activity 53.0±2.2 (%) against the human prostatic adenocarcinoma PC-3 cell line and 33.0±1.0 % against human mammary adenocarcinoma MCF-7 cell line, this activity was higher than the free naproxen. The conjugate 8 showed better activity from 15.3±0.8 to 39.4±1.1 against PC-3, MCF-7 SKLU-1 in comparison with the naproxen alone. For the dendrimer conjugate naproxen 7 the activity against PC-3 and MCF-7 was very close to that of cisplatin. The antiproliferative results obtained with the conjugates of naproxen 7 and 8 were compared to cisplatin, as a reference anticancer drug. The compounds 3, 4 and the conjugates 7 and 8 did not show any activity against the COS-7 African green monkey kidney cell line.

Conclusion

Naproxen was directly conjugated to NH2-terminated dendrimers by an amide bond and OH-terminated dendrimers by an ester bond. The drug-conjugated polyamidoamine dendrimers showed better cellular uptake than free naproxen. Free naproxen and conjugates’ in vitro cytotoxicity studies were performed in U251, PC3, K-562, HCT-15, MCF-7 and SKLU-1 cancer cells using different cytotoxicity assays. Naproxen-conjugates of first and second generation showed significant cytotoxic effects in human prostatic adenocarcinoma PC-3 and human mammary adenocarcinoma MCF-7. Moreover, the naproxen-conjugates improved cytotoxicity compared to the free naproxen. The increased therapeutic efficacy was observed in specific naproxen conjugates of first generation using low doses demonstrating that the conjugate was equally potent as the antiproliferative agent cisplatin.

Supplementary Material

Supplementary material is associated with this manuscript. It contains general experimental procedures, compound characterization data, and copies of 1H and 13C NMR spectra of representative compounds.

Acknowledgment

This work was supported by DGAPA IN101117 grants. EMK was supported by a postdoctoral fellowship from CONACyT-México. We would also like to thank Rios O.H., Velasco L., Huerta S.E., Patiño M.M.R., Peña Gonzalez M.A., Rios Ruiz L. and Garcia Rios E. for technical assistance.

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Myelinated nerve fiber layer associated with other ocular pathology in a 20-year-old myopic man

DOI: 10.31038/JCRM.2019235

Abstract

Background: Myelinated retinal nerve fibers (MRNFs) are usually unilateral and asymptomatic benign lesions associated with mild hypermetropia, emmetropia, or severe myopia. We describe herein an myopic patient with a syndrome of ipsilateral myelinated retinal nerve fibers associated with other pathological changes: epiretinal membrane with pseudohole, vitreomacular traction syndrome and bilateral lattice degeneration.

Methods: Extended ophthalmoscopy was used to evaluate retinal posterior segment. Infrared reflectance imaging helped in visualizing sub-retinal pathology. Detailed images from within the retina were obtained by using optical coherence tomography.

Results: Ophthalmologic examination revealed ipsilateral small temporal myopic conus with lattice degeneration temporally and inferotemporally. The area of myelinated nerve fiber extended into the pappilomacular bundle, but did not reach the fovea. At the fovea, an epiretinal membrane with clinically visible vitreomacular traction and some retinal elevation was found. In the peripheral fundus areas of lattice degeneration temporally and inferiorly was also noted. The OCT scans of the affected eye showed an incomplete posterior vitreous detachment with traction of a thickened posterior hyaloid base to the fovea. There was distortion of the foveal anatomy with a small amount of subfoveal fluid but a full-thickness macular hole could not be detected. Macular traction detachment of retina and epiretinal membrane with macular hole were treated surgically (S/P Repair Complex RD (25g, 20% SF6, membrane peel with gas endotamponade) and vitreomacular traction was released. Lattice degeneration was treated by laser (S/P Laser).

Conclusions: MRNF lesions were stable and although associated with other ocular pathology progression was not observed during follow-up.

Keywords: Myelinated – Myopia – Lattice degeneration – Vitreomacular traction – Coherence tomography

Introduction

Myelinated retinal nerve fibers (MRNFs) are usually unilateral and asymptomatic benign lesions of the retina around the optic disk [1–2]. but it could also be found in other parts of the retina and in fovea [3]. During embryonic development the retinal nerve fibers may retain the myelin coat resulting in abnormal intraocular myelination of the peripheral nerve anterior to the lamina cribrosa [4]. The MRNF may be inherited but early-age trauma to the eye damaging lamina cribrosa may let oligodendrocytes to pass to the retina causing myelination [5]. MRNF has been associated with mild hypermetropia, emmetropia, or severe myopia. The size and the location of opaque nerve fiber patch determine visual field defects in eyes with MRNF [2], [6]. Studying the correlation between the extend of myelinated nerve fibers and refraction anomalies Schmidt D. at al [7]. concluded that myopia only occurred in eyes with wide-spread myelinated nerve fibers but not in eyes with circumscribed myelinated nerve fibers.

Case report

A 20-year-old man presented with severe left eye (OS) central blurred vision worsening during a period of one year. Reading and watching TV were affected activity. On the right eye (OR) he had gradual onset of blurred vision with mildly affected reading. The patient was noted to have an area of myelinated nerve fiber layer in his left eye a number of years ago, which remained stable over several years of follow-up. More recently change in visual acuity of the left eye was noted. The patient’s past ocular history was also notable for anisometropia, but he did not report a history of amblyopia. On examination visual acuity with correction at distance measured 20/25 OD and 20/80 OS. RO examination also revealed a small temporal myopic conus and lattice degeneration temporally – inferotemporally and a few additional areas inferiorly (Fig.1A). Optical Coherence Tomography (OCT) showed normal thickened retinal nerve fibers with an attached hyaloid (Fig.1B). Left eye fundus examination showed abnormal layer of blood vessels and circumferential areas of lattice degeneration temporally and inferotemporally (Fig.1C). The area of myelinated nerve fiber extended into the papillomacular bundle, but did not reach the fovea. At the fovea, an epiretinal membrane with clinically visible vitreomacular traction and some retinal elevation was noted. The OCT scans of the left eye showed an incomplete posterior vitreous detachment with traction of a thickened posterior hyaloid base to the fovea distorting foveal anatomy with a small amount of subfoveal fluid but a full-thickness macular hole could not be detected (Fig. 1D). Myelinated nerve fiber lesions showed hyperreflectibility (Fig. 2). Autofluorescence imaging revealed a dark area in the region of myelinated RNFL (Fig. 3). Macular traction detachment of retina and epiretinal membrane with macular hole were treated surgically (S/P Repair Complex RD (25g, 20% SF6, membrane peel with gas endotamponade) and vitreomacular traction was released. Lattice degeneration was treated by laser (S/P Laser). Initial ocular post-op medication was: Cyclogyl 2%, Gentacidin 0.3%, and Prednisolone Acetate 1%. Three days after surgery Timol (Maleate) 0.25% was added. Retinal examination found periphery laser scarring and lattice degeneration with atrophic hole with laser (inferotemporal). The patient was regularly followed up in order to monitor progression and one year after surgery no disk edema and pallor, no new holes or tears were found and retinal vessels had normal caliber.

JCRM 2019-113 - Dragan Jovanovic USA_F1

Figure 1. Optic disc imaging findings: A, OD color fundus photograph showing circumferential areas of lattice degeneration emporally – inferotemporally. B, OD OCT showing normal thickened retinal nerve fibers with an attached hyaloid . C, OS color fundus photograph showing a large area of MNFL extended into the papillomacular bundle without reaching the fovea. D, OS OCT showing an incomplete posterior vitreous detachment with traction of a thickened posterior hyaloid base to the fovea. Distorted foveal anatomy with a small amount of subvoveal subretinal fluid.

JCRM 2019-113 - Dragan Jovanovic USA_F2

Figure 2. OCT of the right and of the left eye showed hyperreflectivity of myelinated nerve fiber lesions in the left eye.

JCRM 2019-113 - Dragan Jovanovic USA_F3

Figure 3. Autofluorescence imaging reveals a dark area in the region of the myelinated RNFL in OS.

Discussion

MNFL represent an asymptomatic developmental anomaly in which myelin sheaths extend to retinal nerve fibers along their intraocular portion causing displacement of the axons toward the vitreous body causing decreased vessel density in MRNF areas [8]. In our patient MRNF lesions were stable and although associated with other ocular pathology progression was not observed during follow-up. Cases with regression of MRNF associated with inflammatory diseases and glaucoma were also reported in the literature [9], [10]. Our patients was myopic (OD – 10.25 and OS – 5.50) and ophthalmologic examination revealed a small temporal myopic conus in right eye. High myopia is one of the leading causes of low vision in the world. [11] Genetic and environmental factors play role in its development [12]. Physiological myopia is a common optical aberration [13], but in pathological shortness with irreversible conditions such as retinal detachment, and macular atrophy can lead to blindness. In the myopic eye excessive axial elongation can lead to mechanical stretching and thinning of the choroid and RPE. [14], [15]. Changes in peripheral retina of myopic are predisposing factors for retinal detachment and include lattice degeneration, white-without-pressure, pigmentary degenerations, and retinal tears and holes. Association of extensive myelinated nerve fibers and high degree myopia have been reported [16]. Ellis et al [17] found that 83% of patients with myelinated retinal nerve fibers had myopia greater than 6 diopters. It is not clear whether myelination of retinal nerve fibers is the reason for or the result of myopia. In patient with myelinated fibers retinal images may be blurred causing visual deprivation. This deprivation may contribute to myopia by including an axial enlargement. On the other hand, it is also possible that axial elongation predisposes to retinal nerve fiber myelination. Straatsma et al [18] found that 10% of patients with myelinated nerve fibers have myopia, ampliopia, and strabismus. Our patient had refractive error of -9.0 in OD and -5.5 in OS. In pathologic myopia progressive chorioretinal degeneration is often associated [19]. In our patient’s OS where MRNF lesions were found posterior cortical vitreous partially separated from the retina (epiretinal membrane) and some tractional areas remain adherent to portions of the macula causing Vitreomacular Traction Syndrome (VTS).

Compliance with ethical standards

Conflict of interest: The authors declare that they have no conflict of interest.

Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards

Informed consent: Informed consent was obtained from patient’s parents to publish his photo and all other information

References

  1. Straatsma BR, Foos RY, Heckenlively JR, Taylor GN. (1981) Myelinated retinal nerve fibers. Am J Ophthalmol. 91: 25–38.
  2. Kodama T, Hayasaka S, Setogawa T. (1990) Myelinated retinal nerve fibers: Prevalence, location and effect on visual acuity. Ophthalmologica. 200: 77–83. [Crossref]
  3. Serdar O, Mehmet YT. (2017) Ring-shaped myelinated retinal nerve fibers at fovea. Indian J Ophthalmol. 65(7): 630–632. [Crossref]
  4. Darin RG. (2018) Atlas of Retinal OCT. Optical Coherence Tomography 2018, Elsevier;2018
  5. Prakalapakorn SG, Buckley EG. (2012) Acquired bilateral myelinated retinal nerve fibers after unilateral optic nerve sheath fenestration in a child with idiopathic intracranial hypertension. J Pediatr Ophthalmol Strabismus. 16: 534–8. [Crossref]
  6. Bradley R. Straatsma, John R. Heckenlively, Robert Y. Foos, and John K. (1979) Shahinian, Myelinated retinal nerve fibers with ipsilateral myopia, amblyopia, and strabismus. American Jopurnal of Opthalmology. 88: 506–510. [Crossref]
  7. Smitdt D, Meyer JH, Brandi-Dohrn J. (1996–1997) Wide-spread myelinated nerve fibers of the optic disc: do they influence development of myopia? Int Ophthalmol. 20(5): 263–8. [Crossref]
  8. Hollo G. (2016) Infuence of myelinated retinal nerve fibers on retinal vessels density measurement with AngioVue OCT angiography. Int Ophthalmol. 36(6): 915–919. [Crossref]
  9. Sowkia JW, Nadeau MJ. (2013) Regresion of myelinated nerve fibers in a glaucomatous eye. Optom Vis Sci. 90(7): e2018-e220. [Crossref]
  10. Chavis PS, Tabbara KF. (1998) Demyelinization of retinal myelinated nerve fibers in Behcet’s disease. Doc Opthalmol. 95: 157–64. [Crossref]
  11. Hayashi K, Ohno-Matsui K, Shimada N, Moriyama M,Kojima A, Hayashi W, Yasuzumi K, Nagaoka N, Saka N, Yoshida T, Tokoro T, Mochizuki M. (2010) Long-term pattern of progression of myopic maculopathy: a natural history study. Ophthalmology 117: 1595–611. [Crossref]
  12. Pan CW, Zheng YF, Wrong TY, et al. (2012) Variation in prevalence of myopia between generations of migrant Indians living in Singapore. Am J Ophthalmol 154: 376–81. [Crossref]
  13. Baker BJ, Pruett R. (2004) Degenerative myopia. In: Yanoff M, Duker SJ. Ophthalmology: 2nd ed. Spain : Mosby 934–7.
  14. Grossniklaus HE, Green WR. (1992) Pathologic findings in pathologic myopia: Retina 12(2): 127– 133. [Crossref]
  15. Rabb MF, Garoon I, LaFranco FP. (1981) Myopic macular degeneration. Int Ophthalmol Clin 21(3): 51– 69. [Crossref]
  16. Elvan Yalcın, Ozlem Balcı, and Ziya Akıngol (2013 ) Indian J Ophthalmol. 61(10): 606–607;
  17. Ellis GS Jr, Frey T, Gouterman RZ. (1987) Myelinated nerve fibers, axial myopia, and refractory amblyopia: An organic disease. J Pediatr Ophthalmol Strabismus 24: 111–9. [Crossref]
  18. Straatsma BR, Heckenlively JR, Foos RY, Shahinian JK. (1979) Myelinated retinal nerve fibers associated with ipsilateral myopia, amblyopia, and strabismus. Am J Ophthalmol 88: 506–10). [Crossref]
  19. Soubrane  G, Coscas G.J. (2001) Choroidal neovascularization in degenerative myopia. In: Ryan SJed. Retina. 3rd St Louis, Mo Mosby Inc 1136–1152.

What do we know about Food Cravings and Aversions during Pregnancy?

DOI: 10.31038/IGOJ.2019234

Abstract

During pregnancy, it is very common for women to make changes in the choice of foods they eat and often experience cravings and aversions to certain foods. The purpose of this narrative review is to describe the current state of knowledge about the different hypotheses that try to explain the presence of food cravings and aversions during pregnancy and to know the occurrence of these phenomena in different geographical contexts.

The most studied hypothesis relates to food aversions to maternal-fetal protection mechanisms; others with less sustenance link them as preventive of the metabolic syndrome, as a consequence of shortage of resources or compensatory of placental growth. The hypotheses that explain the appearance of food cravings relate them as a consequence of a search for nutrients or active compounds present in the foods craved for, or as a consequence of the hormonal fluctuations that are special to pregnancy.

The prevalence with which cravings and aversions occur varies from 38 to 79%, being less frequent in European populations and more common in the African continent. In general terms, foods craved by pregnant women in Western cultures are chocolate, fruits and fruit juices, sweet foods and, to a lesser extent, meats and dairy products. In geographical contexts of socio-economic vulnerability, foods of animal origin such as meat, cheese and milk, followed to a lesser extent by vegetables, fruits and grains, emerge as usually cravings.

Protein-rich foods of animal origin are largely rejected by pregnant women in Western countries, while cereals and vegetables are frequently avoided by pregnant women in Africa and Asia.

Keywords

Pregnancy, Cravings, Aversions, Food Choice

Introduction

Pregnancy is a complex and vitally important period and its physiology is of great biological and nutritional importance since the contribution of nutrients must be adequate in quantity, quality and distribution so that both the process of embryogenesis and development of the fetus and health of the mother are adequate [1, 2].

It is common for pregnant women to make changes in the choice of foods they eat, which are the result of a complex set of biological and cultural interactions that have implications for maternal and child health [3–6]. Within these food variations appear phenomena that pregnant women frequently experience: cravings and aversions to certain foods. These phenomena, in which causes and consequences are little known, are usually considered as anecdotal and marginal [7].

Several conceptualizations and definitions have been used in relation to the terms “cravings” [4,6,8–11] and “aversions”[4,6,8,10–12], among them the one used by Weigel, who points out that they are phenomena with the following characteristics: sudden appearance, strong intensity and absence prior to pregnancy [11].

It is important to distinguish food cravings during the pregnancy from pica, a condition characterized by the persistent and compulsive consumption of non-nutritive substances such as earth and clay (geophagia), ice (pagophagia), among others [13, 14]. In the case of aversions, it is necessary to differentiate them from food taboos, in which certain foods are not culturally accepted as suitable for consumption in particular phases of the life cycle, such as pregnancy. Taboos in most cases seem to be meaningless since the characterizations of food vary from one population group to another [15, 16].

The important physiological changes of pregnancy, especially hormonal ones, could in part give an answer to understand the complex plot of possible causes that cause food cravings and aversions in the pregnant woman [17–20]. (Graph 1) outlines the hormonal interactions that could influence on the appearance of food cravings and aversions.

IGOJ 2019-112 - Laura Beatriz López Argentina_F1

Graph 1. Possible hormonal influence on food cravings and aversions.

The rabbi, physician and philosopher Maimonides (1138–1204) was one of the first to take into account changes in maternal physiology to describe food cravings, and proposed the theory that they were the result of an imbalance in body fluids, caused by the accumulation of “bad liquids” in the stomach folds of pregnant women, due to their inability to release menstrual blood during conception. When these liquids penetrated the stomach, a woman craved sour and spicy things until these unpleasant juices were eliminated by the vomit. As the pregnancy progressed and the growing fetus reduced the penetration of these fluids, women would be less susceptible to cravings and nausea [21].

Since then and until now, food cravings and aversions during pregnancy have been the focus of research and debate among anthropologists, nutritionists and public health professionals.

The present work consists of a narrative review that aims at describing the current state of knowledge about the different hypotheses that try to explain the presence of food cravings and aversions during pregnancy and to know the occurrence of these phenomena in different geographical contexts.

Hypothesis about the Presence of Food Aversions

Several hypotheses centered on a biological perspective have been postulated in order to understand why some pregnant women present food aversions; possibly the hypothesis of maternal-fetal protection has been the most studied. Other explanations with less bibliographic support link dietary aversions as preventive of the metabolic syndrome during pregnancy, or related to shortage of resources, or as a compensation mechanism for placental growth.

“Maternal-fetal protection hypothesis”

This theory is based on the fact that food aversions could protect the embryo or fetus against certain toxins at a moment of extreme vulnerability: organogenesis. Of the approximately 280 days that gestation lasts, embryonic tissues are more susceptible to teratogenic damage during certain well-defined critical periods, when cell division and differentiation and the morphogenesis of various systems and organs reach a simultaneous peak, produced between weeks 6 and 18. [10]. If the presence of food aversions occurs mostly during these periods, the pregnant woman could have developed different adaptive mechanisms to face the challenges of pregnancy.

This hypothesis is based on the year 1940, when Irving, in a study from Boston, observed that pregnant women with gravid hyperemesis had fewer spontaneous abortions than the usual expectation for that moment, postulating a possible association between nausea and vomiting with positive results during pregnancy [10, 22, 23].

Thirty-six years later, Ernest Hook resumed this observation and raised the “embryo protection hypothesis”, suggesting that in early pregnancy nausea, vomiting, food aversions, together with anatomical and sensory changes evolved as a complex set of symptoms that would make pregnant women avoid or expel foods with strong smells or flavors that could be potentially toxic and / or teratogenic. Their observations were based on the decrease in alcohol consumption, caffeine and the desire to smoke that women presented during pregnancy, which were explained by sensory changes and by nausea and vomiting, symptoms that could act as fetusprotectors [24].

Later in 1988, this hypothesis is extended by Margie Profet [25, 26], who proposes that nausea, vomiting and food aversions would be an evolutionary adaptation mediated by the modification of taste and olfactory sensibility to protect the embryo against the maternal ingestion of “toxins” present in some foods. Certain “toxic” plants that supposedly contain high levels of potentially abortive or teratogenic phytochemicals should be avoided. While humans commonly ingest phytochemicals naturally present in vegetables, and also selectively use phytochemicals in the preparation of food (spices), some of them could be potentially harmful during pregnancy, such as those present in bitter-tasting vegetables and spicy foods with strong flavor. Profet also suggests that the methods of cooking by frying, roasting or toasting would be the frequently aversive or avoided because their strong smells would indicate the presence of potentially mutagenic compounds, as well as decaying animal foods that emit suggestive smells due to the presence of parasites and / or bacteria that cause deterioration and produce toxins. On the other hand, it could be predicted that the best tolerated foods would be those that have mild smells and flavors and that do not decompose easily, such as breads, cereals and processed grains.

Later on, other authors deepened this hypothesis by renaming it “maternal-embryo protection hypothesis”, theorizing that pregnant women learn to avoid and / or expel through vomit potentially dangerous foods, not only for their embryos in development but also for themselves [8,11,12,27,28]. As part of this adaptation that evolved, in a coordinated way, the vomit would expel the noxious substance, while the nausea would be produced by an experience of aversion [27].

Hypothesis about “dietary aversions as preventive of the metabolic syndrome during pregnancy”

This proposal suggests that aversions during pregnancy may have evolved, in part, to motivate women to avoid eating foods that increase the risk of developing certain chronic non communicable diseases, particularly gestational diabetes mellitus [28–30].

Following this line of reasoning, dietary aversions would be an evolutionary tactic in populations without a long history of cereal cultivation to avoid the metabolic syndrome. This idea is based on evidences that come from populations in which, historically; the sugar necessary for fetal growth was not available due to a shortage of cereals, grains and starches or due to intense and regular cycles of hunger. In these cases, aversions to these carbohydrate-rich foods were possibly a mechanism to prevent the gestational metabolic syndrome [28, 29].

Hypothesis about “Scarcity of resources”

From the evolutionary biology, certain authors support that a decrease of the alimentary aversions during pregnancy in vulnerable populations could be predicted, with an important load of infectious diseases, with alimentary insecurity and anthropometric indexes that indicate a deficient maternal nutrition. However, studies in which all these associated factors were evaluated could not demonstrate their relationship with the food aversions of pregnant women [12, 31, 32].

Hypothesis about “Compensation of placental growth”

This hypothesis suggests that dietary aversions in the early stages of pregnancy would improve the growth of the placenta; thus, the fetus would exert a “manipulation” upon the maternal physiology, in such a way that mothers are motivated to avoid highly energetic meals. The restriction of maternal energy would benefit the fetus because, according to this hypothesis, mothers with restricted energy intake will prioritize the destiny of any resource that they have available for the development of the placenta and the embryo [28,33]. This position was based on observations of the severe hunger that affected the West of the Netherlands between the years 1944–1945 and its relationship with the weight of the placenta and neonate [28]. It was observed that when the period of maternal malnutrition occurs only during the first trimester, moment that coincides with the highest prevalence of food aversions, the neonates have weights within the normal range and greater weight of the placenta, effects that are not observed in undernourished mothers in the second half of pregnancy. This finding, which is also observed in animals, suggests that malnutrition in the first trimester would lead to a compensatory placental growth [33–35].

Hypothesis about the presence of food cravings

Different statements try to explain the reasons that could be responsible for the presence of cravings during pregnancy. The hypotheses found are: the search for nutrients or cravings in response to nutritional deficiencies; cravings in relation to the presence of active compounds in the desired foods and cravings as a result of hormonal fluctuations.

Hypothesis: “Cravings as a search for nutrients” or “In response to nutritional deficiencies”

From a biological perspective, it was postulated that cravings could serve to provide depleted nutrients in maternal diets, [9, 28]. This position considers craving as a mechanism to ensure adequate and balanced nutrition during pregnancy, which would motivate pregnant women to seek and consume foods rich in energy and micronutrients essential for fetal development.

Some authors consider that taking into account that the nutritional needs of the fetus increase as their development progresses, the intensity of the cravings should follow the same upward trajectory [9,28,36].

In 2002, the anthropologist Daniel Fessler, from an evolutionary perspective, also suggests that pregnant women may have a particular predisposition to seek through cravings, missing nutrients from their diets due to losses caused by aversions and vomiting; that is, there would be a functional link between cravings and food aversions [27]. These interactions were observed in pregnant women who had aversions to certain foods and they were more likely to have cravings compared to those who did not have food rejections [3]. However, this synergy between aversions and food cravings still remains a controversial issue that requires greater evidence from different geographical, social or cultural contexts [10].

Hypothesis: “Cravings are due to the presence of active compounds in the desired foods”

It is suggested that cravings could be due to the presence of active compounds (phytonutrients) in the desired foods [9]. The benefits of potentially bioactive ingredients are due to the possible ability to alleviate physical and perhaps psychological symptoms associated with pregnancy, such as fatigue, irritability and cramps, among others [9]. Chocolate being one of the foods most desired by pregnant women in some contexts, it is pointed out that women’s inclination to it could be cyclical and hormone dependent [9]. The biologically active components of chocolate such as methylxanthines, biogenic amines and cannabinoid-like fatty acids can trigger transient feelings of well-being during pregnancy [37]. However, this relationship is also questioned because the potentially active ingredients of chocolate are present in small quantities, which would make their potential benefits unlikely [9].

Hypothesis: “Cravings are due to hormonal fluctuations”

This hypothesis relates the presence of cravings with the sensory modifications resulting from the hormonal changes that occur during pregnancy. Several hormones such as estrogen, progesterone, leptin, ghrelin and neropeptide Y, among others, change significantly in this period affecting sensory perception with an increase in sensitivity to smells, taste and smell and indirectly being able to influence the selection pattern of the food. [9, 37, 39]. Despite these observations, there is an information gap that relates the exact nature of the link between hormonal fluctuations during pregnancy and food cravings [9].

(Table 1) summarizes the most relevant hypotheses and their foundations on the possible causes of the appearance of food aversions and cravings during pregnancy.

Table 1. Most relevant hypotheses and their foundations upon the possible causes of the appearance of food aversions and cravings during pregnancy.

Hypotheses

Authors, year (Reference)

Foundations

AVERSIONS

 

Maternal-fetal protection

Hook, 1978 (23)
Profet, 1988 (24)
Bayley, 2002 (8)
Fessler, 2002 (26)
Weigel, 2011 (11)
Placek, 2015 (12) McKerracher, 2016 (27)

Nausea and vomiting work to protect the embryo by expelling dangerous chemicals transmitted by food and resulting in subsequent aversion. At first, the possible relationship between nausea, vomiting and aversions to alcohol, coffee and tobacco is explored. Then, this hypothesis is extended to certain “toxic” potentially abortive or teratogenic plants.

After this, the presence of nausea and vomiting is linked to the development of food aversions and it is theorized that pregnant women learn to avoid and / or expel through vomit potentially dangerous foods not only for the developing embryo, but also for themselves.

Preventive of the metabolic syndrome during pregnancy

Haig, 1996 (44)
McKerracher, 2016 (27)

The aversions during pregnancy may have evolved, in part, to motivate women to avoid eating foods that increase the risk of developing metabolic syndrome and / or gestational diabetes mellitus.

Scarcity of resources

Holland, 2003 (45)
Placek, 2012 (12)

Food insecurity and anthropometric indices that indicate poor maternal nutritional status could predict a decrease in dietary aversions during pregnancy.

Compensation of placental growth

Huxley, 2000 (30).
McKerracher, 2016 (27)

Malnutrition in the first trimester of pregnancy, a period that coincides with food aversions, would lead to compensatory placental growth.

CRAVINGS

Search for nutrients or in Response to nutritional deficiencies

Tierson, 1985 (33)
Orloff, 2014(9)
McKerracer, 2016 (27)

They consider craving as a mechanism to ensure adequate and balanced nutrition during pregnancy, in which women are motivated to seek and consume foods rich in energy and micronutrients essential for fetal development.

Presence of active compounds in the desired foods

Orloff, 2014 (9)

The pregnant woman, through cravings, consumes food with bioactives that produce a sensation of well-being.

Hormonal Fluctuations

Orloff, 2014 (9)

There is a relationship between hormonal changes and the frequency and intensity of cravings in pregnant women.

Although there may be a biological and evolutionary component in the development of these modifications in food preferences, food cravings or aversions do not escape the cultural food patterns that are also involved in the food choices of pregnant women [5]. There are civilizations that have a cultural model in which the cravings must be fulfilled by the pregnant woman, in some cases rituals are performed at the end of pregnancy to ensure that the wishes of the woman and the “fetus” have been fulfilled [9, 12]. However, in other cultural settings, pregnant women do not have a “special” treatment, so cravings are not very valued [12].

In such a way that from an anthropological and cultural perspective, interpreting the meanings behind the expressions of food cravings and aversions and unraveling the biocultural mechanisms of these food choices could be more complex than expected. In addition to evolutionary influences, experiences during an individual’s life can have significant impacts on the nature of food cravings and aversions. Both the context and social status as well as relative wealth can affect the choices of which foods are desired or avoided by the pregnant women [5].

Possible consequences postulated upon the presence of food cravings

Beyond the different theories that can cause food cravings, we have also tried to explain the possible consequences that such cravings could generate in the pregnant woman. A recent explanation suggests a possible association between cravings and the risk of excessive weight gain during pregnancy [9]. This association is based on the high frequency of cravings during pregnancy in North American women, and the increasing increment in the prevalence of pregnant women with greater weight gain than recommended [40–42]. This construction is based on the popular belief that cravings should be fulfilled by pregnant women. A possible explanation could be based on a model in which the cravings result from ambivalence or a tension between giving (please) or avoiding (effort to restrict consumption) the desired food. It is assumed that women, in general, try to resolve this ambivalence in favor of abstinence due to the cultural pattern of thinness, but this model also gives occasional permission to break the restriction, resulting in episodic consumption and potentially excessive of the desired foods [9]. This statement would be supported in part by recent studies [41, 43] that identify cravings during pregnancy as a possible predictor of excess of weight gain.

Another potential risk suggests that cravings for sweet foods are associated with an increased risk of abnormal glucose tolerance and the development of gestational diabetes mellitus [44, 45]. In some studies, women who developed gestational diabetes mellitus had a decreased perception of sweet taste and an increase in food cravings with that taste mainly during the third trimester, compared to healthy pregnant women. However, these associations are weak and other investigations fail to support this association between cravings for sweet-tasting foods and maternal blood glucose levels [45, 46].

Prevalence and characteristic of food cravings and aversions

The prevalence with which cravings occur varies from 40 to 79%, the lowest figure comes from Europe, while the highest prevalence corresponds to the African continent. With respect to food aversions, its occurrence varies from 38% in pregnant women in Asia to 78% in Africa.

The nature of the food desired and / or rejected also has special characteristics according to the geographical context in which they are studied, possibly shaped by cultural, ethnic and / or socio-economic influence. In general terms, foods craved for by pregnant women in Western cultures are chocolate, fruits and fruit juices, sweet foods such as ice cream and desserts and to a lesser extent different types of meat and dairy products. On the other hand, pregnant women in other geographic contexts of greater socioeconomic vulnerability experience cravings mainly for protein foods of animal origin such as meat, cheese and milk followed to a lesser extent by vegetables, fruits and grains.

On the other hand, meat and protein-rich foods such as dairy products are largely avoided by pregnant women from Western countries, followed by coffee, highly spicy foods and to a lesser extent vegetables. Cereals such as wheat, corn and rice and less strongly vegetables and meats are mostly avoided by pregnant women in other geographical areas such as Africa and Asia.

(Table 2) summarizes the prevalence and characterization of food cravings and aversions in different geographical contexts.

Table 2. Prevalence and characterization of food cravings and aversions in different parts of the world.

Author, year (reference)

Place (n)

Prevalence of cravings and foods mostly craved for

Prevalence of aversions and foods mostly aversive

Tsegaye, 1998
(3)

Africa, Etiophia (n:295)

72%
Meat sauce, cheese and milk

65%
Roasted wheat, coffee, wheat bread, meat sauce, kocho and injera.

Nyaruhucha, 2009
(47)

Africa, Tanzania (n: 204)

73%
Meat, mango, yoghurt, orange, banana.

70%
Rice, meat, fish, evo, legumes, tea.

Young, 2012
(5)

Africa, Kenya and Tanzania: (n:188)

56%
Meat and milk.

78%
Corn, millet, rice, buttermilk and blood.
vegetables and fried foods.

Patil, 2012
(48)

Africa, Tanzania (n: 545)

79%
Meat / fish, vegetables, fruits and grains.

63%
Vegetables, meat, fish and grains.

Placek, 2015
(12)

Asia, India (n:149)

50%
Sour foods (immature mango and tamarind), ethnic tasty and strong, vegetables and fruits, grains – starches and meat – sweets.

60%
Fruits, tasty and strong ethnic foods, meat, vegetables and sweets, non-alcoholic beverages, starch-dairy products and ice cream.

Qureshi, 2015
(49)

Asia, Pakistan (n: 110)

78%
Sweets, salty foods, spicy and fried food

38%
Poultry products, sweets, tea, milk and rice and fried foods, legumes, spicy and vegetable foods.

Mc Kerracher, 2016
(27)

Oceania
Fiji Islands, Yasawa (n: 70)

Bananas, mango, green leafy vegetables, fish and meat.

Fish, cassava, meat, non-fish aquatic foods, imported starches, locally grown starches and rarely spicy, sour or bitter-tasting vegetables.

Bayley, 2002
(8)

Europe, Great Britain (n: 99)

61%
Fruits and fruit juices, sweet foods (sweets, chocolates, cookies).

54%
Coffee, high-spiced foods, meats and protein-rich foods.

Hill, 2015
(43)

Europe, Great Britain (n: 1693)

39%
Sweet foods (chocolate, sweets, ice cream, desserts), fruits and dairy products.

Not studied

Coronios Vargas, 1992
(4)

América, USA
(n: 160)

dairy products, chocolate, tea
vegetables, meats, sweets
cereals, fermented fish, fruits a

Vegetables, meats and dairy products.

Weigel, 2011
(11)

América, Ecuador  (n: 849)

69%
Fruits and fruit juices (limes, apples, oranges, grapes, pineapple, tangerines, watermelons, mangoes and strawberries), meats, (poultry, fish, shellfish) eggs, foods rich in carbohydrates with starch.

74%
Different types of meats (beef, pork, lamb, liver, other organs, sausages), poultry (chicken), fish (tilapia, sea bass, tuna), seafood (shrimp, prawns, squid) and chicken or quail eggs, “toxic vegetables” such as cabbage, cauliflower, broccoli, Brussels sprouts, onions, eggplants, tomatoes, turnips, potatoes and mellocos, an indigenous tuber similar to potatoes, white rice, wheat noodles, corn, barley and other foods with carbohydrates with starch.

Orloff, 2014
(9)

América, USA (n: 200)

Sweet foods (chocolate, candies), carbohydrates with high calories and flavors (pizza, chips) animal protein (meats, chicken), fruits, cheeses, creams, other carbohydrates, fast foods.

Not studied.

Orloff, 2016
(38)

América, USA (n: 83)

Sweet foods, as chocolate, cookies, ice creams and fast foods

Not studied.

Farland, 2015
(42)

América, USA (n: 2022)

45%
Sweet foods (candies, desserts, cookies, fruit, fruit juices, cereals with sugar, ice cream, yogurt), salty (chips, fried potatoes, cheeses, fried foods, tasty (eggs, meats, mixed dishes, seafood), starches (bread, rice, pasta, potatoes).

Not studied.

Flaxman, 2000
(10)

Systematic review

Cravings: 21 studies, n: 6239

Aversions: 20 studies, n: 5.432

67%
Fruits and fruit juices, sweet foods, desserts and chocolate, followed by dairy products and cream ice cream and, to a lesser extent, meat.

65%
Meat, fish, poultry and eggs, soft drinks and vegetables

aVariations in the selection according to ethnic origin.

Conclusion

Cravings and food aversions are frequent phenomena that affect the selection of food during pregnancy; its etiology is still unclear. Numerous hypotheses focused on biological, cultural and anthropological approaches attempt to explain their occurrence. Although the description of food cravings and aversions during pregnancy has been studied by various authors, there is no uniformity of criteria in the modalities used for their characterization. Different types of questionnaires, the vast majority of which have not been validated, have been used to identify these phenomena. Having diagnostic tools specially designed to know the occurrence and describe the cravings and aversions during pregnancy is an important step to learn more about the relationship these changes may have in the selection of foods with nutritional status and maternal-fetal health.

Acknowledgement

This Word was supported by the University of Buenos Aires (UBACyT Code: 20020170100385BA).

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A rare case of distant metastasis of primary malign pericardial mesothelioma with 18F-FDG PET/CT

DOI: 10.31038/JCRM.2019234

ABSTRACT

Primary pericardial mesothelioma is a rare malignant tumor derived from the pericardial mesothelial cell layers. 65-year-old man was admitted to hospital with dyspnea and chest pain. Pericardial effusion and pericardial tamponade were observed with transthoracic echocardiography. Contrast-enhanced computed tomography (CECT) demostrated pericardial effusion, diffuse pericardial thickening and pleural effusion in both hemithorax. The final diagnosis was proven as primary malignant pericardial mesothelioma with histopathological evaluation. Subsequently, F-18 FDG PET-CT scan demonstrated high FDG uptake in pericardial thickening areas. Additionally, increased FDG uptake was also seen in the hypodense lesions in the both adrenal gland lesions and in liver.

Keywords

PET-CT, echocardiography, primary malign pericardial mesothelioma, FDG

INTRODUCTION

Malignant mesothelioma (MPM) is a rare, aggressive malignant tumor derived from the mesothelial cells of serosal membranes. Malignant mesothelioma may occur most frequently from the pleura (90%), less frequently from the peritoneum (6–10%) and from the pericardium, and very rarely from the tunica vaginalis in the testis [1]. Primary pericardial mesotheliomas (PPM) very rare malignancy (incidence 0,0022 %). It represents 6% of all mesothelioma cases [2]. It usually provides nonspecific findings such as dyspnea, fever, cough and chest pain. It is more common in men. The mean age was 46 (19–76) years [3]. Mesotheliomas particularly metastasize to the intratorasic lymph nodes or lung, distant extrathorasic metastasis is very rarely observed [4]. Various imaging methods can be used for the diagnosis such as echocardiography (ECO), chest X-ray, chest CT, magnetic resonance imaging (MRI) and positron emission tomography-computed tomography (PET-CT) [5]. PET-CT imaging have an important role in staging, treatment response, recurrence detection and prognosis in pleural mesothelioma [6]. In contrast to pleural mesothelioma, a few case reports with PPM is described by FDG PET-CT [7].

CASE

A 65-year-old male was admitted to the cardiology clinic with complaints of dyspnea and chest pain. He had no prior history of exposure to asbestos. Echocardiography showed pericardial effusion and tamponade findings. Diagnostic and therapeutic pericardiocentesis with pericardial drain was performed, all laboratory analyses showed normal results, cultivations and polymerasechain reaction (PCR) for tuberculosis were negative. Contrast-enhanced computed tomography (CECT) showed pericardial effusion, diffuse pericardial thickening and pleural effusion in both hemithorax (Figure 1-F).

JCRM 2019-112 - Tarik Sengoz Turkey_F1

Figure 1. A-MIP imaging of PET. B.C.D.E- Axial fusion imaging. B.C-Diffuse FDG uptake in pericardial thickining (SUVmax: 6,2). D- Focal FDG uptake in both adrenal glands (SUVinax: 3,l and 5,8). E-Focal FDG uptake in liver (SUVmax: 4,0). F-Axial CECT show diffuse pericardial thickining and effusion. G-liistopathological evaluation of malignant pericardial mesotheliomas (H&E).

F-18 FDG PET-CT scan demostrated intense uptake in diffuse pericardial thickening areas, with a maximum standardized uptake value (SUVmax) of 6.2 (Figure 1-A). Fused PET-CT images indicated the thickened pericardium with high FDG uptake (Figure 1-B,C). Furthermore, fused PET-CT images showed increased FDG uptake both in adrenal gland lesions (SUVmax: 3.1–5.8) (Figure 1-D) and in the hypodense lesion with a diameter of 1 cm in in liver segment 4A (SUVmax: 4.0) (Figure 1-E). Cytologic evaluation of pericardial effusion demonstrated with malignant pericardial mesothelioma. However, immunohistochemistry evaluation was not able to be performed. The case was evaluated as the PPM with liver and bilateral surrenal gland metastases. While the chemotherapy was planning, the patient had multiorgan insufficiency and emergency dialysis. Cardiac arrest developed two times during the dialysis and resulted in death.

DISCUSSION

PPM is a very rare malignant tumor of 6% of all mesotheliomas [8]. It can be seen in the form of mass formation or disseminated pericardial thickening. The effect of asbestos exposure is not as clear as pleural and peritoneal mesothelioma. The symptoms are usually nonspecific (fatigue, shortness of breath, chest pain, cough, etc.). It may indicate pericardial effusion, constrictive pericarditis, cardiac tamponade, and congestive heart failure in the clinic [9]. Imaging methods such as chest radiography, transthoracic echocardiography, CECT, MRI are used in the diagnosis.

In ECO and chest X-ray radiography, an enlarged heart silhouette and pericardial effusion are described, whereas the pericardial mass cannot be differentiated. In a review of 28 pericardial mesothelioma cases, mediastinel mass could be differentiated in only one of 24 cases with X-ray graph [3]. Although CECT is an effective examination to demonstrate tumor invasion and pericardial thickening, sometimes large pericardial effusion complicate the evaluation of the mass [10]. ECO and CECT have a low sensitivity (12–44%) in detecting pericardial mass (3). The use of MRI is limited, high signal intensity in T2-weighted image has been demonstrated in one patient [11].

FDG is a glucose analogue and offers metabolic information on the basis of increased glucose uptake due to the increased glucose requirement in cancer cells. PET-CT is frequently used in the diagnosis, staging and treatment response of many different cancers. Since the use of PET-CT in pleural mesothelioma has been well known [6], the knowledge in PPM is limited. There was no information about FDG PET-CT in the review of Thomson et al. with 27 PPM cases between 1972–1992 [3] and in the review of Nilsson et al. with 29 PPM cases between 1994–2008 [12]. After 2008, 5 PPM cases confirmed with PET-CT were found [13–17] . 3 of 5 cases were female and 2 of them were male. The average age is 52 (19–72). The characteristics of 5 cases are summarized in Table 1. In 3 of the patients, PET-CT showed no regional lymph nodes and distant metastases, while the other 2 cases had mediastinel lymph node metastasis [15,17]. In our case, liver and bilateral surrenal gland metastasis were detected. Thus, our case was the first case with liver and adrenal metastasis detected by PET-CT. Metastasis is seen in 25–45% of PPM cases. Generally, regional lymph nodes, lung and kidney metastases were detected [18]. Nilsson et al. study, metastasis was defined in 16 (55%) of 29 PPM cases (lymph nodes, liver and lung metastasis) [12]. Cytological examination of pericardial fluid in PPM does not always distinguish between reactive / malignant cells. Pericardial biopsy may be required for the final diagnosis [19]. Although the diagnosis was made after pericardiectomy in 5 cases in literature, our patient was diagnosed with pericardiocentesis (Table 1).

Table 1. Cases of pericardial mesothelioma with F-18 FDG PET/CT published in the literature

Case

Age

Sex

Symptom

Asbestos exposure

Radiological imaging

PET-CT

Pathology

Our case

65

M

Dyspnea, chest pain

none

USG: pericardial effusion

CT: pericardial effusion, pericardial thickining

PPM (SUVmax:6.2), liver (SUVmax:4.0) and bilateral adrenal (SUVmax:3.1-5.8) met

pericardiosentesis

3

72

F

unspecified

none

CT: pericardial thickining

PPM (SUVmax not specified)

pericardial biopsy

4

58

F

Fewer, fatigue

unspecified

X-ray: enlarged cardiac silhouette

USG: pericardial effusion without ventricul dilatation

CT: pericardial mass

PPM (SUVmax:12.9) and dissemine pericardial spread

Subtotal pericardiectomy

5

19

F

Dyspnea, chest pain, low exercise capacity

unspecified

X-ray: enlarged cardiac silhouette

USG: pericardial effusion without ventricul dilatation

CT: pericardial thickining/effusion

MR: pericardial mass

PPM (SUVmax:5.22) and mediastinel lymph node metastasis (SUVmax:1.6)

Partial pericardiectomy

7

54

M

Dyspnea

none

USG: pericardial effusion without ventricul dilatation

CT: pericardial thickining/effusion

PPM (SUVmax:7.5)

pericardiectomy

8

57

M

Dyspnea, ankle edema

unspecified

USG: constrictive pericarditis

PPM (SUVmax:19.5) and mediastinel lymph node metastasis

pericardiectomy

M: male, F:female, USG: transthoracic echocardiography, CT: Computed tomography, MR: Magnetic resonance imaging, PET-CT: positron emission tomography- computed tomography, PPM: primary pericardial mesothelioma

Treatment is often palliative, curative treatment is not possible in PPM. Surgical resection, chemotherapy and radiotherapy are the treatment options. Average survival was reported as 10 months in one study [19]. Our patient was died 16 day after the diagnosis.

Consequently, PET-CT can change the management of patients with PPM by showing the distant metastasis. However, the shortness of survival and the palliative treatment are the factors that limit the effect of PET-CT on the treatment plan. Our case is differentiated due to liver and bilateral surrenal metastasis from PPM confirmed by PET-CT in the literature. In the future, it can be predicted that PET-CT have an important role for PPM like pleural mesothelioma.

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