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Τρίτη, 3 Ιανουαρίου 2017

Vancomycin resistant Enterococcus faecium (VRE) vertebral osteomyelitis






Highlights

Enterococcus faecium as an emerging pathogen responsible for vertebral osteomyelitis after spinal surgery
Management of infections complicating spinal surgery is controversial.
Multidisciplinary approach consider virulence, microbiological features of causative pathogens and patient's risk factors.
The treatment of postoperative instrumented spinal infection should be made case-by case.

Abstract

Objective

Case report and literature review.

Background

Enterococcus faecium is an emerging pathogen responsible for post procedural infections in patients who have undergone spinal decompression surgery. In this case report, the authors discuss and review recent literature on approaches to post-operative spinal infection.

Case report

We herein report the case of a 55-year-old HIV-negative Caucasian Italian woman who showed vertebral osteomyelitis with abscesses around the interbody cage caused by an Enterococcus faecium vancomycin resistant gen-Van A, following a Transforaminal Lumbar Interbody Fusion (TLIF). The same strain was detected in disc biopsy, urine culture and rectal swab. After the implant (screws, bars and cage) was removed and a suitable medical therapy administered, the infection resolved completely. The strain was identified and its susceptibility profile was characterized; biofilm-associated genes and biofilm-induced antimicrobial resistance is highlighted.

Conclusions

In any case, the management of infections complicating spinal surgery is controversial, and various mono or combined surgical and/or anti-infective timing approaches to remove infected implants have been proposed. The authors suggest a multidisciplinary approach taking into account virulence, microbiological features of causative pathogens and patient's risk factors. More efforts should be directed towards the early identification of pathogens in surgical specimens.

Keywords

  • Spinal surgery
  • Vertebral osteomyelitis
  • Enterococcus faecium
  • Transforaminal Lumbar Interbody Fusion (TLIF)

1. Background

Surgical site infection (SSI) after spinal surgery is a challenging medical problem that results in increased rates of morbidity, length of hospital stay and health care costs [1]. The reported incidence of infection following posterior spinal instrumentation surgery is between 2.6% and 3.8% [2][3][4][5] and [6]. Bacteria isolated from disc material are more frequent in patients with disc herniation than ones with other spinal disorders[7] and [8]Staphylococcus aureus is the most common cause of SSI, although infections due to Staphylococcus epidermidisEnterococcus faecalisPseudomonas spp.,Enterobacter cloacae, and Proteus mirabilis have also been reported [9] and [10]. The surgical procedure seems to be the most significant variable affecting rate of infection. The risk of infection following a simple lumbar discectomy is < 1% due to shorter operative times, less muscle trauma, and generally healthier patients than those requiring more extensive spinal procedures. When more extensive decompression is performed, without fusion, the risk of infection rises to 2%. When fusion is added to the procedure, operative time is longer and blood loss is greater. In this case, the infection rate rises to 6%. Other factors include extended pre-hospitalization, high blood loss (> 1000 mL), and prolonged operative time (> 3 h) [11]. (Although rates of infection are clearly lower in younger patients because of fewer comorbidities, other significant risk factors are: diabetes mellitus, obesity, and a history of an SSI [2].) Accurate diagnosis is essential in order to effectively eradicate the infecting organisms, but this is often difficult to achieve. Specific clinical signs, laboratory and radiographic investigations that aid diagnosis of infection may be absent. Inflammatory markers together with the clinical symptoms (low back and radicular pain) should alert the physician to the possibility of infection [12]Enterococcus spp. is an emerging opportunistic pathogen that causes implant-related SSI. Treatment of enterococcal prosthetic joint infection is difficult, in part due to biofilm-associated antimicrobial resistance. The antibiotic resistance properties of E. faecium strains have recently been associated with biofilm formation which leads to resistance to environmental stress, and adhesion to eukaryotic cells, such as those of the urinary tract [9][10],[11] and [13]. We report the clinical and surgical management of a case of disc infection due to Vancomycin Resistant Enterococcus faecium (VRE) after surgical decompression.

2. Case report

A 55-year-old HIV-negative Caucasian Italian woman with fever and low back pain lasting one month was admitted to our Emergency Surgical Department in April 2015. Her medical history was remarkable for hypertension and coronary artery disease. Before treatment, the patient had had several episodes of urinary tract infection, and a urine culture resulted in the isolation of Enterococcus spp. susceptible to vancomicin, gentamicin and ampicillin (minimal inhibitory concentration, MIC for ampicillin < 64 g/ml). Surgical history revealed that the patient had undergone L3–L5 open decompression and a 360° fusion with pedicle screws in L3–L4–L5 as well as a Peek interbody cage by TLIF in L4–L5 since 8 months prior the admission to our surgical setting, for a severe low back pain due to L3–L4, L4–L5 instability and diffuse spondyloarthrosis ( Fig. 1 and Fig. 2). A physical examination of the patient at admission showed fever (temperature, 38.9 °C [102 °F]) and left L3–L4–L5 radicular hypoesthesia. Initial laboratory studies revealed the following values: white blood cell (WBC) count, 27.3 × 104 cells/mm3 (74% neutrophils, 10% bands, 10% lymphocytes, and 3% eosinophils); hemoglobin level, 12.7 g/dL; platelet count, 2.7 × 105 platelets/mm3; serum creatinine level, 0.9 mg/dL; aspartate aminotransferase level, 29 U/L; alanine aminotransferase level, 27 U/L; total bilirubin level, 1.5 mg/dL; indirect bilirubin level, 0.5 mg/dL; and lactate dehydrogenase level, 2900 U/L. A lumbar puncture was performed. The opening pressure was 15 mm Hg, and analysis of cerebrospinal fluid (CSF) revealed the following values: WBC count, 28 cells/mm3; glucose level, 58 mg/dL; and protein level, 19 mg/dL. Microscopic examinations, aerobic and anaerobic bacterial cultures as well as acid-fast bacillus test (AFB) and fungal cultures to identify pathogens in the CSF were negative; polymerase chain reaction (PCR) tests for relevant viral and bacterial infectious agents such as Mycobacterium tuberculosis were negative. Moreover, bacterial cultures and other analyses for other pathogens which are epidemiologically relevant in our geographic area (e.g. Rickettsia conoriiBrucella spp.) were negative, as previously reported in another case of suspected infection involving the CNS [14]. A Lumbar CT scan showed areas of bone remodeling with sclerotic margins at both L4 and L5, somatic cortical profiles consistent with an inflammatory process (Fig. 3A–B). A Magnetic Resonance Imaging (MRI) of the lumbar sacral tract confirmed osteomyelitis of the L3–L4–L5 bodies, especially around the cage at the L4–L5 interbody level. The infection seemed to reach the screws in the L4–L5 body and the left paravertebral region; there was another quota of pathological tissue both in the prevertebral L5 and in the subcutaneous space, with 8 cm extended fluid collection (Fig. 3C–D). The results of blood, urine and fluid sample cultures were negative. Therefore, a medical therapy with intravenous cefuroxime (140 mg/kg per day) and vancomycin (2 g/day) for suspected vertebral osteomyelitis, was administered. On day 18 of hospitalization, the patient became febrile (temperature, 39.4 °C [103 °F]) without clinical manifestations of sepsis or other suspected focus of infection. A transthoracic echocardiogram showed no valvular abnormality or vegetation. A head CT scan without contrast was unremarkable. Culture of blood and urine were performed. Enterococcus faecium strain was isolated from the urine culture. It was resistant to ampicillin (MIC ≥ 64 μg/ml) and vancomycin (MIC of minimum inhibitory concentration ≥ 256 μg/ml), and exhibited high-level resistance to aminoglycosides (high-level resistance to gentamicin was tested for using the 120 μg gentamicin disc) and susceptibility to rifampin, daptomycin, tygeciclyne and linezolid [15] and [16]. The patient was given rifampicin and daptomycin for possible systemic Enterococcus faeciuminfection. The same resistant strain was isolated from the patient's rectal swab. A persistent fever over the following days prompted our multidisciplinary neurosurgical and infection team to develop a surgical strategy. Therefore, a surgical lumbar wound exploration was performed; instrumentation was all removed and a wound debridement was carried out. Once completed, fibrin sealant (Vivostat®) was sprayed on the operative field, in order to prevent CSF leakage [17][18][19][20][21][22] and [23]. Disc biopsy culture identifiedEnterococcus faecium. The isolate showed the same susceptibility profile as the strain isolated from the urine culture. At discharge, 6 months of oral antibiotic therapy with Linezolid plus Rifampicin plus Doxycyclin was prescribed. After six months of anti-infective treatment, MRI investigations showed that the inflammatory disease had progressively resolved ( Fig. 4). At the final follow up the neurologic examination was unremarkable. No motor or sensory deficit was evident. Patient referred just low back pain which was significantly lower than pre operatory status. Analysis of E. faecium strains isolated from disc biopsy, rectal swab and urine culture by PCR amplification revealed the presence of the vanA gene [15]. A new posterior transpedicle fixation to correct lumbar segmental instability has been proposed to the patient but she has actually refused.
Fig. 1
Fig. 1. 
Pre-operative lumbar MRI. A. Sagittal view. A diffuse spondyloarthrosis, with herniated discs in L3–L4 and microinstability at L4–L5 is documented. B Axial view. The L3–L4 level is depicted.
Fig. 2
Fig. 2. 
Post-operative lumbar CT scan. Pedicle screws in L3, L4 and L5 bilaterally and intersomatic L4–L5 cage by TLIF.
Full-size image (70 K)
Fig. 3. 
A–B: Post operative CT scan (8 months). An area of bone remodeling in both L4 and L5 somatic cortical profiles (orange arrow) is depicted C–D Post operative lumbar MRI scan. C. T2 weighted sagittal images. D. T1 weighted, post contrast MRI. Lumbar enhanced MRI scan revealed a pathological enhancement in vertebral bodies of L4, L5, vertebral canal and paravertebral L3–L5 region. All these findings were suggestive of surgical site infection. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 4
Fig. 4. 
Post-medical treatment lumbar MRI. Six months after anti-infective treatment, MRI showed a progressive resolution of infection.

3. Discussion

In 2014, scientific literature addressed the issue of instrumentation removal or retention in the attempt to reduce infection following spinal surgical procedures, especially after Posterior/Transforaminal Lumbar Interbody Fusion [16][24] and [25]. The management of infections is currently under debate because, as reported by Wei-Hua et al., it is likely that the implants do not interfere with the body's attempt to fight infection, especially precocious infection [25]. The more complicated procedures and more reconstruction levels involved in fusion surgery with instrumentation may explain the higher revision and mortality rates[26] and [27]. In this manuscript the authors describe and discuss the role of Enterococcus faecium as an emerging pathogen responsible for vertebral osteomyelitis after spinal surgery. Enterococci occur naturally among the normal flora in the human gastrointestinal tract. Initially thought to be harmless commensal organisms in hospitalized patients, enterococci have emerged as significant nosocomial pathogens. At present, Enterococci are known to be the cause of important nosocomial infections such as endocarditis, bacteremia and urinary tract infections, especially in elderly female patients [28]. Enterococci are intrinsically resistant to several antibiotics and possess the ability to acquire resistance through the exchange of genetic material [29]. As a result, they have become more resistant to multiple antibiotics [13] and [29]. According to the European Antibiotic Resistance Surveillance System, an international network that collects data on antibiotic resistance of bloodstream-infecting isolates in 28 European countries (http://www.earss.rivm.nl/), in Italy the proportion of VRE was higher than 10% in 2001 and 2015. Colonization and infection with vancomycin-resistant enterococci are associated with prolonged hospitalization, exposure to cephalosporins and vancomycin, and the use of antianaerobic agents [30]. Compared to Enterococcus faecalisE. faecium isolates are more resistant to penicillin, and large molecules such as nafcillin, oxacillin, ticarcillin, ertapenem, most cephalosporins, and aztreonam. Moreover E. faecium is more impermeable to aminoglycosides, and the serum concentrations of aminoglycosides required for bactericidal activity are much higher than other pathogens [29][30],[31] and [32]. Two hospital outbreaks have been reported in Italy in the last decade; one was due to VRE belonging to the species Enterococcus faecalis (VRE) in a neurosurgical ICU[29]. Management of post-operative spinal infection is controversial, and various treatment options have been proposed: some advocate medical therapy only, some suggest irrigation and serial wound debridement plus antibiotic therapy, while others report that infection can be eradicated only by removing implants [25][26] and [27]. Chaichana et al. retrospectively reviewed 817 consecutive adult patients who underwent instrumented posterior lumbar fusion for degenerative spine disease between 1993 and 2010; among 817 pts, 37 (4.5%) developed postoperative spine infection [12].
Because patterns of infection acquired in patients undergoing operation are ever changing, it is an essential part of nosocomial infection surveillance programs to periodically document the epidemiologic features of infection in these patients [33]Table 1 reassume old and new risk factor for infection following neurosurgery procedure [2][34][35][36],[37] and [38].
Table 1.
Risk factors for Enterococcus spp. infection in adult patients in a neurosurgery setting.
Increased riskEmerging risk factors
Age (≥ 70 years)History of urinary tract infection
Sex, femaleEmergence of regional clones of Enterococcus faecium
DiabetesVancomycin-resistant Enterococcus (VRE) colonization
Hematologic malignancyNumber of VRE-colonized patients on the unit
Solid tumorTransferred from rehabilitation facilities and long-term care facilities
Steroid therapyPolymicrobial infection
Previous hospitalizationType of surgery: genitoperineal surgeries
Length of stay in hospitalAdmission for other surgical pathology (wound infection, enteric peritonitis)
Urinary catheterHeart disease
Management of implant retentionDiverticulosis
Exchange (one or two stage)Overweight (BMI between 25.0 and 29.9)
Median (IQR) of antibiotic treatment
Obesity (BMI of 30 or higher)
Biofilm formation is a crucial step in the pathogenesis of many subacute and chronic bacterial infections, including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-sensitive S. aureus (MSSA), Candida species, and Enterococcus species foreign body-related infections.
There is general consensus that the adhesion of microbes to a surface influences bacterial metabolism, like microorganisms involved in device-related infection: they are in a dormant, that is a stationary phase of growth, and the analysis of their growth reports increased biofilm growth rates in comparison to the effects of effluents on planktonic growth activity (1). Parsek and Singh (2) were the first to attempt to define the significance of biofilm infection. Like other scholars, they recognized the consequences of biofilm formation by bacteria, especially in surgery (3, 4). Today the main problem for the microbiologist remains biofilm identification, which requires particularly sophisticated morphological techniques such as microscopy or fluorescence in situ hybridization (FISH), as often neither culture nor biomolecular investigations are helpful (5, 6). Obviously antibiotics have limited efficacy on implant-associated infection because not all antibiotics can overcome the biofilm in sufficient quantities to clear the microorganism, hence some studies have looked at combined treatment options (infectious and surgical management) to avoid infection [39],[40][41][42][43][44] and [45]. Recent research has shown how some bacterial species, such as enterococcus, are able to enter bone cells and induce osteoblast apoptosis, osteoclast recruitment, and highly destructive osteomyelitis [46]. Biofilm formation in the pathogenesis of enterococcal infections is now widely recognized and underscores the importance of taking the pathogenesis of biofilm infections into consideration when comparing the management of postoperative infection due to strain biofilm-associated genes and biofilm-induced antimicrobial resistance after spinal instrumentation [47].
This controversial aspect, especially in enterococal infection, should be solved with appropriate controlled studies. In our case report, the decision to remove instrumentation led to the resolution of the infection. Information on the strain, its susceptibility profile, vancomycin genotype and clonal relationship were collected for our clinical information, and represent the goal of biofilm associated pathogens causative of implant-related infections. Cost-effective analysis should be conducted in subsequent studies to determine the costs involved in the prevention of invasive VRE infections in the surgical setting: implementation of active surveillance culture, VRE decolonization and probiotics should be studied further.

4. Conclusion

A delayed infection after instrumented spine surgery can be difficult to diagnose. We report a very rare surgical site infection due to Enterococcus faecium following a urinary tract infection. Effective treatment usually includes irrigation and wound debridement, followed by prolonged administration of antibiotics and, in severe cases, by the removal of the implants. However, if the infection is not deep, probably the instrumentation can be left in place. Bacterial biofilm formation is central in the pathogenesis of infections related to foreign material, and E. faecalis and E. faecium can form biofilm. Therefore, considering that there is no clear consensus on how to manage patients with postoperative instrumented spinal infection, currently the best choice of treatment should be made case-by-case.

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Declaration of interest: The authors report no declarations of interest. No funds were received in support of this work.
Corresponding author at: Department of Experimental Biomedicine and Clinical Neurosciences, School of Medicine, Neurosurgical Clinic, University of Palermo, Via del Vespro 129, 90100 Palermo, Italy.

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1. Chadha NK, Gordon KA, James AL, Papsin BC. Tinnitus is prevalent in children with cochlear implants. International Journal of Pediatric Otorhinolaryngology. 2009;73:671-675. [abstract]

2. Akdogan O, Ozcan I, Ozbek C, Dere H. Tinnitus after cochlear implantation. Auris Nasus Larynx. 2009;36:210-212. [abstract]

3. Pan T, Tyler RS, Ji H, Coelho C, Gehringer AK, Gogel SA. Changes in the tinnitus handicap questionnaire after cochlear implantation. American Journal of Audiology. 2009;18:144-151. [abstract]

4. Andersson G, Freijd A, Baguley DM, Idrizbegovic E. Tinnitus distress, anxiety, depression, and hearing problems among cochlear implant patients with tinnitus. Journal of the American Academy of Audiology. 2009;20:315-319. [abstract]

5. Rothholtz VS, Tang Q, Wu EC, Fine EL, Djalilian H, Zeng F-G. Exploring the parametric space of tinnitus suppression in a patient with a cochlear implant. Laryngoscope. 2009;119.

6. Di NW, Cianfrone F, Scorpecci A, Cantore I, Giannantonio S, Paludetti G. Transtympanic electrical stimulation for immediate and long-term tinnitus suppression. International Tinnitus Journal. 2009;15:100-106.[abstract]

7. Litre CF, Theret E, Tran H et al. Surgical treatment by electrical stimulation of the auditory cortex for intractable tinnitus. Brain Stimulation. 2009;2:132-137. [abstract]

8. Evans RW, Ishiyama G. Migraine with transient unilateral hearing loss and tinnitus. Headache: The Journal of Head & Face Pain. 2009;49:756-759. [abstract]

9. Pirodda A, Brandolini C, Raimondi MC, Ferri GG, Borghi C. Tinnitus as a warning for preventing vasovagal syncope. Medical Hypotheses. 2009;73:370-371. [abstract]

10. Anderson JE, Teitel D, Wu YW. Venous hum causing tinnitus: case report and review of the literature. Clinical Pediatrics. 2009;48:87-89. [abstract]

11. Liess BD, Lollar KW, Christiansen SG, Vaslow D. Pulsatile tinnitus: a harbinger of a greater ill? Head & Neck. 2009;31:269-273. [abstract]

12. Singh DP, Forte AJ, Brewer MB, Nowygrod R. Bilateral carotid endarterectomy as treatment of vascular pulsatile tinnitus. Journal of Vascular Surgery. 2009;50:183-185. [abstract]

13. Delgado F, Munoz F, Bravo-Rodriguez F, Jurado-Ramos A, Oteros R. Treatment of dural arteriovenous fistulas presenting as pulsatile tinnitus. Otology and Neurotology. 2009;30:897-902. [abstract]

14. Cowley PO, Jones R, Tuch P, McAuliffe W. Pulsatile tinnitus from reversal of flow in an aberrant occipital artery: Resolved after carotid artery stenting. American Journal of Neuroradiology. 2009;30:995-997. [abstract]

15. Stimmer H, Borrmann A, Loer C, Arnold W, Rummeny EJ. Monaural tinnitus from a contralateral inferior colliculus hemorrhage. Audiology & Neurotology. 2009;14:35-38. [abstract]

16. Latifpour DH, Grenner J, Sjodahl C. The effect of a new treatment based on somatosensory stimulation in a group of patients with somatically related tinnitus. International Tinnitus Journal. 2009;15:94-99. [abstract]

17. Department of Health. Provision of services for adults with tinnitus: a good practice guide. 2009. [full text]

18. DH. Tinnitus Map of Medicine care pathway. 2010. [Full text]

19. BTA. Tinnitus: guidelines for primary care. 2010. [Full text]

20. Schneider P, Andermann M, Wengenroth M et al. Reduced volume of Heschl's gyrus in tinnitus. NeuroImage. 2009;45:927-939. [abstract]

21. Landgrebe M, Langguth B, Rosengarth K et al. Structural brain changes in tinnitus: grey matter decrease in auditory and non-auditory brain areas. NeuroImage. 2009;46:213-218. [abstract]

22. Melcher JR, Levine RA, Bergevin C, Norris B. The auditory midbrain of people with tinnitus: Abnormal sound-evoked activity revisited. Hearing Research. 2009;257:63-74. [abstract]

23. Lanting CP, de KE, van DP. Neural activity underlying tinnitus generation: Results from PET and fMRI. Hearing Research. 2009;255:1-13. [abstract]

24. Kaltenbach JA. Insights on the origins of tinnitus: an overview of recent research. Hearing Journal. 2009;62:26-31. [Full text]

25. Shulman A, Goldstein B, Strashun AM. Final common pathway for tinnitus: theoretical and clinical implications of neuroanatomical substrates. International Tinnitus Journal. 2009;15:5-50. [abstract]

26. Schutte NS, Noble W, Malouff JM, Bhullar N. Evaluation of a model of distress related to tinnitus. International Journal of Audiology. 2009;48:428-432. [abstract]

27. Hesser H, Pereswetoff-Morath CE, Andersson G. Consequences of controlling background sounds: the effect of experiential avoidance on tinnitus interference. Rehabilitation Psychology. 2009;54:381-390.[abstract]

28. Argstatter H, Krick C, Bolay HV. Music therapy for chronic tinnitus. Heidelberg treatment model. Psychotherapeut. 2009;54:17-26. [abstract]

29. Lugli M, Romani R, Ponzi S, Bacciu S, Parmigiani S. The windowed sound therapy: A new empirical approach for an effective personalized treatment of tinnitus. International Tinnitus Journal. 2009;15:51-61.[abstract]

30. Langguth B, Salvi R, Elgoyhen AB. Emerging pharmacotherapy of tinnitus. Expert Opinion on Emerging Drugs. 2009;14:687-702. [abstract]

31. Campbell KCM. Emerging pharmacologic treatments for hearing loss and tinnitus. ASHA Leader. 2009;14:14-18. [Full text]

32. Hesser H, Westin V, Hayes SC, Andersson G. Clients' in-session acceptance and cognitive defusion behaviors in acceptance-based treatment of tinnitus distress. Behaviour Research & Therapy. 2009;47:523-528. [abstract]

33. Hesser H, Andersson G. The role of anxiety sensitivity and behavioral avoidance in tinnitus disability. International Journal of Audiology. 2009;48:295-299. [abstract]

34. Shulman A, Goldstein B. Subjective idiopathic tinnitus and palliative care: a plan for diagnosis and treatment. Otolaryngologic Clinics of North America. 2009;42:15-38. [abstract]

35. Forti S, Costanzo S, Crocetti A, Pignataro L, Del BL, Ambrosetti U. Are results of tinnitus retraining therapy maintained over time? 18-month follow-up after completion of therapy. Audiology & Neuro-Otology. 2009;14:286-289. [abstract]

36. Bessman P, Heider T, Watten VP, Watten RG. The tinnitus intensive therapy habituation program: a 2-year follow-up pilot study on subjective tinnitus. Rehabilitation Psychology. 2009;54:133-138. [abstract]

37. Gudex C, Skellgaard PH, West T, Sorensen J. Effectiveness of a tinnitus management programme: A 2-year follow-up study. BMC Ear, Nose and Throat Disorders. 2009;9. [Full text]

38. Henry J, Zaugg T, Myers P, Kendall C, Turbin M. Principles and application of educational counseling used in progressive audiologic tinnitus management. Noise and Health. 2009;11:33-48. [abstract]

1. Hazell JW, Jastreboff PJ. Tinnitus. I: Auditory mechanisms: a model for tinnitus and hearing impairment. J Otolaryngol. 1990;19:1-5. [Abstract]

2. Jastreboff PJ, Jastreboff MM. Tinnitus Retraining Therapy (TRT) as a method for treatment of tinnitus and hyperacusis patients. J Am Acad Audiol. 2000 Mar;11(3):162-77. [Abstract]

3. Marcondes RA, Sanchez TG, Kii MA, Langguth et al. Repetitive transcranial magnetic stimulation improve tinnitus in normal hearing patients: a double-blind controlled, clinical and neuroimaging outcome study. Eur J Neurol. 2009. [Epub ahead of print] ) [Abstract]

4. Cannon SC Pathomechanisms in channelopathies of skeletal muscle and brain. Annu Rev Neurosci. 2006;29:387-415. [Abstract]

5. Davies E, Knox E, Donaldson I. The usefulness of nimodipine, an L-calcium channel antagonist, in the treatment of tinnitus. Br J Audiol. 1994;28:125-129. [Abstract]

6. Baguley DM, Jones S, Wilkins I, Axon PR, Moffat DA. The inhibitory effect of intravenous lidocaine infusion on tinnitus after translabyrinthine removal of vestibular schwannoma: a double-blind, placebo-controlled, crossover study. Otol Neurotol. 2005;26:169-176. [Abstract]

Eggermont JJ. Cortical tonotopic map reorganization and its implications for treatment of tinnitus. Acta Otolaryngol Suppl. 2006;9-12. [Abstract]

Hoke ES, Muhlnickel W, Ross B, Hoke M. Tinnitus and event-related activity of the auditory cortex. Audiol Neurootol. 1998;3:300-331. [Abstract]

Mirz F, Pedersen B, Ishizu K et al. Positron emission tomography of cortical centers of tinnitus. Hear Res. 1999;134:133-144. [Abstract]

Muhlnickel W, Elbert T, Taub E, Flor H. Reorganization of auditory cortex in tinnitus. Proc Natl Acad Sci U S A. 1998;95:10340-10343. [Abstract]

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Schlee W, Hartmann T, Langguth B, Weisz N. Abnormal resting-state cortical coupling in chronic tinnitus. BMC Neurosci. 2009;10:11. [Full text]

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HIPPOCRATE'S OATH

"I swear by Apollo, the healer, Asclepius, Hygieia, and Panacea, and I take to witness all the gods, all the goddesses, to keep according to my ability and my judgment, the following Oath and agreement:

To consider dear to me, as my parents, him who taught me this art; to live in common with him and, if necessary, to share my goods with him; To look upon his children as my own brothers, to teach them this art.

I will prescribe regimens for the good of my patients according to my ability and my judgment and never do harm to anyone.

I will not give a lethal drug to anyone if I am asked, nor will I advise such a plan; and similarly I will not give a woman a pessaryto cause an abortion.

But I will preserve the purity of my life and my arts.

I will not cut for stone, even for patients in whom the disease is manifest; I will leave this operation to be performed by practitioners, specialists in this art.

In every house where I come I will enter only for the good of my patients, keeping myself far from all intentional ill-doing and all seduction and especially from the pleasures of love with women or with men, be they free or slaves.

All that may come to my knowledge in the exercise of my profession or in daily commerce with men, which ought not to be spread abroad, I will keep secret and will never reveal.

If I keep this oath faithfully, may I enjoy my life and practice my art, respected by all men and in all times; but if I swerve from it or violate it, may the reverse be my lot."

MAIMONIDE'S PRAYER

"Almighty God, Thou has created the human body with infinite wisdom. Ten thousand times ten thousand organs hast Thou combined in it that act unceasingly and harmoniously to preserve the whole in all its beauty the body which is the envelope of the immortal soul. They are ever acting in perfect order, agreement and accord. Yet, when the frailty of matter or the unbridling of passions deranges this order or interrupts this accord, then forces clash and the body crumbles into the primal dust from which it came. Thou sendest to man diseases as beneficent messengers to foretell approaching danger and to urge him to avert it.

"Thou has blest Thine earth, Thy rivers and Thy mountains with healing substances; they enable Thy creatures to alleviate their sufferings and to heal their illnesses. Thou hast endowed man with the wisdom to relieve the suffering of his brother, to recognize his disorders, to extract the healing substances, to discover their powers and to prepare and to apply them to suit every ill. In Thine Eternal Providence Thou hast chosen me to watch over the life and health of Thy creatures. I am now about to apply myself to the duties of my profession. Support me, Almighty God, in these great labors that they may benefit mankind, for without Thy help not even the least thing will succeed.

"Inspire me with love for my art and for Thy creatures. Do not allow thirst for profit, ambition for renown and admiration, to interfere with my profession, for these are the enemies of truth and of love for mankind and they can lead astray in the great task of attending to the welfare of Thy creatures. Preserve the strength of my body and of my soul that they ever be ready to cheerfully help and support rich and poor, good and bad, enemy as well as friend. In the sufferer let me see only the human being. Illumine my mind that it recognize what presents itself and that it may comprehend what is absent or hidden. Let it not fail to see what is visible, but do not permit it to arrogate to itself the power to see what cannot be seen, for delicate and indefinite are the bounds of the great art of caring for the lives and health of Thy creatures. Let me never be absent- minded. May no strange thoughts divert my attention at the bedside of the sick, or disturb my mind in its silent labors, for great and sacred are the thoughtful deliberations required to preserve the lives and health of Thy creatures.

"Grant that my patients have confidence in me and my art and follow my directions and my counsel. Remove from their midst all charlatans and the whole host of officious relatives and know-all nurses, cruel people who arrogantly frustrate the wisest purposes of our art and often lead Thy creatures to their death.

"Should those who are wiser than I wish to improve and instruct me, let my soul gratefully follow their guidance; for vast is the extent of our art. Should conceited fools, however, censure me, then let love for my profession steel me against them, so that I remain steadfast without regard for age, for reputation, or for honor, because surrender would bring to Thy creatures sickness and death.

"Imbue my soul with gentleness and calmness when older colleagues, proud of their age, wish to displace me or to scorn me or disdainfully to teach me. May even this be of advantage to me, for they know many things of which I am ignorant, but let not their arrogance give me pain. For they are old and old age is not master of the passions. I also hope to attain old age upon this earth, before Thee, Almighty God!

"Let me be contented in everything except in the great science of my profession. Never allow the thought to arise in me that I have attained to sufficient knowledge, but vouchsafe to me the strength, the leisure and the ambition ever to extend my knowledge. For art is great, but the mind of man is ever expanding.

"Almighty God! Thou hast chosen me in Thy mercy to watch over the life and death of Thy creatures. I now apply myself to my profession. Support me in this great task so that it may benefit mankind, for without Thy help not even the least thing will succeed."

Information for Health Professionals

Information for Patients

Modern challenged parts of the oath:

  1. To teach medicine to the sons of my teacher. In the past, medical schools gave preferential consideration to the children of physicians.
  2. To practice and prescribe to the best of my ability for the good of my patients, and to try to avoid harming them. This beneficial intention is the purpose of the physician. However, this item is still invoked in the modern discussions of euthanasia.
  3. I will not give a lethal drug to anyone if I am asked, nor will I advise such a plan. Physician organizations in most countries have strongly denounced physician participation in legal executions. However, in a small number of cases, most notably the U.S. states of Oregon,[10] Washington,[11]Montana,[12] and in the Kingdom of the Netherlands,[13] a doctor can prescribe euthanasia with the patient's consent.
  4. Similarly, I will not give a woman a pessary to cause an abortion. Since the legalization of abortion in many countries, the inclusion of the anti-abortion sentence of the Hippocratic oath has been a source of contention.
  5. To avoid violating the morals of my community. Many licensing agencies will revoke a physician's license for offending the morals of the community ("moral turpitude").
  6. I will not cut for stone, even for patients in whom the disease is manifest; I will leave this operation to be performed by practitioners, specialists in this art. The "stones" referred to are kidney stones or bladder stones, removal of which was judged too menial for physicians, and therefore was left for barbers (the forerunners of modern surgeons). Surgery was not recognized as a specialty at that time. This sentence is now interpreted as acknowledging that it is impossible for any single physician to maintain expertise in all areas. It also highlights the different historical origins of the surgeon and the physician.
  7. To keep the good of the patient as the highest priority. There may be other conflicting 'good purposes,' such as community welfare, conserving economic resources, supporting the criminal justice system, or simply making money for the physician or his employer that provide recurring challenges to physicians
http://www.worldallergy.org/educational_programs/world_allergy_forum/barcelona2008/rabe/

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