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1.  Comparison of Pyogenic Spondylitis and Tuberculous Spondylitis 
Asian Spine Journal  2014;8(2):216-223.
Pyogenic spondylitis and tuberculous spondylitis are common causes of spinal infection. It is difficult to differentiate tuberculous spondylitis and pyogenic spondylitis clinically and radiologically. Recently magnetic resonance imaging has been reported to be beneficial for early diagnosis and differential diagnosis of the spondylitis, and is being used extensively for diagnosis. However, the diagnosis must be considered in combination with corresponding changes in clinical manifestations, radiological findings, blood and tissue cultures and histopathological findings. Conservative treatments, including antimicrobial medications, are started initially. Surgical treatments, which include anterior or posterior approach, single-stage or two-stage surgery, with or without instrumentation, may be performed as indicated.
PMCID: PMC3996349  PMID: 24761207
Pyogenic spondylitis; Tuberous spondylitis; Differential diagnosis
2.  Atypical Noncontiguous Multiple Spinal Tuberculosis: A Case Report 
Korean Journal of Spine  2014;11(2):77-80.
Spinal tuberculosis-associated symptoms are not so unique as to immediately indicate the proper diagnosis in most cases. Distinguishing spinal tuberculosis (Pott's disease) from pyogenic spondylitis is often difficult, and lesions metastatic from systemic malignancy are the other major entity from which spinal tuberculosis must be distinguished.
Clinical Presentation
A 27-year-old male patient presented with a history of back pain after a minor trauma 1 month ago. Computed tomography and magnetic resonance imaging of the thoracic spine showed multiple osteolytic bone lesions at the bodies of T9, T10 and T11 vertebrae and the spinous processes of T12 and L1. Other noncontiguous osteolytic lesions were noted at S2 body and right sacro-iliac joint.
To confirm the pathologic diagnosis, the patient underwent an open biopsy for the T12 and L1 spinous process lesions and a percutaneous transpedicular biopsy on T9, T10, T11 lesions. Frozen biopsy was reported as compatible with chronic granulomatous caseating necrosis without malignant cells. The final diagnosis was an atypical presentation of multiple spinal tuberculosis. The patient received an appropriate enteral anti-tuberculosis therapy and recovered without any complications. Follow-up MRI taken after a year of medical treatment revealed marked resolution of the lesions.
Current research indicates the incidence of multi-level noncontiguous, remote vertebral tuberculosis is 1.1% to 16%. Because tuberculous spondylitis could represent variant and atypical pattern, the disease should be considered in differential diagnosis along with other diseases such as metastatic neoplasm, pyogenic spondylitis, especially when the radiologic studies are revealing multiple spinal lesions.
PMCID: PMC4124923  PMID: 25110488
Spondylitis; Spinal tuberculosis; Pott's disease
3.  Post-traumatic Back Pain Revealed as Tuberculous Spondylitis -A Case Report- 
The Korean Journal of Pain  2010;23(1):74-77.
Tuberculous spondylitis is a very rare disease, but it can result in bone destruction, kyphotic deformity, spinal instability, and neurologic complications unless early diagnosis and proper management are done. Because the most common symptom of tuberculous spondylitis is back pain, it can often be misdiagnosed. Atypical tuberculous spondylitis can be presented as a metastatic cancer or a primary vertebral tumor. We must make a differential diagnosis through adequate biopsy. A 30-year-old man visited our clinic due to back and chest pain after a recent traffic accident. About 1 year ago, he had successfully recovered from tuberculous pleurisy after taking anti-tuberculosis medication. We performed epidural and intercostal blocks but the pain was not relieved. For the further evaluation, several imaging and laboratory tests were done. Finally, we confirmed tuberculous spondylitis diagnosis with the biopsy results.
PMCID: PMC2884205  PMID: 20552079
back pain; biopsy; differential diagnosis; tuberculous spondylitis
4.  Surgical Treatment of Pyogenic Spondylitis with the Use of Freeze-Dried Structural Allograft 
Korean Journal of Spine  2014;11(3):136-144.
Radical debridement and reconstruction is necessary for surgical treatment of pyogenic spondylitis to control infection and to provide segmental stability. The authors identified 25 patients who underwent surgery for pyogenic spondylitis using freeze-dried structural allograft for reconstruction. This study aimed to evaluate and demonstrate the effectiveness and safety of a freeze-dried structural allograft during the surgical treatment of pyogenic spondylitis.
From January 2011 to May 2013, we retrospectively reviewed 25 surgically treated patients of pyogenic spondylitis. Surgical techniques used were anterior radical debridement and reconstruction with a freeze-dried structural allograft and instrumentation. In these 25 patients, we retrospectively examined whether the symptoms had improved and the infection was controlled after surgery by evaluating laboratory data, clinical and radiological outcomes. The average follow-up period was 15.7 months (range, 12.2-37.5 months).
The infection resolved in all of the patients and there were no cases of recurrent infection. The mean Visual Analog Scale score was 6.92 (range, 5-10) before surgery and 1.90 (range, 0-5) at the time of the last follow-up. Preoperatively, lower extremity motor deficits related to spinal infection were noted in 10 patients, and they improved in 7 patients after surgery. Follow-up computed tomographic scans were obtained from 10 patients, and osseous union between the vertebral body and the structural allograft was achieved in 2 patients.
The freeze-dried structural allograft can be a safe and effective alternative for surgical treatment of pyogenic spondylitis, and another option for vertebral reconstruction instead of using the other materials.
PMCID: PMC4206958  PMID: 25346759
Spondylitis; Allografts
5.  The evaluation of the clinical, laboratory and the radiological findings of the fifty-five cases diagnosed with tuberculous, Brucellar and pyogenic spondylodiscitis 
In this study, the evaluation of the clinical, laboratory and radiological findings belonging to 55 cases that were hospitalized in our clinic to be followed-up and were diagnosed with tuberculous, brucellar and pyogenic spondylodiscitis (SD) was aimed.
Materials and Methods:
The cases with SD were evaluated retrospectively. Hematological, serological, biochemical laboratory tests and imaging technics were used for diagnosis.
Of 55 cases aged ranging between 25 to 79, 33 (59%) were female. The cases with tuberculous SD (TBSD), brucellar SD (BSD) and pyogenic SD (PSD) were found in 24 (43%), 12 (21%) and in 19 (34%) patients. Erytrocyte sedimentation rate, increased C-reactive protein, and leucocytosis were present in 51 (91%), 22 (39%) and 8 (14%) cases. The number of the cases with history of previous surgery or trauma was 14 (25%). Diagnosis of TBSD was established by acid fast bacilli positiveness and Löwenstein Jensen culture positiveness, in two and seven patients, respectively. While all 12 cases with BSD had positive standard tube aglutination test, only 3 (25%) had hemoculture positivity. In PSDs, diagnosis was confirmed with culture positivity in 9 of 19 cases.Of the cases in our study, 89% responded to medical treatment while three required surgery and three died (5.5% and 5.5%, respectively).
SD may develop secondary to infections or following spinal surgical procedures and traumas. Also, the importance of endemicity should be kept in mind, beside the helpful diagnostic findings while treatment regulation.
PMCID: PMC3271606  PMID: 22346185
Brucellosis; pyogenic spondylodiscitis; spondylodiscitis; tuberculosis; vertebral osteomyelitisIntroduction
6.  Microbiology and Epidemiology of Infectious Spinal Disease 
Infectious spinal disease is regarded as an infection by a specific organism that affects the vertebral body, intervertebral disc and adjacent perivertebral soft tissue. Its incidence seems to be increasing as a result of larger proportion of the older patients with chronic debilitating disease, the rise of intravenous drug abuser, and the increase in spinal procedure and surgery. In Korea, studies assessing infectious spinal disease are rare and have not been addressed in recent times. The objectives of this study are to describe the epidemiology of all kind of spinal infectious disease and their clinical and microbiological characteristics as well as to assess the diagnostic methodology and the parameters related to the outcomes.
A retrospective study was performed in all infectious spinal disease cases presenting from January 2005 to April 2010 to three tertiary teaching hospitals within a city of 1.5 million in Korea. Patient demographics, risk factors, clinical features, and outcomes were assessed. Risk factors entailed the presence of diabetes, chronic renal failure, liver cirrhosis, immunosuppressants, remote infection, underlying malignancy and previous spinal surgery or procedure. We comparatively analyzed the results between the groups of pyogenic and tuberculous spinal infection. SPSS version 14 statistical software was used to perform the analyses of the data. The threshold for statistical significance was established at p<0.05.
Ninety-two cases fulfilled the inclusion criteria and were reviewed. Overall, patients of tuberculous spinal infection (TSI) and pyogenic spinal infection (PSI) entailed 20 (21.7%) and 72 (78.3%) cases, respectively. A previous spinal surgery or procedure was the most commonly noted risk factor (39.1%), followed by diabetes (15.2%). The occurrence of both pyogenic and tuberculous spondylitis was predominant in the lumbar spine. Discs are more easily invaded in PSI. At initial presentation, white cell blood count and C-reactive protein levels were higher in PSI compared to TSI (p<0.05). Etiological agents were identified in 53.3%, and the most effective method for identification of etiological agents was tissue culture (50.0%). Staphyococcus aureus was the most commonly isolated infective agent associated with pyogenic spondylitis, followed by E. coli. Surgical treatment was performed in 31.5% of pyogenic spondylitis and in 35.0% of tuberculous spondylitis cases.
Many previous studies in Korea usually reported that tuberculous spondylitis is the predominant infection. However, in our study, the number of pyogenic infection was 3 times greater than that of tuberculous spinal disease. Etiological agents were identified in a half of all infectious spinal disease. For better outcomes, we should try to identify the causative microorganism before antibiotic therapy and make every effort to improve the result of culture and biopsy.
PMCID: PMC4185315  PMID: 25289121
Spondylitis; Osteomyelitis; Pyogenic; Tuberculosis; Spinal infection
7.  Safety and Efficacy of Pedicle Screws and Titanium Mesh Cage in the Treatments of Tuberculous Spondylitis of the Thoracolumbar Spine 
Asian Spine Journal  2008;2(2):64-73.
Study Design
This is a retrospective series.
We wanted to analyze the safety and effectiveness of using the newer generation metallic implants (pedicle screws and/or titanium mesh) for the treatment of tuberculous spondylitis.
Overview of the Literature
There have been various efforts to prevent the development of a kyphotic deformity after the treatment of tuberculous spondylitis, including instrumentation of the spine. Pedicle screws and titanium mesh cages have become more and more popular for treating various spinal problems.
Twenty two patients who had tuberculous spondylitis were treated with anterior radical debridement and their anterior column of spine was supported with a tricortical iliac bone graft (12 patients) or by mesh (10 patients). Supplementary posterior pedicle screw instrumentation was performed in 17 of 22 patients. The combination of surgeries were anterior strut bone grafting and posterior pedicle screws in 12 patients, anterior titanium mesh and posterior pedicle screws in 5 patients and anterior mesh only without pedicle screws in 5 patients. The patients were followed up with assessing the laboratory inflammatory parameters, the serial plain radiographs and the neurological recovery.
The erythrocyte sedimentation rate and C-reactive protein levels were eventually normalized and there was no case of persistent infection or failure to control infection in spite of a mettalic implant in situ. The overall correction of kyphotic deformity was initially 8.9 degrees, and the loss of correction was 6.2 degrees. In spite of some loss of correction, this technique effectively prevented clinically significant kyphotic deformity. The preoperative Frankel grades were B for 1 patient, C for 4, D for 4 and E for 13. At the final follow-up, 7 of 9 patients recovered completely to Frankel grade E and only two patients showed a Frankel grade of D.
Stabilizing the spine with pedicle screws and/or titanium mesh in patients with tubercuous spondylitis effectively prevents the development of kyphotic deformity and this did not prevent controlling infection when this technique was combined with radical debridement and anti-tuberculous chemotherapy.
PMCID: PMC2852092  PMID: 20404959
Tuberculous spondylitis; Pedicle screw; Titanium mesh
8.  A Clinical Analysis of Surgical Treatment for Spontaneous Spinal Infection 
The purpose of the study was to determine the clinical effects of anterior radical debridement on a series of patients with spontaneous spinal infection.
We retrospectively analyzed the clinical characteristics of 32 patients who underwent surgical treatment from January 2000 to December 2005 in our department. The average follow-up Period was 33.4 months (range, 6 to 87 months). Thirty-two patients presented with the following : 23 cases with pyogenic spondylitis, eight with tuberculous spondylitis and one with fungal spondylitis. The indications for surgery were intractable pain, failure of medical management, neurological impairment with or without an associated abscess, vertebral destruction causing spinal instability and/or segmental kyphosis.
The study included 15 (46.9%) males and 17 (53.1%) females ranging in age from 26 to 75 years (mean, 53.1 years). Diabetes mellitus (DM) and pulmonary Tbc were the most common predisposing factors for pyogenic spondylitis and tuberculous spondylitis. Staphylococcus aureus (13%) was the main organism isolated. The most prevalent location was the lumbar spine (75%). Changes in the pain score, Frankel's classification, and laboratory parameters demonstrated a significant clinical improvement in all patients. However, there were recurrent infections in two patients with tuberculous spondylitis and inappropriate debridement and intolerance of medication and noncompliance. Autologous rib, iliac bone and allograft (fibular) were performed in most patients. However, 10 patients were grafted using a titanium mesh cage after anterior radical debridement. There were no recurrent infections in the 10 cases using the mesh cage with radical debridement.
The findings of this study indicate that surgery based on appropriate surgical indications is effective for the control of spinal infection and prevention of recurrence with anterior radical debridement, proper drug use and abscess drainage.
PMCID: PMC2588210  PMID: 19096563
Spinal infection; Spinal instrumentation; Surgical mesh
9.  Tuberculous Spondylitis after Percutaneous Vertebroplasty: Misdiagnosis or Complication? 
Korean Journal of Spine  2013;10(2):97-100.
So far, there have been few previous reports of tuberculous spondylitis occurring after percutaneous vertebroplasty. We report an unusual case of tuberculous spondylitis diagnosed after percutaneous vertebroplasty in a patient who had a history of pulmonary tuberculosis for the first time. A 58-year-old woman, who had a history of complete recovery from pulmonary tuberculosis six years previously, was hospitalized due to severe back pain after a fall. Radiological studies revealed a fresh compression fracture at the T12 thoracic vertebra. The back pain improved dramatically, and the patient was discharged two days after the vertebroplasty. However, cold sweats and a low grade fever with severe back pain developed four weeks after the procedure. Magnetic resonance imaging revealed a severe kyphosis and the T11-T12 disc space had collapsed with heterogeneous signal intensity. The results of the culture of the biopsy specimens were negative, and did not lead to identification of the causative micro-organism. However, the polymerase chain reaction for Mycobacterium tuberculosis was positive. Treatment for tuberculous spondylitis was started and she underwent posterior fusion and instrumentation from T9-L2 after the markers for infection returned to normal. After surgical intervention, the pain improved and the kyphotic deformity was corrected.
PMCID: PMC3941724  PMID: 24757469
Tuberculous spondylitis; Percutaneous vertebroplasty
10.  Diagnostic Accuracy of Quantitative PCR (Xpert MTB/RIF) for Tuberculous Meningitis in a High Burden Setting: A Prospective Study 
PLoS Medicine  2013;10(10):e1001536.
Vinod Patel and colleagues evaluate the sensitivity and specificity of quantitative PCR using Xpert MTB/RIF for diagnosis of TB meningitis in the high-burden setting of South Africa.
Please see later in the article for the Editors' Summary
Tuberculous meningitis (TBM) is difficult to diagnose promptly. The utility of the Xpert MTB/RIF test for the diagnosis of TBM remains unclear, and the effect of host- and sample-related factors on test performance is unknown. This study sought to evaluate the sensitivity and specificity of Xpert MTB/RIF for the diagnosis of TBM.
Methods and Findings
235 South-African patients with a meningeal-like illness were categorised as having definite (culture or Amplicor PCR positive), probable (anti-TBM treatment initiated but microbiological confirmation lacking), or non-TBM. Xpert MTB/RIF accuracy was evaluated using 1 ml of uncentrifuged and, when available, 3 ml of centrifuged cerebrospinal fluid (CSF). To evaluate the incremental value of MTB/RIF over a clinically based diagnosis, test accuracy was compared to a clinical score (CS) derived using basic clinical and laboratory information.
Of 204 evaluable patients (of whom 87% were HIV-infected), 59 had definite TBM, 64 probable TBM, and 81 non-TBM. Overall sensitivity and specificity (95% CI) were 62% (48%–75%) and 95% (87%–99%), respectively. The sensitivity of Xpert MTB/RIF was significantly better than that of smear microscopy (62% versus 12%; p = 0.001) and significantly better than that of the CS (62% versus 30%; p = 0.001; C statistic 85% [79%–92%]). Xpert MTB/RIF sensitivity was higher when centrifuged versus uncentrifuged samples were used (82% [62%–94%] versus 47% [31%–61%]; p = 0.004). The combination of CS and Xpert MTB/RIF (Xpert MTB/RIF performed if CS<8) performed as well as Xpert MTB/RIF alone but with a ∼10% reduction in test usage. This overall pattern of results remained unchanged when the definite and probable TBM groups were combined. Xpert MTB/RIF was not useful in identifying TBM among HIV-uninfected individuals, although the sample was small. There was no evidence of PCR inhibition, and the limit of detection was ∼80 colony forming units per millilitre. Study limitations included a predominantly HIV-infected cohort and the limited number of culture-positive CSF samples.
Xpert MTB/RIF may be a good rule-in test for the diagnosis of TBM in HIV-infected individuals from a tuberculosis-endemic setting, particularly when a centrifuged CSF pellet is used. Further studies are required to confirm these findings in different settings.
Please see later in the article for the Editors' Summary
Editors' Summary
Worldwide, tuberculosis (TB) is the leading cause of death among people living with HIV. The risk of developing TB is estimated to be 12–20 times greater in people with HIV than in people without HIV. The World Health Organization reported that, in 2011, there were 8.7 million new cases of TB, of which 1.1 million were among people living with HIV. TB infection in people living with HIV is a major problem in sub-Saharan Africa, where up to 80% of individuals infected with TB are also infected with HIV.
TB is caused by a bacterial infection spread through the air from one person to another when the infected person coughs or sneezes, for example. It usually affects the lungs, but it can also affect other parts of the body including the brain, where it leads to meningitis. People with meningitis caused by TB are often seriously ill. Many may develop brain damage, and 30% will die, particularly if they aren't diagnosed quickly and treatment is delayed. TB meningitis is therefore a serious health concern in countries with high rates of HIV and TB co-infection.
Why Was This Study Done?
There is currently no simple test to diagnose TB meningitis. The tests that are available detect only about 50% of cases. They are expensive and practical to use only in a high-tech environment, and are therefore unsuitable for low-income countries.
Recently, a new test has become available to detect TB, known as Xpert MTB/RIF. The test is used to detect the DNA (the molecular biological instructions for each organism) of the bacteria that causes TB. It is accurate at detecting TB lung infection, requires minimal training to operate, and is relatively inexpensive. It is now being used to diagnose TB in countries with high rates of the disease, including South Africa. However, thus far its use has been limited to detecting the TB bacterium in sputum samples (a mixture of saliva and phlegm) from people with a lung infection. The few studies that have assessed whether the test can be used to detect TB meningitis have been small and inconclusive.
This study was carried out to determine whether Xpert MTB/RIF could be used to detect TB bacteria in the cerebrospinal fluid (the fluid that surrounds the brain and spinal cord) in people with TB meningitis. The researchers wanted to find out whether the test would be sensitive (correctly identifying patients with TB meningitis) and specific (correctly identifying patients without TB meningitis). They also wanted to address more practical questions such as how much cerebrospinal fluid needs to be collected and how the sample needs to be processed to ensure accurate results.
What Did the Researchers Do and Find?
The researchers used the Xpert MTB/RIF test to analyze cerebrospinal fluid samples from 204 patients with suspected TB meningitis. These patients were recruited from hospitals in South Africa between January 2008 and December 2011.
Standard diagnostic tests were used to categorize these patients as either definitely having TB meningitis, possibly having TB meningitis, or not having TB meningitis. Among patients infected with HIV, the Xpert MTB/RIF correctly identified 62% of those with TB meningitis and 95% of those without TB meningitis.
The researchers also assessed whether it would be more cost-effective to use the test only for cases where the standard diagnostic procedure was uncertain, i.e., to avoid testing in cases where TB meningitis was very likely following the normal clinical assessment. Based on the researchers' theoretical analysis, this would reduce test use by only about 10%.
What Do These Findings Mean?
This study suggests that Xpert MTB/RIF is a useful diagnostic test for TB meningitis in patients infected with HIV living in areas where there are high levels of TB infection. It is not known how well the test would perform in places where TB levels are low, and the test did not perform well in individuals without HIV, although there were very few of these patients. The Xpert MTB/RIF test correctly identified more positive cases than the other tests used to diagnose TB meningitis, within 24 hours of first seeing a patient. However, the test accuracy was best when the cerebrospinal fluid sample was centrifuged (spinning the sample very fast to concentrate the test material) to achieve the best results. This means additional apparatus would be required, resulting in higher cost and requiring more training. The researchers conclude that this test could still be useful in settings where resources are limited.
There are also important questions that remain unanswered. This study shows only that the Xpert MTB/RIF test is useful in determining that a patient has TB meningitis. It is not useful in determining that a patient does not have TB meningitis. Further research is needed to determine whether the test will be effective in areas with lower rates of TB, as well as whether its use will improve clinical practice and ultimately lead to better outcomes for patients. The hope is that the test will result in more rapid diagnosis and faster treatment, reducing the number of avoidable deaths from TB meningitis.
Additional Information
Please access these websites via the online version of this summary at
• This study is further discussed in a PLOS Medicine Perspective by David Boulware
• The US National Institutes of Health provides information on TB meningitis
• The World Health Organization provides information on tuberculosis and HIV
• The US Centers for Disease Control and Prevention has a factsheet on HIV and TB
• also provides information about HIV and TB
PMCID: PMC3805498  PMID: 24167451
11.  Delayed Diagnosis of Tuberculous Spondylitis Masked by Concomitant Methicillin Resistant Staphylococcus Aureus Infection 
We present a case of tuberculous spondylitis in which diagnosis was masked by a concomitant pyogenic infection. The patient had undergone percutaneous needle aspiration of an abscess in the cavity of the psoas muscle. Early results from the culture regimen showed isolation of methicillin-resistant Staphylococcus aureus. After eight weeks, mycobacterium tuberculosis was grown at regimen which was cultured at the same site. Initial isolation of pyogenic bacteria, considered to be highly virulent organisms, led to delayed diagnosis and treatment of the tuberculosis.
PMCID: PMC2851091  PMID: 20379481
Tuberculous spondylitis; Pyogenic spondylitis; Concomitant infection
12.  Pyogenic, tuberculous, and brucellar vertebral osteomyelitis: a descriptive and comparative study of 219 cases 
Annals of the Rheumatic Diseases  1997;56(12):709-715.
OBJECTIVES—To describe a large series of patients with vertebral osteomyelitis (VO), and to compare the clinical, biological, radiological, and prognostic features of pyogenic (PVO), tuberculous (TVO), and brucellar vertebral osteomyelitis (BVO).
METHODS—A retrospective multicentre study, which included 219 adult patients with VO with confirmed aetiology, who were diagnosed between 1983 and 1995 in two tertiary care centres. Of these patients, 105 (48%) had BVO, 72 (33%) PVO, and 42 (19%) TVO.
RESULTS—One hundred and forty eight (67.6%) patients were male and 71 (32.4%) female. The mean (SD) age was 50.4 (16.4) years (range 14-84) and the mean (SD) duration of symptoms before the diagnosis was 14 (16.8) weeks. In 127 patients (57.9%) the vertebral level involved was lumbar, in 70 (31.9%) thoracic, and in 16 (7.3%) cervical. One hundred and nineteen patients (54.4%) received only medical treatment and 100 (45.6%) required both medical and surgical treatment. The presence of diabetes mellitus, intravenous drug abuse, underlying chronic debilitating diseases or immunosuppression, previous infections, preceeding bacteraemia, recent vertebral surgery, leucocytosis, neutrophilia, and increased erythrocyte sedimentation rate (ESR) were significantly associated to PVO. A prolonged clinical course, thoracic segment involvement, absence of fever, presence of spinal deformity, neurological deficit, and paravertebral or epidural masses, were significantly more frequent in the group of TVO. The need for surgical treatment and the presence of severe functional sequelae were more frequent in the groups of PVO and TVO.
CONCLUSION—There are significant clinical, biological, radiological, and prognostic differences between BVO, PVO, and TVO. These differences can point to the causal agent and orient the initial empirical medical treatment while awaiting a final microbiological diagnosis.

PMCID: PMC1752312  PMID: 9496149
13.  Imaging findings of Pott’s disease 
European Spine Journal  2012;22(Suppl 4):567-578.
Tuberculosis (TB) continues to be an important public health problem in developed countries especially in deprived socioeconomic groups, older people, immunocompromised patients, drug-therapy resistant cases and the immigrant population. The spine is the most frequent location of musculoskeletal TB. The wide range of clinical presentations results in difficulties and delays in diagnosis. Advanced disease mimics other infections and malignancy. The diagnosis of spinal infections relies on three main factors: clinical symptoms, imaging and bacteriological culture. Advanced imaging such as Magnetic Resonance Imaging (MRI), Multidetector Computed Tomography (MDCT) and Fluor18-Deoxiglucose Positron Emission Tomography combined with CT (F-18 FDG PET–CT) demonstrate lesion extent, serve as guide for biopsy with aspiration for culture, assist surgery planning and contribute to follow-up. Diagnosis of TB cannot be established solely on the basis of clinical tests or imaging findings and biopsy may be required. Differential diagnosis between tuberculous and pyogenic spondylitis is of clinical importance, but may be difficult on the basis of radiological findings alone. Findings not pathognomonic but favoring tuberculous etiology include: slow progression of lesions with late preservation of disk space, involvement of several contiguous segments, large intraosseous and paraspinal abscesses containing calcifications, and body collapse with kyphotic deformity. In this essay the highlights of TB imaging are reviewed through published literature. In addition, we review retrospectively the radiological findings of 48 patients with tuberculous spondylitis treated from 1993 to 2010. There were 23 male and 25 female patients with a mean age of 53 years.
PMCID: PMC3691403  PMID: 22684257
Tuberculosis; Spinal infection; Imaging modalities; Imaging-guided percutaneous biopsy
14.  Simultaneous Anterior and Posterior Surgery in the Management of Tuberculous Spondylitis with Psoas Abscess in Patients with Neurological Deficits 
Asian Spine Journal  2008;2(2):94-101.
Study Design
This is a retrospective study.
We wanted to evaluate the treatment outcomes of performing simultaneous anterior and posterior surgery for patients with tuberculous spondylitis and psoas abscess.
Overview of Literature
Although various treatment options have been used for spinal tuberculosis, there are only a few reports on the treatment of tuberculous spondylitis with psoas abscess.
Between March 1997 and February 2006, we performed operations on 14 cases of tuberculous spondylitis with psoas abscess. All the cases underwent anterior debridement with an interbody bone graft and posterior fusion with using pedicle screws.
Under the Frankel classification, 1 case improved by two grades, 10 cases improved by 1 grade and 3 cases demonstrated no change. The Kirkaldy-Willis functional outcomes were classified as excellent in 10 cases and good in 4. One year after surgery, bony union was confirmed in all 14 cases. The mean kyphotic angle of the spinal lesion was 12.4° and the mean lordotic angle at the final follow-up was 6.4°. Postoperative complications (superficial wound infections) were encountered in 2 cases.
Our results demonstrate that anterior debridement with interbody bone grafting and posterior instrumented fusion can provide satisfactory results for treating tuberculous spondylitis with psoas abscess in patients with neurological deficits.
PMCID: PMC2852085  PMID: 20404963
Tuberculous spondylitis; Psoas abscess; Neurological deficit; Anterior and posterior surgery
15.  AB 85. Presentation of cases of non tuberculous mycobacteria lung disease in immunocompetent patients 
Journal of Thoracic Disease  2012;4(Suppl 1):AB85.
Nontuberculous mycobacteria (NTM) are acid-fast microorganisms that commonly cause lung disease in immunocompromised patients and patients with preexisting structural lung disease. Four cases of NTM infection in immunocompetent patients are presented.
Patients and methods: Case 1
A 62-year-old patient with clinical and radiological features compatible with tuberculosis (TB) and positive sputum smear for acid-fast bacilli was treated with first-line agents. After three months and while the patient was improving M. intracellular resistant to macrolides was identified in two culture samples. Targeted therapy was initiated 6 months after the onset of symptoms. Case 2. A 48-year-old man, already under antiTB treatment for 6 months, was evaluated due to clinical and radiological lack of improvement. Radiological findings were suggestive of TB but there was no microbiological verification. M. intracellular resistant to macrolides was identified. Targeted therapy was initiated 9 months after the onset of symptoms. Case 3. A 73-year-old patient, with history of TB 8 and 2 years ago and known resistance to rifampicin, presented with clinical findings of TB and positive sputum for acid-fast bacilli. Empirical therapy with second line antiTB agents was initiated. The negative nucleic acid amplification test for M. tuberculosis and the absence of clinical improvement led to identification of M. kansasii. Targeted therapy was initiated 3 months after the onset of symptoms. Case 4. A 60-year-old patient with bronchiectasis and a history of recurrent respiratory infections over 10 years, presented with clinical and radiological findings consistent with TB. Treatment with first-line antiTB agents was initiated without laboratory confirmation. M. avium was identified by molecular methods. Targeted therapy was initiated 1.5 months after initial evaluation, whereas the patient´s history of recurrent infections could be attributed to M. avium.
NTM can cause infection even to immunocompetent individuals without structural lung disease. NTM infection cannot be differentiated from TB based on clinical and radiological features. Therefore diagnosis is based on NTM identification by molecular methods. Therapy and prognosis are different from TB. Mycobacterial identification is an important part of the diagnostic algorithm of tuberculosis.
PMCID: PMC3537375
16.  Retroperitoneoscopic drainage of complicated psoas abscesses in patients with tuberculous lumbar spondylitis 
European Spine Journal  2011;21(3):470-473.
Nowadays, endoscopic techniques are widely used in surgical procedures. Retroperitoneoscopy has been an extremely valuable tool for a wide variety of urologic disorders, whereas, it has limited use in orthopedic procedures.
We performed retroperitoneoscopic drainage (in combination with medical treatment) of complicated psoas abscess on 12 patients with tuberculous spondylitis. All the procedures were done under general anesthesia and in the lateral decubitus position. Psoas abscess was evacuated during procedure, and postoperatively, drainage was continued through a large silastic tube. The definitive diagnosis and the treatment were made based on the results of culture-antibiogram and PCR testing.
Complete clinical and radiologic remission was observed in all patients in 3–6 months. The complication was not observed in any case postoperatively.
Retroperitoneoscopic drainage of psoas abscesses gains advantages in terms of rapid recovery, minimal invasiveness, absence of radiation, and shorter hospital stay. This procedure can be used not only for cold abscesses but also for other pathologies of lumbar vertebral area.
PMCID: PMC3296847  PMID: 22015814
Retroperitoneoscopy; Tuberculous spondylitis; Psoas abscess
17.  Anterior Debridement and Strut Graft with Pedicle Screw Fixation for Pyogenic Spondylitis 
Asian Spine Journal  2007;1(2):91-97.
Study Design
A retrospective study.
We evaluated the results of the use of anterior debridement and interbody fusion followed by posterior spinal instrumentation.
Overview of Literature
An early diagnosis of pyogenic spondylitis is difficult to obtain. The disease can be treated with various surgical methods (such as anterior debridement and bone graft, anterior instrumentation, and posterior instrumentation).
This study included 20 patients who received anterior debridement and interbody fusion with strut bone graft followed by posterior spinal fusion for pyogenic spondylitis between 1996 and 2005. We analyzed the culture studies, the correction of the kyphotic angle, blood chemistry, the bony union period, and the amount of symptom relief.
In terms of clinical symptoms relief, eight patients were grouped as "excellent", eleven patients as "good", and one patient as "fair". The vertebral body cultures were positive in 14 patients showing coagulase (-) streptococcus and S. aureus. The average times for normalization of the erythrocyte sedimentation rate and C-reactive protein level were 3.3 and 1.9 months, respectively. Four months was required for bony union. For complications, meralgia paresthetica was found in two cases.
Due to early ambulation and the correction of the kyphotic angle, anterior interbody fusion with strut bone graft and posterior instrumentation could be another favorable method for the treatment of pyogenic spondyulitis.
PMCID: PMC2857475  PMID: 20411131
Pyogenic spondylitis; Anterior interbody fusion; Posterior instrumentation
18.  Laminotomy with Continuous Irrigation in Patients with Pyogenic Spondylitis in Thoracic and Lumbar Spine 
Pyogenic spondylitis often results in acute neurological deterioration requiring adequate surgical intervention and appropriate antibiotic treatment. The purpose of this study was to conduct an analysis of the clinical effect of continuous irrigation via laminotomy in a series of patients with pyogenic spondylitis in thoracic and lumbar spine.
The authors conducted a retrospective investigation of 31 consecutive patients with pyogenic thoracic and lumbar spondylitis who underwent continuous irrigation through laminotomy from 2004 to 2008. The study included 22 men and 9 women, ranging in age from 38 to 78 years (mean 58.1 years). The average follow-up duration was 13.4 months (range, 8-34 months). We performed debridement and abscess removal after simple laminotomy, and then washed out epidural and disc space using a continuous irrigation system. Broad spectrum antibiotics were administered empirically and changed according to the subsequent culture result. Clinical outcomes were based on the low back outcome scale (LBOS), visual analogue scale (VAS) score, and Frankel grade at the last follow-up. Radiological assessment involved plain radiographs, including functional views.
Common predisposing factors included local injection for pain therapy, diabetes mellitus, chronic renal failure, and liver cirrhosis. Causative microorganisms were identified in 22 cases (70.9%) : Staphylococcus aureus and Streptococcus spp. were the main organisms. After surgery, LBOS, VAS score, and Frankel grade showed significant improvement in most patients. Spinal stability was maintained during the follow-up period, making secondary reconstructive surgery unnecessary for all patients, except one.
Simple laminotomy with continuous irrigation by insertion of a catheter into intervertebral disc space or epidural space was minimally invasive and effective in the treatment of pyogenic spondylitis. This procedure could be a beneficial treatment option in patients with thoracolumbar spondylitis combined with minimal or moderate destructive change of vertebrae.
PMCID: PMC3243837  PMID: 22200016
Irrigation; Laminotomy; Pyogenic; Spondylitis; Thoracolumbar
19.  Percutaneous Discectomy—Continuous Irrigation and Drainage for Tuberculous Lumbar Spondylitis: A Report of Two Cases 
Case Reports in Medicine  2009;2009:632981.
Percutaneous curettage and continuous irrigation were performed for definitive diagnosis and treatment of tuberculous (TB) lumbar spondylitis. Under local anaesthesia, affected lumbar discs were curetted using a procedure of percutaneous nucleotomy, and in-tube and the out-tube were placed for continuous irrigation. The period of continuous irrigation was 12–16 days. Mycobacterium tuberculosis was demonstrated in case 1 by culture and PCR, whereas histology showed tuberculous lesion with caseous necrosis in both cases. Postoperative MRI showed markedly reduced abscesses after 3 months in both cases. The signal intensity in vertebral bodies was improved. In Case 2, CT observations showed remodeling over time in the vertebral body cavities. This method is advantageous in that although minimally invasive, it achieves identification of pathogenic bacteria and treatment simultaneously. This surgical procedure is expected to prove effective for both TB and pyogenic spondylitis.
PMCID: PMC2774484  PMID: 19902008
20.  An unusual case of paradoxical enlargement of lymph nodes during treatment of tuberculous lymphadenitis in immunocompetent patient and literature review 
Female, 21
Final Diagnosis:
Tuberculous lyphadenitis
Cough dry • fever • subcutaneous mass • weight loss
Clinical Procedure:
Unusual clinical course
Enlargement of lymph nodes during treatment of Tuberculous lymphadenitis is well recognized phenomenon in HIV infected patient with ample literature to help guide management. On the contrary, it poses a clinical challenge to distinguish between paradoxical reaction and treatment failure in HIV-seronegative patients and require high index of suspicion.
Case Report:
We report a case of 21 year old female of Bangladeshi origin with tuberculous lymphadenitis diagnosed on the basis of strong clinical history and radiologic findings. Patient’s clinical symptoms and lymphadenopathy initially improved but worsened after three months of RIPE therapy. This prompted re imaging and excision biopsy of enlarging lymph node to exclude other masqueraders. Patient was continued on same antituberculous treatment. Oral prednisone was added with subsequent clinical improvement and decrease in the size of lymphadenopathy.
Paradoxical reaction during anti tuberculous treatment must be considered after careful exclusion of medication non adherence, development of resistance and other similar conditions.
PMCID: PMC3700484  PMID: 23826468
paradoxical reaction (PR); highly active anti-retroviral therapy (HAART); rifampin; isoniazid; pyrazinamide and ethambutol (RIPE); tuberculosis (TB); Kikuchi’s disease (KD); tuberculosis lymphadenitis (TL)
21.  Establishing the diagnosis of tuberculous vertebral osteomyelitis 
European Spine Journal  2012;22(Suppl 4):579-586.
The aim of this article has been to analyze the clinical and radiological data suggesting tuberculous vertebral osteomielitis (TVO), and then discuss the steps to be followed to achieve an aetiological diagnosis.
A thorough literature search was carried out to identify the best clinical and microbiological evidence for a fast and efficient diagnosis of TVO.
The clinical and radiological diagnosis of spinal tuberculosis suffers from serious limitations, with a high percentage of cases requiring vertebral biopsy to reach a definitive diagnosis. The increasing incidence of multidrug-resistant tuberculosis has highlighted the insufficiency of the histopathological diagnosis and the need for microbiological diagnosis. Unfortunately, the maximum sensitivity of spinal tuberculosis cultures is 80 %, and traditional methods require 6 to 8 weeks for the isolation, identification and sensitivity study. New culture media and identification methods have improved sensitivity and reduced the time required for the identification. Molecular methods have now been integrated into a single test, with identification of the mycobacterium responsible and its sensitivity to rifampicin. Additionally, multiplex-PCR tests have been developed that allow a rapid differential diagnosis between granulomatous spondylodiscitis.
All patients with subacute inflammatory back or neck pain showing suggestive radiological findings should be studied to rule out TVO. If there is no clear evidence of tuberculosis from another location or indication for surgery, a percutaneous vertebral biopsy should be performed. When TVO is suspected, all spinal or paravertebral tissue samples should be sent simultaneously to pathology and microbiology laboratories for appropriate processing.
PMCID: PMC3691410  PMID: 22576157
Tuberculosis; Vertebral osteomyelitis; Diagnosis; Molecular methods
22.  Role of the BACTEC radiometric method in the evaluation of patients with clinically probable tuberculous meningitis 
Confirmation of tuberculous meningitis (TBM) and initiation of treatment are often delayed due to limitations in isolating Mycobacterium tuberculosis from cerebrospinal fluid (CSF).
To evaluate the role of the BACTEC radiometric method in a clinical setting for the early diagnosis of TBM.
Materials and Methods:
Patients meeting criteria for clinically probable TBM over a 3 year period were included. Clinical features, results of CSF investigations (protein, glucose, cell count, Ziehl-Neelsen staining, culture in Löwenstein-Jensen (LJ) medium and BACTEC) and brain CT imaging were reviewed. Drug sensitivity was tested using BACTEC. Patients were started on standard treatment and functional outcome, and response at discharge and follow-up were assessed. Patients were divided according to whether or not M. tuberculosis was isolated by BACTEC and the clinical, radiological, and laboratory features compared.
Sixty patients were evaluated. The mean age was 30 years ± 11.7 years. Headache and fever were the most common symptoms and the mean duration was 26 days. CT findings were hydrocephalus (n=21), basal exudates (n=16), and tuberculoma (n=14). In 40 patients, M. tuberculosis was isolated by BACTEC and average 15 days was required for detection, whereas it was 30 days in LJ medium. Results of drug-sensitivity testing (n=32) were obtained average 7 days after isolation. Patients from whom M. tuberculosis had been isolated by BACTEC more often had tuberculomas in CT imaging (P=0.018).
Use of the BACTEC method allows early confirmation in patients with clinically probable TBM. It can guide clinicians in the rational use of anti-tuberculosis treatment by confirming diagnosis and identifying drug- sensitivity.
PMCID: PMC2924511  PMID: 20814497
Early diagnosis; tuberculous meningitis; tuberculoma; cerebrospinal fluid; culture
23.  Literature Review and Clinical Presentation of Cervical Spondylitis Due to Salmonella Enteritidis in Immunocompetent 
Asian Spine Journal  2014;8(2):206-210.
A 48-year-old woman was presented to our clinic with some fever and neck pains for about one month. Based on the symptoms and results of image, an empirical diagnosis of tuberculous cervical spondylitis was made. The pain was not significantly decreased after anti-tuberculosis therapy. And, 3 weeks later, she was re-admitted to our hospital for the unbearable pain. An exploration of the C4/5 by the anterior medial approach was recommended to evaluate the germ and debridement. Bacteriological tests showed that the pathogen was Salmonella Enteritidis. The pain was relieved significantly after operation and sensitive antibiotic treatments. Infections with Salmonella Typhi or Salmonella Paratyphi have been well-documented, while there are few reports of cervical spondylitis caused by Salmonella Enteritidis. We reported a case of a healthy woman with whom pyogenic cervical spondylitis of Salmonella Enteritidis was corroborated and treated and reviewed according to previous reports about spondylitis caused by Salmonella Enteritidis in the literature.
PMCID: PMC3996347  PMID: 24761205
Salmonella Enteritidis; Cervical vertebrae; Spondylitis; Immunocompetent
From the foregoing description of the histological changes in the leptomeninx it is quite evident that we are dealing with a chronic, stationary, healing form of tuberculous inflammation. This statement is substantiated, in the first place, by the clinical history. The only reasonable interpretation of the symptoms would establish the duration of the process as four months. The imaginable contingency that there existed first a meningeal syphilitic lesion that was dispersed by the iodide of potassium only to be followed by a tuberculous infection is so remote and unlikely that it need not be discussed. At all events the tuberculous leptomeningitis, which presented a typical distribution, began insidiously, existed at times in a latent condition, and pursued a very anomalous course, marked by a relative mildness of all the symptoms, and thus it came about that when an apparent or real improvement followed the administration of iodide of potassium able observers were induced to make an erroneous diagnosis. Death occurred as a result of an intercurrent infection. The long duration of the process is also shown, anatomically, by the thick layer of firm, translucent and gelatinous material that matted together the structures at the base, and also by the evident adhesions between the pia and the brain. The histological examination furnishes proof positive of the correctness of the conclusion in regard to the peculiar character of this process because it shows: (1) That the tuberculous proliferation is uniform in development and has reached nearly the same stage of evolution throughout the entire extent of the leptomeninx involved; it is not a process that has advanced by exacerbations and irregular extensions; the lesions are, generally speaking, of nearly the same age everywhere and must have begun at about the same time. (2) That only a very limited degree of caseous degeneration is present, pointing to an early arrest of the activity of the tubercle bacillus or to a very decided diminution or attenuation of its virulence. (3) That the subendothelial intimal proliferations of epithelioid cells, so generally found in acute tuberculous leptomeningitis,* have in this case become more or less completely changed into distinct fibrous tissue in which but very slight, if any, direct evidence of its tuberculous origin can be found. It is only by recognizing that the chronic endarteritis is most marked in correspondence with the most advanced adventitial tuberculous changes, and by finding an imperfect, much altered giant cell in one district of intimal thickening, that we were able to establish the direct kinship of the endovascular changes with those of the pia in general. (4) That acute inflammatory changes, in the form of emigration of polymorphonuclear leucocytes and of fibrinous exudation, are entirely absent in all parts of the district involved. The presence of a turbid serous fluid is of course not at all inconsistent with the view that the anatomical changes are of long duration. (5) That the granulation tissue present is, in general, undergoing fibrillation and contains a rich supply of enabryonal capillary vessels as well as of larger blood-vessels of evidently new formation. The absence of any considerable extent of polymorphonuclear leucocytic infiltration in this tissue has already been referred to. The cells in the granulation tissue correspond to the cells of embryonal or formative connective tissue. Vacuolation is rarely present. (6) That the unusually large number of giant cells present are remarkably free from evidences of necrosis and degeneration of the character ordinarily observed in tuberculous proliferations, that they do not contain in demonstrable form tubercle bacilli, and that the majority of the giant cells seem to be separating into individual cells and smaller masses often with, but sometimes also without, evidences of nuclear disintegration. The possibility that these phenomena may signify fusion instead of the sundering of cells will be discussed below. For these reasons there can be no doubt that the general claim that we are dealing with an instance of chronic, healing tuberculous meningitis must be regarded as established beyond dispute. The growth of tubercle bacilli in the glycerine-agar tubes, inoculated with the fluid from the pial meshes, and the demonstration of tubercle bacilli, though in very small numbers, between the cells of the embryonal tissue, furnish the positive evidence that we are actually dealing with a tuberculous process due to living and not to dead bacilli. The degree of virulence of the cultures of tubercle bacilli was, unfortunately perhaps, not studied. The presence of living tubercle bacilli in a tissue free from active and acute changes characteristic of tuberculosis demonstrates that, whatever the actual degree of virulence of the bacilli may have been, the tissue in which they were found was at this time relatively immune from their action. The manner in which this immunity was produced, and in which the process of healing was initiated, need not be discussed at this time any further than to again direct attention to the fact that the bacilli lost their virulency as regards the cells in this leptomeninx before these cells underwent any marked degree of degeneration. The cells of the tuberculous proliferations survived the further action of the bacilli whose original effect it was to initiate cell accumulation or proliferation; the cells also retained sufficient vitality to develop, in some instances at any rate, into formative cells according as their origin would dictate, e. g. into fibroblasts. That fibroblasts are formed only by embryonal connective tissue cells, and not by wandering cells, such as the large mononuclear leucocytes, we are well aware, is possibly still a disputable assumption, and we do not consider it pertinent to discuss the question any further in connection with this study, but would only emphasize the point that some of the cells of tuberculous proliferations may, under favorable circumstances, become formative cells, and, furthermore, that the amount of formative tissue produced may be far in excess of what is actually needed for purposes of repair only. Surely the appearances here noted indicate that the bacillus of tuberculosis has the power to stimulate fixed cells to multiply, unless one assumes that all, or almost all, the formative cells here seen are derived from wandering cells attracted by the presence of the bacillus and its products. As to the ultimate fate of the formative and other cells in this healing tuberculous tissue no final statements can be made. It must be remembered that it is only one stage in the process of healing that is dealt with. The well marked evidences of fibrillation, the quite extensive formation of new vessels, the absence of evidences of degenerative changes in the uninuclear cells, all point to the production of new fibrous tissue as sure to occur, but it seems quite probable that occasional epithelioid cells may undergo or have undergone dropsical or other forms of degeneration, although it is certainly apparent that so far as the small cells are concerned the involution of the tuberculous tissue is not occurring through disintegration. Perhaps the most interesting feature in this case is the opportunity it affords to study the changes in the giant cells of healing, non-degenerated tuberculous tissue. In the first place, the large number of giant cells is quite remarkable. The general characters of the tissue in which they are found recall the fact that giant cells are regarded as quite constant elements in chronic mild tuberculosis; often the giant cells are the only cells that contain bacilli (Koch). In this instance the giant cells do not contain bacilli that are demonstrable by the usual methods; neither do they contain bodies that can be definitely interpreted as degenerate forms of bacilli such as those found by Metchnikoff, Stchastny, Weicker, and others, in the giant cells of Spermophilus guttatus, in avian and in human tuberculosis. Metchnikoff states, however, that he knows of the occurrence of such degenerate forms only in the Spermophilus guttatus under the circumstances mentioned, and in the rabbit and guinea-pig in mammalian tuberculosis, but not in man; consequently, the manner in which the giant cells rid themselves of the bacilli undoubtedly present in their interior at some time during their existence, must as yet remain without any explanation. In the description of the histological changes the various appearances presented by the giant cells are described somewhat minutely. The essential observations made concern, in my opinion, the further fate of giant cells which are still found to persist in healing nondegenerated tuberculous tissue. It was, I believe, quite conclusively shown that the consecutive changes appear to consist in the breaking up of the nuclei, the removal of the detritus by phagocytes, and the formation of a few apparently viable uninuclear cells in the case of more degenerated, exhausted giant cells, while other, and, as it would seem, better preserved or younger giant cells, separate into a number of individual, uninuclear cells with but little or no nuclear disintegration. Objection might be raised to this interpretation of the appearances in the giant cells. While no one could very well dispute the view that part of the giant cells are undergoing retrogressive and absorptive changes with the production of some viable cells, a question might well be raised concerning the nature of the process taking place in those giant cells that have been spoken of as splitting up or dividing into uninuclear cells and smaller multinucleated masses without much evidence of nuclear disintegration. It might be claimed that the process is one of fusion of many cells to form giant cells, and not one of division of fully formed giant cells into small cells. But a broad view of the processes described speaks against fusion. In the first place we are not dealing with a stage of tuberculous proliferation (Baumgarten), or cell accumulation (Metchnikoff), in which one would look for the production of giant cells, no matter which view concerning the histogenesis of tubercle be assumed as the correct one, because it has been demonstrated that, from whichever point of view the lesions are examined, the same positive conclusion that they are in the process of healing is reached; there is, therefore, no occasion for the formation of new giant cells in such wide-spread degree throughout the district involved. It might he claimed that the cells became arrested and, as it were, fixed in the act of fusion which was taking place in the early stage of the meningitis, but it would be difficult to understand the nature of the stimulus that could hold the cells together in such a peculiar manner for such a long time. It must be remembered that bacilli or bacillary detritus could not be found among the incomplete or in the complete giant cells. In the second place the difference between the cells that are undergoing disintegration and those regarded as dividing is essentially, to a certain extent at any rate, one of degree, because in the first instance there is not much, if any, doubt but that viable smaller cells are also formed, and in the second instance some, though often very slight, evidence of nuclear fragmentation is nearly always present; it would also be correct to infer that in advanced subdivision of a giant cell much, and perhaps all, of the nuclear detritus produced might have been removed up to the last trace; finally, the two extremes of these changes in the giant cells are connected by transition stages passing by gradation from the one to the other. Hence it is justifiable to conclude, for the time being, that in healing non-degenerated tuberculous tissue, the multinucleated giant cells may in part disintegrate and undergo absorption, in part form viable small cells; that both these changes may, and usually do, affect the same cell, but that in one class of cells—presumably the older or the more exhausted—the retrogressive process is predominant, while in a second class of cells—presumably the young and vigorous—the progressive changes are the more marked. In this connection it may be pointed out that while there cannot very well be any question but that we are dealing only with dividing and not coalescing cells, yet if this conclusion should be disputed and found incorrect, then the only remaining alternative would be to infer that this tissue furnished a unique and striking example of the formation of plasmodial masses by fusion in human tuberculosis, a conclusion to which many pathologists would refuse to subscribe, if for no other reason than because it is not in accordance with the almost universally accepted teachings of Baumgarten and Weigert in regard to the mode of formation of the giant cells in tuberculosis. Believing as I do that the giant cells under consideration are in the act of division and not at all of fusion, there remain to be discussed some of the histological and other features presented by the dividing cells. Many of the giant cells, perhaps the majority, contain larger and smaller vacuoles in the protoplasm. The exact significance of this vacuolation is not always clear. When the vacuolation accompanies an evident solution of the nucleus (karyolysis), there cannot be any doubt but that we are in the presence of a distinctly retrogressive process. Vacuoles are also most numerous in the giant cells that present other evidences of degeneration, such as coarseness of the granules in the protoplasm and extensive nuclear disintegration, but they occur as well around nuclei that stain deeply, around cells that seem to be separating from the giant cell, and even about nuclei that present mitoses. The formation of vacuoles seems to be responsible, to a certain extent at any rate, for the diminution in the volume of disintegrating and dividing giant cells, as shown by the clear spaces that form about them; these spaces are too large and occur too uniformly to be attributed solely to artificial shrinking produced by the hardening in alcohol. Further undoubted evidence of retrogression in certain giant cells is the occurrence of nuclear disintegration, or karyorhexis, which sets free larger and smaller chromatin masses that are recognized in the giant cell as well as in the interior of the phagocytes usually found around such cells. Almost all the polymorphonuclear leucocytes found in this tissue are met with around giant cells with broken-up nuclei. In many nuclei of disintegrating giant cells can be noted appearances that correspond well to certain stages in the complicated karyorhexis observed in anæmic necrosis by Schmaus and Albrecht; some of the nuclei with budding processes correspond particularly well with those in certain of their drawings; the interior of giant cells of tuberculous tissue may, it would seem, present conditions favorable to the development of this series of postnecrotic nuclear change. Vacuolation, karyolysis and karyorhexis are the essential steps that lead to destruction of the whole or parts of some of the giant cells; associated with these processes there is usually observed a splitting up of the body of the giant cell into irregular fragments with as well as without nuclei; and, as described, more or less phagocytosis of the resulting remnants of various kinds is seen. But evident degenerative and necrotic processes in a giant cell may be associated with progressive changes. While some nuclei undergo vacuolation or break up, others seem to become richer in chromatin and to stain more deeply at the same time that they seem to acquire cell bodies quite distinct from the protoplasm of the giant cells: this hyperchromatosis does not, therefore, seem to be a stage in karyorhexis. A very few but undoubted karyokinetic figures were found, together with evidences of division of the cell body formed in the giant cell protoplasm. Precisely similar changes are described by Klebs in healing pulmonary tuberculosis of the guinea-pig; the nuclei of the giant cells became rich in chromatin and karyokinetic figures occurred. Krückmann among others has found occasional mitoses in giant cells around foreign bodies, as well as elsewhere, but it would seem that such mitoses have always been interpreted as indicating the probable mode of formation of the giant cells rather than of their involution. The question of mitosis in existing multinucleated cells has recently been studied by Krompecher, who concludes that the individual nuclei of such cells may undoubtedly divide by mitosis, either simultaneously or at separate times. Division by amitosis can also occur, but mitosis is the only progressive form of division, amitosis being a retrogressive, disintegrating process that must be looked upon as an evidence of degeneration of the nucleus. Ziegler states that in division of giant cells whose nuclei have multiplied by mitosis it may happen that the separating cell remains enclosed in the protoplasm of the mother cell. A singular phase in the involution of the giant cells in this pia is to be found in the existence of progressive changes side by side with nuclear necrosis and with degeneration; this finding indicates that giant cells may contain many independent elements which, though apparently fused into one large cell, may preserve their individuality so that while some nuclei die, others proliferate and perhaps feed on the remnants of their dead brethren and form new, viable small cells. The nuclei in giant cells may be looked upon as representing independent centres, capable at times of existing even though the cell protoplasm is disintegrated. Many of the giant cells separate into individual cells, unaccompanied or unassociated with much evidence of necrosis. These cells may be regarded as the more vigorous forms. Here also are observed occasional mitoses—but on the whole extremely few—and very constantly an evident increase in the amount of chromatin in the nuclei of the new cells as compared with the amount ordinarily found in the nuclei of giant cells. These deductions concerning the persistence of the vitality of some of the nuclei, even in the presence of molecular and morphological changes in the cytoplasm and in other nuclei of the giant cell that lead to disintegration, are not entirely without the support of previous observations on cells, which, although made under different conditions, are nevertheless, it would seem, applicable to cells in general. Thus the brilliant investigations of Loeb upon the effects of various unfavorable surroundings, such as absence of oxygen or reduction of the amount of water, upon the cleavage of eggs of many kinds, show that the conditions which arrest development are qualitatively alike for nucleus and protoplasm, but quantitatively less for the protoplasm; when the irritability of the protoplasm is suspended the nucleus may segment without segmentation of the protoplasm, but upon re-establishment of favorable conditions the protoplasm may divide into about as many spheres as there are nuclei preformed—the nucleus persists, preserves the irritability of the cell and stimulates the protoplasm to segmentation. From the appearances of the giant cells here described it would seem, then, that some nuclei are able to maintain their vitality longer than others in the same cell, and under certain conditions to stimulate parts of the protoplasm to segment; in other cells all the nuclei have, as a rule, preserved their irritability. The groups of cells formed by the dividing of the giant cells can be traced by studying the process at the different stages in the different parts of the tissue. They assume an oval or spindle-shaped form, becoming more and more like the formative and endothelioid cells of young connective tissue, but their ultimate fate cannot be determined because it concerns essentially only one limited period in the involution of the tissue. It may be said with reasonable certainty, however, that the new cells do not form blood-vessels, but as regards their forming lymph-vessels nothing definite can be concluded. It would not be safe to draw any definite conclusions, from the appearances described, with regard to the origin and the mode of formation of the giant cells. The resulting small cells in general resemble very much endothelial and formative cells, but some of them are, at certain stages at any rate, not unlike large mononuclear leucocytes; their final fully developed or mature condition being unknown, no positive inference can be drawn as to their pre-giant-cell origin. The evidence points to the fact that the most probable origin of the giant cells, as indicated by their form and the apparent future career of their descendants, would be the fixed mesoblastic cells of the pia. In regard to the mode of formation of the giant cells it is quite clear that it must involve some process which is not incompatible with the viability of the small cells which may spring from the giant cells. Whether this would speak more in favor of formation by fusion than by karyokinesis of a single cell without division of the cell body cannot be well determined, and as long as authors are not agreed upon the question of the production of living, procreative cells by amitosis (direct segmentation, direct and indirect fragmentation) it would not be profitable to discuss the compatibility or incompatibility of the views of those investigators who trace the origin of giant cells to amitotic division, with the progressive changes that giant cells have been shown to be capable of. The fact that giant cells in tuberculous tissue, under certain conditions, undergo progressive changes and separate into small, living cells proves that they are not, as claimed by Baumgarten, Weigert and others, necrobiotic elements that are doomed to destruction from their very inception. On the other hand it lends more strength, if that were necessary, to the teleological view urged by Metchnikoff that they are living, defensive cells (whatever their origin may be), formed for the distinct purpose, like plasmodial masses in general, of isolating and removing foreign, harmful bodies, in this case the tubercle bacillus, and, having accomplished their object without being destroyed or exhausted, or the cause of their formation being removed or neutralized in some way, they, or their nuclei, may retain enough irritability to form a larger or smaller number of living, small, uninuclear cells.
PMCID: PMC2117963  PMID: 19866866
25.  Association of Variants at 1q32 and STAT3 with Ankylosing Spondylitis Suggests Genetic Overlap with Crohn's Disease 
PLoS Genetics  2010;6(12):e1001195.
Ankylosing spondylitis (AS) is a common inflammatory arthritic condition. Overt inflammatory bowel disease (IBD) occurs in about 10% of AS patients, and in addition 70% of AS cases may have subclinical terminal ileitis. Spondyloarthritis is also common in IBD patients. We therefore tested Crohn's disease susceptibility genes for association with AS, aiming to identify pleiotropic genetic associations with both diseases. Genotyping was carried out using Sequenom and Applied Biosystems TaqMan and OpenArray technologies on 53 markers selected from 30 Crohn's disease associated genomic regions. We tested genotypes in a population of unrelated individual cases (n = 2,773) and controls (n = 2,215) of white European ancestry for association with AS. Statistical analysis was carried out using a Cochran-Armitage test for trend in PLINK. Strong association was detected at chr1q32 near KIF21B (rs11584383, P = 1.6×10−10, odds ratio (OR) = 0.74, 95% CI:0.68–0.82). Association with disease was also detected for 2 variants within STAT3 (rs6503695, P = 4.6×10−4. OR = 0.86 (95% CI:0.79–0.93); rs744166, P = 2.6×10−5, OR = 0.84 (95% CI:0.77–0.91)). Association was confirmed for IL23R (rs11465804, P = 1.2×10−5, OR = 0.65 (95% CI:0.54–0.79)), and further associations were detected for IL12B (rs10045431, P = 5.2×10−5, OR = 0.83 (95% CI:0.76–0.91)), CDKAL1 (rs6908425, P = 1.1×10−4, OR = 0.82 (95% CI:0.74–0.91)), LRRK2/MUC19 (rs11175593, P = 9.9×10−5, OR = 1.92 (95% CI: 1.38–2.67)), and chr13q14 (rs3764147, P = 5.9×10−4, OR = 1.19 (95% CI: 1.08–1.31)). Excluding cases with clinical IBD did not significantly affect these findings. This study identifies chr1q32 and STAT3 as ankylosing spondylitis susceptibility loci. It also further confirms association for IL23R and detects suggestive association with another 4 loci. STAT3 is a key signaling molecule within the Th17 lymphocyte differentiation pathway and further enhances the case for a major role of this T-lymphocyte subset in ankylosing spondylitis. Finally these findings suggest common aetiopathogenic pathways for AS and Crohn's disease and further highlight the involvement of common risk variants across multiple diseases.
Author Summary
Ankylosing spondylitis is a common inflammatory arthritis primarily affecting the spine and pelvis. The disease is highly heritable (heritability>90%), and the major genetic allele for the disease, HLA-B27, contributes approximately half the genetic risk for the condition. Ankylosing spondylitis and inflammatory bowel disease (Crohn's disease and ulcerative colitis) frequently occur together in the same families and individuals, suggesting that they share common risk factors. We tested whether genes associated with Crohn's disease are also associated with ankylosing spondylitis and confirmed that the two diseases share associations at chromosome 1q32 near KIF21B, STAT3, IL12B, CDKAL1, LRRK2/MUC19, and chromosome 13q14. These associations were present even in ankylosing spondylitis cases with no clinical inflammatory bowel disease. These findings greatly expand our understanding of why these conditions co-occur and provide further evidence of pleiotropy in human disease pathology. As the genes IL23R, STAT3, and IL12B all influence Th17 lymphocyte differentiation/activation, this provides further evidence implicating the Th17 lymphocyte subset in the pathogenesis of ankylosing spondylitis.
PMCID: PMC2996314  PMID: 21152001

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