Differential risk of tuberculosis reactivation among anti-TNF therapies is due to drug binding kinetics and permeability.

Increased rates of tuberculosis (TB) reactivation have been reported in humans treated with TNF-α (TNF)-neutralizing drugs, and higher rates are observed with anti-TNF Abs (e.g., infliximab) as compared with TNF receptor fusion protein (etanercept). Mechanisms driving differential reactivation rates and differences in drug action are not known. We use a computational model of a TB granuloma formation that includes TNF/TNF receptor dynamics to elucidate these mechanisms. Our analyses yield three important insights. First, drug binding to membrane-bound TNF critically impairs granuloma function. Second, a higher risk of reactivation induced from Ab-type treatments is primarily due to differences in TNF/drug binding kinetics and permeability. Apoptotic and cytolytic activities of Abs and pharmacokinetic fluctuations in blood concentration of drug are not essential to inducing TB reactivation. Third, we predict specific host factors that, if augmented, would improve granuloma function during anti-TNF therapy. Our findings have implications for the development of safer anti-TNF drugs to treat inflammatory diseases.

Intramedullary tuberculoma of the Spinal Cord, Clinical features & imaging: Possibility of early diagnosis with imaging?

Involvement of vertebral column is common in tuberculosis(TB) but intramedullary tuberculomas are rare. Spinal intramedullary tuberculoma are extremely rare, seen in only 2 of 100,000 cases of TB and 2 of 1000 cases of CNS TB. Intramedullary tuberculomas normally respond well to conventional antituberculous medications, requiring surgery only occasionally. MRI is optimal diagnostic modality in intramedullary tuberculoma as it can show specific findings. This report describes a case of Intramedullary Tuberculoma of the Spinal Cord with clinical features and specific MRI findings with review of litreture.

Neurologic manifestations of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome: a case series.

BACKGROUND: Paradoxical neurologic tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a potentially life-threatening condition that occurs within 3 months after starting combination antiretroviral therapy (ART). The reports in the published literature are anecdotal, and the prevalence and outcomes of neurologic TB-IRIS are unknown. METHODS: We prospectively assessed patients with suspected TB-IRIS from June 2005 through October 2007 at our hospital in Cape Town, South Africa. We defined paradoxical TB-IRIS and paradoxical neurologic TB-IRIS with use of consensus clinical case definitions. We collected data on tuberculosis diagnosis, ART, details of TB-IRIS diagnosis, other opportunistic infections, corticosteroid use, and outcome. RESULTS: We reviewed 279 patients with suspected TB-IRIS, 54 (19%) of whom had suspected neurologic TB-IRIS, and 225 (81%) of whom had suspected non-neurologic TB-IRIS. Paradoxical TB-IRIS was diagnosed in 190 patients; 23 (12%) of these 190 patients had neurologic TB-IRIS (95% confidence interval, 7%-17%). Eight had meningitis, 7 had tuberculoma, 5 had both tuberculoma and meningitis, and 3 had radiculomyelopathy. Twenty (87%) of the 23 patients with neurologic TB-IRIS required hospital admission (median duration, 12 days; interquartile range, 6-24 days), and 21 (91%) received corticosteroids (median duration, 58 days; interquartile range, 29-86 days). Outcomes 6 months after the initial assessment for neurologic deterioration were as follows: 16 (70%) of the patients were alive (10 of these patients had documented full physical and mental recovery), 3 (13%) were dead, and 4 (17%) were lost to follow-up. CONCLUSIONS: Paradoxical neurologic TB-IRIS accounts for 12% of paradoxical TB-IRIS cases. Neurologic TB-IRIS causes considerable short-term morbidity but has reasonable long-term outcomes. Further research is needed to devise optimal diagnostic and management strategies for patients with tuberculosis who experience neurologic deterioration after starting ART.

Immune reconstitution syndrome in a patient with AIDS with paradoxically deteriorating brain tuberculoma.

A 54-year-old man with an underlying AIDS experienced fever and lethargy. Magnetic resonance imaging (MRI) showed multiple small ring-enhancement lesions over pons, basal ganglion, thalami, and bilateral cerebral hemisphere. Because of the concurrent pulmonary tuberculosis (TB), presumptive diagnosis of tuberculous meningitis and brain tuberculoma was made. The patient's condition clinically improved after a 3-month anti-TB treatment coupled with highly active antiretroviral therapy (HAART), and his CD4-T lymphocyte count was increased from 17 cells/mm(3) (HIV viral load, 294,000 copies per milliliter) to 153 cells/mm(3) (HIV viral load, 5930 copies per milliliter). However, the follow-up MRI disclosed disappearance of some old brain lesions and development of some new ones; some previously identified tuberculoma became smaller in size, while some other enlarger. Of note, ring-enhanced brain lesions were found over the left frontal lobe and left posterior fossa with perifocal edema and hyperintensity in diffusion weighted MRI indicating abscess formation. Steroid was added based on the presumed paradoxical reaction of brain tuberculoma. Complete resolution of brain lesions was found on MRI 9 months later. Tuberculoma should be considered in a patient with AIDS with numerous intracranial lesions if TB involving other site(s) is definitively diagnosed, especially when the patient is receiving prophylactic trimethoprim-sulfamethoxazole and/or serologically negative for toxoplasmosis. Our report demonstrated the peculiar phenomenon of paradoxical reaction of brain tuberculoma during immune reconstitution and strengthens the belief that additional use of steroids for paradoxical reaction of brain tuberculoma is indicated after exclusion of other causes for the progressively enlarging brain lesions.

[Pituitary tuberculosis: a case report]. / La tuberculose hypophysaire: à propos d'un cas.

Through a case of sellar and suprasellar tuberculoma which presented with central diabetes insipidus, the authors report the frequency of pituitary tuberculoma, its physiopathology, clinical presentation hormonal and radiological findings thus management and evolution. A 42 years old woman, with a history of erythema nodosum, presented with polyuria polydipsia (PUPD), amenorrhea and galactorrhea. Endocrine investigations showed central diabetes insipidus, elevated serum prolactin levels and cortisol failure. Magnetic resonance imagining scans (MRI) revealed a nodular thickening of the pituitary enlargement and loss of posterior pituitary hypointensity signal. Etiologic inquiry has removed the diagnosis of sarcoidosis, Langerhan's histosis, autoimmune hypophysitis and sellar metastasis. The history of erythema nodosum, the positivity of tuberculin skin test and the presence of koch bacillus in the bronchial fluid after culture led to a diagnosis of tuberculosis. Treatment was started with four drug antitubercular chemotherapy regimen for 2 months, and tow drug antitubercular chemotherapy regimen for 16 months. This treatment is associated with hydrocortisone, desmopressin nasal spray and bromocriptine. Under treatment, there was an improvement in clinical condition, disapearence of headache, PUPD and galactorrhea thus normalization of prolactin. A follow-up MRI, 8 months later, showed that pituitary lesion has been completely removed, suggesting our clinical and biology presumption. Pituitary tuberculosis is rare, however, when encountered, they may present a diagnostic difficulty. Accurate diagnosis and management is important because pituitary tuberculoma is curable.

Brain-stem tuberculoma. An analysis of 11 patients.

The clinical and radiologic findings in 11 patients with brain-stem tuberculoma were reviewed. Clinical manifestations included various combinations of focal signs and symptoms of subacute onset, similar to those produced by other space-occupying lesions of the brain stem. Evidence of systemic tuberculosis was found in six cases (55%). Computed tomography (CT) usually showed an isodense or hyperdense brain-stem mass with abnormal contrast enhancement; associated supratentorial granulomas were found in four cases, and hydrocephalus was found in two cases. Magnetic resonance imaging showed irregular brain-stem lesions with long T1 and short T2 relaxation times. Cerebrospinal fluid findings were also nonspecific, as smears for acid-fast bacilli were most often negative. An incorrect diagnosis of pontine glioma was made in one patient. In contrast, proper integration of data from CT and magnetic resonance imaging findings, cerebrospinal fluid analysis, and x-ray films of the chest permitted an accurate diagnosis in ten cases. Prompt therapy with antituberculous drugs resulted in clinical improvement, documented by CT, in most patients. Brain-stem tuberculoma should be suspected in patients with space-occupying lesions of the brain stem who live in geographic areas where tuberculosis is endemic. Early diagnosis and prompt medical therapy are important in preventing mortality and reducing morbidity.

Appearance of tuberculoma during the course of TB meningitis.

A patient with tuberculous meningitis is described, who developed brainstem tuberculoma after 7 months of adequate drug therapy and while improving satisfactorily. The possible factors resulting in the development of tuberculoma are discussed. The tuberculoma responded to the medical therapy. Tuberculoma should be looked for if the condition of the patient worsens or if the patient develops new neurological signs during the course of TB meningitis.

Tuberculosis of the nervous system. A clinical, radiological and pathological study of 39 consecutive cases in Riyadh, Saudi Arabia.

Thirty-seven consecutive adults and 2 children with tuberculosis of the nervous system were studied. Twenty-eight patients (72%) had intracranial or intraspinal tuberculomas and only 11 patients (28%) had tuberculous meningitis. Of the 14 patients (36%) with intracranial tuberculomas 6 presented with epilepsy of late onset including convulsive status epilepticus(2). The 6 patients with multiple tuberculomas some of which were situated in the infratentorial compartment were surprisingly free of major neurological disability of systemic disturbance. Thirteen patients (33%) presented with spinal cord compression due to tuberculoma. Eight of these had associated bony abnormalities such as collapsed vertebrae and loss of pedicles usually regarded as characteristic of malignant disease and 2 presented with clinical features of acute transverse myelitis. Eleven patients (28%) had tuberculous meningitis. One of these died, 1 had a protracted illness with gait ataxia and hydrocephalus and 1 other patient was disabled by hemiplegia, dysphasia and epilepsy but the remaining 8 recovered fully. Tuberculosis outside the nervous system was found in 13 patients (33%) in 12 (31%) of whom it was pulmonary. Acid fast bacilli were demonstrated by Ziehl-Neelsen stain in 16 patients (52%) out of 31 from whom specimens were available. Mycobacterium tuberculosis was eventually cultured from only 6 specimens. These data suggest that the clinical and radiological features of tuberculosis of the nervous system in Saudi Arabia may differ substantially from those reported from other countries. In our study there was low morbidity and low fatality rate. Two patients had infratentorial tuberculomas, and 8 patients had bony abnormalities in the vertebral column, typical of malignant disease.

Tuberculoma of the ulnar nerve: case report.

A peripheral nerve tuberculoma, the third on record, involved the ulnar nerve, as did the other two. This case report is followed by a discussion of the pathogenesis and diagnosis of this lesion. Its pathogenesis is unclear. Direct infection from a tuberculous sister was disproved, and infection via a local wound is highly unlikely. A previous, silent form of tuberculosis seems to have been the cause.

Tuberculosis of the parotid salivary gland.

An interesting and rare case of tuberculosis involving a parotid gland is discussed. Although pulmonary tuberculosis is not uncommon in Turkey, primary parotid gland involvement is rare. The patient was treated by parotidectomy and antituberculous chemotherapy.

[Radiological aspects of hepatic tuberculoma. 3 cases]. / Aspects radiologiques du tuberculome hépatique. Trois cas.

Localized macronodular tuberculosis of the liver is rare. Tuberculous involvement of the liver is usually a diffuse process. We report 3 cases in which clinical and imaging features suggested the diagnosis of macronodular hepatic tuberculoma which was pathologically confirmed by percutaneous biopsy. In the first case, abdominal CT-scan showed a noncalcified hypodense nodular lesion in segment IV of the liver with an enhancing peripheral rim. In the second case, ultrasound showed 4 homogenous hypoechoic hepatic nodules. In the third case, a nodule was incidentally identified in segment VII of the liver. The lesion was hypoechoic with ultrasound, hypodense without enhancement on CT-scan, and hyperintense on both T1- and T2-weighted MR imaging. After percutaneous biopsy, pathologic examination showed peripheral granulomous lesions in all patients with central caseous necrosis consistent with tuberculosis in two patients despite a negative for Zielh stain. Specific M. tuberculosis culture was positive in the first patient, negative in the second patient, and was not performed in the third patient. Appropriate treatment resulted in disappearance of hepatic lesions on follow-up imaging examinations. These 3 cases show that clinical and imaging features of hepatic tuberculoma are not specific and that percutaneous biopsy of lesions provides a definite diagnosis.

Intracranial tuberculoma.

In North America, central nervous system involvement by tuberculosis is uncommon. This patient review describes the clinical and radiological features of this unusual neurologic lesion. Special emphasis is given to the methods of arriving at the correct diagnosis, to the efficacy of combination antituberculous therapy, and to the possibility of paradoxical expansion of these lesions during the course of successful treatment.

[Functional activity of alveolar macrophages in exacerbation of pulmonary tuberculosis]. / Funktsional'naia aktivnost' al'veoliarnykh makrofagov pri obostrenii tuberkuleza legkikh.

The authors estimated the cellular composition of bronchoalveolar lavage fluid, the functional activity of alveolar macrophages from the recovery of tetrazolium nitroblue (TNB test) in 39 patients with an exacerbation of secondary forms of pulmonary tuberculosis before and after prodigiosane stimulation, made a correlation analysis in order to elucidate the correlations between the parameters of a TNB test and the count of macrophages and neutrophils. On an exacerbation of tuberculosis, the activity of a population of alveolar macrophages did not increase, but in its infiltrative form, it even decreased as compared with the normal values. After prodiogiosane stimulation, the in vitro activity of alveolar macrophages increased by almost 60% in infiltrative tuberculosis and by 100% in fibrocavernous tuberculosis; there was no substantial rise in the activity in tuberculoma. The poor protective functions of alveolar macrophages were compensated by the enhanced inflow of alveolar macrophages and neutrophils into the airway lumens, as suggested by the correlation between their activity and count.

[Blood autotransfusion in the surgical treatment of pulmonary tuberculosis]. / Autogemotransfuziia pri khirurgicheskom lechenii tuberkuleza legkikh.

Clinical observations in 250 patients with different forms of tuberculosis have shown that blood autotransfusion during operations on the lungs is a safe and effective curative method allowing to considerably reduce the amount of donor blood and to maintain stable indices of central hemodynamics during operation and in the postoperative period.

Tuberculoma of the central nervous system.

Tuberculosis is among the oldest and most devastating infectious diseases worldwide. Nearly one third of the world's population has active or latent disease, resulting in 1.5 million deaths annually. Central nervous system involvement, while rare, is the most severe form of tuberculosis. Manifestations include tuberculoma and tuberculous meningitis, with the majority of cases occurring in children and immunocompromised patients. Despite advancements in imaging and laboratory diagnostics, tuberculomas of the central nervous system remain a diagnostic challenge due to their insidious nature and nonspecific findings. On imaging studies tuberculous meningitis is characterized by diffuse basal enhancement, but tuberculomas may be indistinguishable from neoplasms. Early diagnosis is imperative, since clinical outcomes are largely dependent on timely treatment. Stereotactic biopsy with histopathological analysis can provide a definitive diagnosis, but is only recommended when non-invasive methods are inconclusive. Standard medical treatment includes rifampicin, isoniazid, pyrazinamide, and streptomycin or ethambutol. In cases of drug resistance, revision of the treatment regimen with second-line agents is recommended over the addition of a single drug to the first-line regimen. Advances in genomics have identified virulent strains of tuberculosis and are improving our understanding of host susceptibility. Neurosurgical referral is advised for patients with elevated intracranial pressure, seizures, or brain or spinal cord compression. This review synthesizes pertinent findings in the literature surrounding central nervous system tuberculoma in an effort to highlight recent advances in pathophysiology, diagnosis, and treatment.

Tuberculous optochiasmatic arachnoiditis: a devastating form of tuberculous meningitis.

Tuberculous meningitis is primarily a disease of the meninges of brain and spinal cord along with adjacent brain parenchyma. The characteristic pathological changes are meningeal inflammation, basal exudates, vasculitis and hydrocephalus. Tuberculous meningitis has a strong predilection for basal parts of the brain. Exudates, if dominantly present in the interpeduncular, suprasellar and Sylvian cisterns, result in optochiasmatic arachnoiditis and tuberculoma. Optochiasmatic arachnoiditis and tuberculoma are devastating forms of tuberculous meningitis and often associated with profound vision loss. This clinical entity more frequently affects young adults. In a recent study, on the multivariate logistic regression analysis, female sex, younger age and raised cerebrospinal fluid protein content were identified as predictors for developing optochiasmatic arachnoiditis. Frequently, optochiasmatic tuberculoma and optochiasmatic arachnoiditis develop paradoxically while a patient is being treated with anti-TB drugs. MRI reveals confluent enhancing lesions that are present in the interpeduncular fossa, pontine cistern, and the perimesencephalic and suprasellar cisterns. Management of tuberculous optochiasmatic arachnoiditis and optochiasmatic arachnoiditis tuberculoma has been variable. Treatment of optochiasmatic arachnoiditis continues to be a challenge and the response is generally unsatisfactory. In isolated case reports and in small series, corticosteroids, methyl prednisolone, thalidomide and hyaluronidase have been used with variable success. The benefit from neurosurgery is controversial and deterioration may follow the initial temporary improvement. Management of paradoxical optochiasmatic arachnoiditis is also controversial. Some patients regain vision following treatment with anti-TB drugs and continued usage of corticosteroids. Neurosurgery may be considered in the patients with either treatment failure or when diagnosis is in doubt. In conclusion, presence of optochiasmatic arachnoiditis or tuberculoma has important therapeutic and prognostic implications for patients of tuberculous meningitis.

[THE PATHOGENESIS OF LUNG TUBERCULOMAS UNDER THE CONDITIONS OF A FAR NORTH REGION].

The specific features of the pathogenesis of lung tuberculomas were studied in 302 patients among the indigenes and newcomers in the Far-North. The predominant formation of caseous foci from the tuberculous infiltrate located in the lung tissue in most cases was ascertained to be the specific feature of the development of lung tuberculomas under the conditions of a Far- North region, in Yakutia in particular. Tuberculoma formation shows a peculiar combination of evolving foci of acute specific pneumonia with a torpid inflammatory process, which contributes to the formation of multiple and large tuberculomas in the presence of significant pneumosclerosis. At the same time, homogeneous tuberculomas most commonly formed in both newcomers and indigenes.