Extrapulmonary Tuberculosis: Pathophysiology and Imaging Findings.

Extrapulmonary tuberculosis (TB) represents approximately 15% of all TB infections. It is difficult to diagnose on the basis of imaging characteristics and clinical symptoms, and biopsy is required in many cases. Radiologists must be aware of the imaging findings of extrapulmonary TB to identify the condition in high-risk patients, even in the absence of active pulmonary infection. In extrapulmonary TB, the lymphatic system is most frequently affected. The presence of necrotic lymph nodes and other organ-specific imaging features increases the diagnostic probability of extrapulmonary TB. Disseminated infection and central nervous system involvement are the most frequent manifestations in immunosuppressed patients. Renal disease can occur in immunocompetent patients with very long latency periods between the primary pulmonary infection and genitourinary involvement. In several cases, gastrointestinal, solid-organ, and peritoneal TB show nonspecific imaging findings. Tuberculous spondylitis is the most frequent musculoskeletal manifestation. It is usually diagnosed late and affects multiple vertebral segments with extensive paraspinal abscess. Articular disease is the second most frequent musculoskeletal manifestation, and synovitis is its predominant imaging finding.©RSNA, 2019.

Oxidative and endoplasmic reticulum stress in tuberculous meningitis related seizures.

BACKGROUND AND PURPOSE: High oxygen consumption and high polyunsaturated fatty acid content in the brain may render it vulnerable to oxidative stress and endoplasmic reticulum (ER) stress. We report the role of these parameters in tuberculous meningitis (TBM) patients with seizures and correlate these with clinical radiological, and laboratory findings. METHODS: Serum oxidative stress markers ; Catalase, Superoxide dismutase (SOD), Glutathione (GSH), Protein-carbonyl, Malonaldehyde (MDA) were measured using spectrophotometer and ER stress markers-ATF4, CHOP, XBP1 and GRP-78 using RT-PCR in TBM patients, 29 with seizures, 20 without seizures and 20 matched controls. In 10 patients, sequential estimation of oxidative stress and ER stress markers was also measured. RESULTS: In comparison to controls, TBM patients had significant difference in the expression of oxidative stress and ER stress markers. Serum MDA (P=0.02), protein-carbonyl (P < 0.01) were significantly higher and SOD (P=0.02) and GSH (P < 0.01) significantly lower in the patients with seizures compared to those without seizures. The ER stress markers were insignificantly elevated in TBM patients with seizures. On sequential evaluation, oxidative stress and ER stress markers increased following seizures and returned to baseline at the time of discharge. CONCLUSION: The results suggest some role of oxidative stress and ER stress in TBM, but do not predict its outcome.

Thalidomide and Phosphodiesterase 4 Inhibitors as Host Directed Therapeutics for Tuberculous Meningitis: Insights From the Rabbit Model.

Tuberculous meningitis (TBM) is the most devastating form of extrapulmonary Mycobacterium tuberculosis infection in humans. Severe inflammation and extensive tissue damage drive the morbidity and mortality of this manifestation of tuberculosis (TB). Antibiotic treatment is ineffective at curing TBM due to variable and incomplete drug penetration across the blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barriers. Adjunctive corticosteroid therapy, used to dampen the inflammation, and the pathologic manifestation of TBM, improves overall survival but does not entirely prevent the morbidity of the disease and has significant toxicities, including immune-suppression. The rabbit has served as a fit for purpose experimental model of human TBM since the early 1900s due to the similarity in the developmental processes of the brain, including neuronal development, myelination, and microglial functions between humans and rabbits. Consistent with the observations made in humans, proinflammatory cytokines, including TNF-α, play a critical role in the pathogenesis of TBM in rabbits focusing the attention on the utility of TNF-α inhibitors in treating the disease. Thalidomide, an inhibitor of monocyte-derived TNF-α, was evaluated in the rabbit model of TBM and shown to improve survival and reduce inflammation of the brain and the meninges. Clinical studies in humans have also shown a beneficial response to thalidomide. However, the teratogenicity and T-cell activation function of the drug limit the use of thalidomide in the clinic. Thus, new drugs with more selective anti-inflammatory properties and a better safety profile are being developed. Some of these candidate drugs, such as phosphodiesterase-4 inhibitors, have been shown to reduce the morbidity and increase the survival of rabbits with TBM. Future studies are needed to assess the beneficial effects of these drugs for their potential to improve the current treatment strategy for TBM in humans.

Meningitis de etiología mixta: tuberculosa y bacteriana por germen no identificado / Meningitis of mixed ethiology (tuberculous and unindentified bacteria)

Se presenta un caso de paciente masculino de 54 años de edad, sin inmunosupresión ni evidencia de la misma durante su hospitalización, que consulta por cefalea y signos meníngeos. Se realiza Punción Lumbar (PL) compatible con meningitis bacteriana por lo que se indica tratamiento empírico con mejoría franca de la sintomatología con excepción de la esorientación. Una vez en mejores condiciones se reciben los valores de la ADA los cuales están elevados compatibles con Tuberculosis Meníngea (TBM). Se realiza nueva PL para confirmar dicho valor, lo que se logra y además se demuestra un aumento leve. A los 20 días de la hospitalización, y luego de la mejoría franca, el paciente presenta nuevamente cefalea, fiebre y bradilalia por lo que se inicia tratamiento anti TB con mejoría progresiva de los síntomas. Se presenta el caso y se revisa la literatura(AU)

We present a 54-year-old male patient, with no immunosuppression who consulted for headache and meningeal signs. Lumbar tap (LT) was compatible with bacterial meningitis and empirical treatment was startes with a clear improvement in symptomatology, except for disorientation. Then ADA values were received and its values were francly compatible with Meningeal Tuberculosis (TBM). A new LT was performed to confirm this value, also showeds a slight increase. Twenty days after the hospitalization, and after the frank improvement, the patient again presented again with headache, fever and bradylalia, thus initiating anti-TB treatment with progressive improvement of symptoms. The case is presented and the literature is reviewed(AU)

Title: role of matrix metalloproteinase -9 in progression of tuberculous meningitis: a pilot study in patients at different stages of the disease.

BACKGROUND: TBM (Tuberculous meningitis) is severe form of tuberculosis causing death of one third of the affected individuals or leaving two-third of the survivors disabled. MMP-9 (Matrix metalloproteinase-9) is produced by the central nervous system in a variety of inflammatory conditions and has a role in the breakdown of extracellular matrix and blood-brain barrier. METHODS: In this study, the levels of MMP-9 and its inhibitor, TIMP-1 (tissue inhibitor of metalloproteinases-1), were screened using zymography and reverse zymography in cerebrospinal fluid and serum of tuberculous meningitis patients at different stages of the disease. Further, role of MMP-9 as therapeutic target was studied in C6 glioma cells infected with Mycobacterium tuberculosis H37Rv. Cells were treated with dexamethasone or SB-3CT (specific inhibitor of MMP-9) in combination with conventional antitubercular drugs. RESULTS: MMP-9 levels in patients were increased as the disease progressed to advanced stages. The infection led to increased MMP-9 levels in C6 glioma cells and specific inhibition of MMP-9 by SB-3CT augmented bacillary clearance when used along with antitubercular drugs. CONCLUSION: MMP-9 plays a prominent role in progression of tuberculous meningitis from initial to advanced stages. Increased levels of MMP-9 during advancement of the disease leads to degeneration of nervous tissue and blood brain barrier disruption. Hence, MMP-9 can be considered as a therapeutic target for efficient management of TBM and can be explored to inhibit further progression of the disease if used at an early stage.

Adequacy of Rifampin Absorption after Jejunostomy Tube Administration.

It is not always possible to administer antituberculosis pharmacotherapy orally for reasons that may be a direct consequence of tuberculosis itself. To our knowledge, no published literature is available regarding antituberculosis drug absorption via feeding tube. We present the case of a patient with tuberculosis meningitis who required medication administration via percutaneous endoscopic jejunostomy (PEJ) tube. Blood samples were collected during the continuation phase of antituberculosis therapy, immediately before dose administration, and then at 1, 2, 4, and 6 hours after dose administration for quantification of serum rifampin concentrations. Assaying these concentrations by high-pressure liquid chromatography demonstrated a peak serum rifampin level (C(max)) of 18 µg/ml and total rifampin exposure (area under the curve from 0-6 hours [AUC(0-6)]) of 50.1 µg/ml. These are high compared with rifampin C(max) and AUC(0-6) values reported in patients after oral rifampin administration; C(max) tends to range between 4.0-10.5 µg/ml and AUC(0-6) 7.0-52.9 µg/ml after oral administration of 600 mg at steady state. Based on our patient's results, therefore, rifampin administered by PEJ tube appears to be well absorbed, with preservation of adequate C(max) and AUC values. It is worth noting that this was in the context of drug administration in the fasted state. In the absence of any published evidence of adequate absorption via jejunal feeding tube in the nonfasted state, it would seem prudent to ensure that patients are fasted when rifampin is administered via PEJ tube, just as patients are when oral rifampin is administered. This report represents the first documented evidence, to our knowledge, of adequate rifampin absorption when administered via PEJ tube and provides important reassurance for health care providers, patients, and families facing similar clinical scenarios.

Spinal cord involvement in tuberculous meningitis.

OBJECTIVES: To summarize the incidence and spectrum of spinal cord-related complications in patients of tuberculous meningitis. SETTING: Reports from multiple countries were included. METHODS: An extensive review of the literature, published in English, was carried out using Scopus, PubMed and Google Scholar databases. RESULTS: Tuberculous meningitis frequently affects the spinal cord and nerve roots. Initial evidence of spinal cord involvement came from post-mortem examination. Subsequent advancement in neuroimaging like conventional lumbar myelography, computed tomographic myelography and gadolinium-enhanced magnetic resonance-myelography have contributed immensely. Spinal involvement manifests in several forms, like tuberculous radiculomyelitis, spinal tuberculoma, myelitis, syringomyelia, vertebral tuberculosis and very rarely spinal tuberculous abscess. Frequently, tuberculous spinal arachnoiditis develops paradoxically. Infrequently, spinal cord involvement may even be asymptomatic. Spinal cord and spinal nerve involvement is demonstrated by diffuse enhancement of cord parenchyma, nerve roots and meninges on contrast-enhanced magnetic resonance imaging. High cerebrospinal fluid protein content is often a risk factor for arachnoiditis. The most important differential diagnosis of tuberculous arachnoiditis is meningeal carcinomatosis. Anti-tuberculosis therapy is the main stay of treatment for tuberculous meningitis. Higher doses of corticosteroids have been found effective. Surgery should be considered only when pathological confirmation is needed or there is significant spinal cord compression. The outcome in these patients has been unpredictable. Some reports observed excellent recovery and some reported unfavorable outcomes after surgical decompression and debridement. CONCLUSIONS: Tuberculous meningitis is frequently associated with disabling spinal cord and radicular complications. Available treatment options are far from satisfactory.

Paradoxical reaction in HIV negative tuberculous meningitis.

This review focusses on paradoxical reactions occurring during the treatment of tuberculous meningitis (TBM) in human immunodeficiency virus-negative cases. A paradoxical reaction is defined as the worsening of a pre-existing lesion or the appearance of new lesion in a patient whose clinical symptoms initially improved with anti-tuberculosis treatment. A number of different paradoxical reactions have been reported in patients with TBM including expansion of existing cerebral tuberculomas, and appearance of new tuberculomas, hydrocephalus, and optochiasmatic and spinal arachnoiditis. While the exact mechanism of paradoxical reactions is uncertain, an exaggerated immune reaction against Mycobacterium tuberculosis-associated antigens is currently the most accepted theory for tuberculous paradoxical reaction. Corticosteroids are considered to have a beneficial effect in the management of paradoxical reactions. Immuno-modulatory drugs, including tumor necrosis factor-α antagonists, thalidomide and interferon-γ have been used in isolated cases with more severe forms of paradoxical reactions.

Primary diffuse leptomeningeal gliomatosis mimicking tuberculous meningitis.

Primary diffuse leptomeningeal gliomatosis is a disease with an aggressive course that can result in death. To date, 82 cases have been reported. Here, the case of a 3-year-old male patient presenting with strabismus, headache, and restlessness is reported. Physical examination revealed paralysis of the left abducens nerve, neck stiffness, and bilateral papilledema. Tuberculous meningitis was tentatively diagnosed, and antituberculosis treatment was initiated when cranial imaging revealed contrast enhancement around the basal cistern. Craniocervical magnetic resonance imaging (MRI) was performed when there was no response to treatment, and it revealed diffuse leptomeningeal contrast enhancement around the basilar cistern, in the supratentorial and infratentorial compartments, and in the spinal region. Primary diffuse leptomeningeal gliomatosis was diagnosed by a meningeal biopsy.

Bladder dysfunction and urodynamic study in tuberculous meningitis.

BACKGROUND: Micturitional disturbances in tuberculous meningitis have been reported infrequently and that too without urodynamic studies. Bladder dysfunction in tuberculous meningitis is often considered secondary to tuberculous radiculomyelopathy. We, in this study, evaluated the incidence and pattern of bladder dysfunction in tuberculous meningitis. MATERIALS AND METHOD: In this prospective study, 51 patients were included. In addition to clinical evaluation, patients were subjected to a urodynamic study along with magnetic resonance imaging (MRI) of brain and spine. Patients were followed up for 6 months. A follow-up urodynamic study was performed after 6 months. RESULTS: Out of 51 patients, urinary symptoms were present in one-third of the patients. Approximately, 70% (36) of the patients had urodynamic abnormalities. The commonest (22/51) urodynamic abnormality was detrusor hyporeflexia/areflexia. Other urodynamic abnormalities were neurogenic detrusor overactivity in 10, detrusor sphincter dyssynergia in 6, normal detrusor activity in 19, reduced bladder sensation in 12, raised cystometric capacity in 9, and larger volumes of post-void residual urine in 12 patients. Six patients were unable to void on command. Three patients with neurogenic detrusor overactivity had leak during study. MRI showed spinal meningeal enhancement in 37, lumbosacral arachnoiditis in 25, myelitis in 12 patients, CSF loculations in 6, and cord atrophy in 5 patients. Spinal arachnoiditis and urinary symptoms showed significant association with urodynamic abnormalities. Follow-up urodynamic study showed resolution of urodynamic abnormalities in 72.6% of the patients with treatment. Seven (28%) patients, with normal baseline urodynamic findings, paradoxically developed new abnormalities. CONCLUSION: Bladder dysfunctions, in tuberculous meningitis, are frequently encountered. A significant association exists between urodynamic abnormalities and tuberculous lumbosacral arachnoiditis and myeloradiculopathy.

Tuberculous hypertrophic pachymeningitis presenting as visual blurring and headaches.

Hypertrophic cranial pachymeningitis is a rare chronic fibrosing inflammatory disease characterised by localized or diffuse thickening of duramater, leptomeninges, and tentorium. The etiology is diverse and includes infectious, granulomatous and inflammatory disorders, collagen vascular disorders, carcinoma, lymphoma, meningioma en plaque, sarcoidosis, haemodialysis, mucopolysaccharidosis, intrathecal drug administration, and meningeal carcinomatosis diseases. Intracranial hypotension is also an important image mimicker. Most often patients present with complaint of headache, vomiting, cranial nerve palsy, ataxia, raised intracranial pressure and focal neurological deficit. Other signs and symptoms are inconstant and variable. The imaging features of hypertrophic cranial pachymeningitis include dural thickening, dural mass, sinus thrombosis, venous congestion with white matter changes. Extensive preoperative imaging studies usually are essential by Computerised Tomography (CT) or Magnetic Resonance Imaging (MRI). The radiological findings may be characteristic of hypertrophic cranial pachymeningitis, may not divulge the underlying etiology. Meningeal biopsy is essential for diagnosing the cause. We reviewed a case of a tuberculous hypertrophic cranial pachymeningitis.

Diagnosis and therapy of tuberculous meningitis in children.

Children are among the subjects most frequently affected by tuberculous meningitis (TBM) due to their relative inability to contain primary Mycobacterium tuberculosis infection in the lung. TBM is a devastating disease with about 30% mortality among the most severe cases; moreover, 50% of survivors have neurological sequelae despite an apparently adequate administration of antibiotics. Early diagnosis and prompt treatment are crucial for reducing the risk of a poor outcome. However, especially in children, the best and most rapid way to confirm the diagnosis is controversial; the optimal choice, dose, and treatment duration of anti-tuberculosis drugs are not precisely defined, and the actual importance of adjunctive therapies with steroids and neurosurgery has not been adequately demonstrated. This review is an effort to discuss present knowledge of the diagnosis and treatment of pediatric TBM in order to offer the best solution to address this dramatic disease. In conclusion, we stress that new studies in children are urgently needed because data in the early years of life are more debatable than those collected in adults. In the meantime, when treating a child with suspected TBM, the most aggressive attitude to diagnosis and therapy is necessary, because TBM is a devastating disease.

Hyperexcitability of the facial nerve in tuberculous meningitis.

INTRODUCTION: Facial myokymias (FM) are continuous, involuntary, undulating movements of the facial muscles associated with spontaneous electromyographic activity, such as fasciculations and myokymic discharges. They may occur in healthy individuals, or be secondary to multiple sclerosis, posterior fossa tumors, or an inflammatory process. PATIENT AND RESULTS: We describe the case of a 31-year-old man who presented with headache, vomiting, low fever, and disorientation. Cerebrospinal fluid findings included low glucose and high protein content and lymphocyte pleocytosis, with positive culture for Myobacterium tuberculosis. The patient was diagnosed with tuberculous meningitis. Magnetic resonance imaging showed high contrast enhancement in the basal meninges and a left frontal tuberculoma. Over the course of the disease, he experienced FM and persistent, involuntary contraction of the facial muscles. The electromyogram recorded myokymic discharges. DISCUSSION: Tuberculous meningitis is a rare cause of FM. The presence of myokymic discharges on electromyography verified the peripheral origin of facial nerve hyperexcitability in this case, in contrast to persistent contraction of the facial muscles, which has a central origin. The phenomena were transitory and only positive symptoms were observed, with no facial nerve injury. CONCLUSION: Tuberculous meningitis is a rare cause of facial nerve hyperexcitability, which can have a peripheral, nuclear, or supranuclear origin.

Recovery of vision after adjuvant thalidomide in a child with tuberculous meningitis and acute lymphoblastic leukemia.

A 7-year-old child, on maintenance chemotherapy for acute lymphoblastic leukemia, developed tuberculous meningitis complicated by progressive basal meningeal inflammation and abscess formation, in spite of adequate tuberculosis treatment and adjunctive corticosteriod therapy. The child became blind as a result of involvement of the optic chiasm. After 2 months of adjunctive thalidomide therapy, the child regained vision and cranial magnetic resonance imaging showed marked reduction of the inflammatory changes previously demonstrated. Progression of intracranial tuberculous infection, in spite of a treatment that is generally considered to be adequate, is well recognized. Previous reports of a possible beneficiary role of thalidomide in these cases support an immunological basis. The present case suggests a role for thalidomide in the treatment of blindness due to involvement of the optic chiasm in progressive basal tuberculous meningitis.

Secretory phospholipase A2 plays an essential role in microglial inflammatory responses to Mycobacterium tuberculosis.

In previous studies, we have shown that reactive oxygen species (ROS)-mediated inflammatory signaling is essential for microglial proinflammatory responses to Mycobacterium tuberculosis (Mtb). To further investigate the molecular mechanisms governing these processes, we sought to describe the role of phospholipase A(2) (PLA(2)) in Mtb-induced ROS generation and inflammatory mediator release by microglia. Inhibition of secretory PLA(2) (sPLA(2)), but not cytosolic PLA(2) (cPLA(2)), profoundly abrogated Mtb-mediated ROS release, the generation of various inflammatory mediators (tumor necrosis factor, interleukin-6, cyclooxygenase-2, inducible nitric oxide synthase, and matrix metalloproteinase-2 and -9), and the activation of nuclear factor (NF)-kappaB and MAPKs (ERK1/2, p38, and JNK/SAPK) by murine microglial BV-2 cells or primary mixed glial cells. Interruption of the Ras/Raf-1/MEK1/ERK1/2 pathway abolished Mtb-induced sPLA(2) activity, whereas the blockage of JNK/SAPK or p38 activity had no effect. Specific inhibition of sPLA(2), but not cPLA(2), suppressed the upregulation of ERK1/2 phosphorylation by Mtb stimulation, suggesting the existence of a mutual dependency between the ERK1/2 and sPLA(2) pathways. Moreover, examination of the protein kinase C (PKC) family revealed that classical PKCs are involved in Mtb-induced sPLA(2) activation by microglia. Taken together, our results demonstrate for the first time that sPLA(2), either through pathways comprising Ras/Raf-1/MEK1/ERK1/2 or the classical PKC family, plays an essential role in Mtb-mediated ROS generation and inflammatory mediator release by microglial cells.

Clinical and immunologic features of an atypical intracranial mycobacterium avium complex (MAC) infection compared with those of pulmonary MAC infections.

Members of the Mycobacterium avium complex (MAC) may cause chronic pulmonary infections in otherwise healthy elderly persons but rarely invade parts of the body outside of the lungs in immunocompetent hosts. We present a case of an isolated intracranial MAC infection in an apparently immunocompetent individual and review previous reports. We studied the T-cell and monocyte responses in healthy volunteers, individuals with a pulmonary MAC infection, and one individual with an isolated intracranial MAC infection. Genomic DNA from the individual with the brain MAC infection was studied for gamma interferon (IFN-gamma) receptor mutations. Individuals with localized pulmonary MAC infections showed increased activation of monocytes and enhanced monocyte and T-cell tumor necrosis factor alpha (TNF-alpha) production in response to lipopolysaccharide and MAC antigens but defects in T-cell IFN-gamma secretion. The individual with an intracranial MAC infection showed a lack of monocyte activation and deficiencies in both monocyte and T-cell TNF-alpha production and monocyte interleukin-12 (IL-12) production but had preserved T-cell IFN-gamma production. Mutations or deletions in the IFN-gamma receptor were not detected in the individual with the intracranial MAC infection. Our data suggest that distinct immune defects characterize two different manifestations of MAC infection. A relative defect in IFN-gamma production in response to MAC may predispose an individual to localized but partially controlled lung disease, whereas defects leading to reduced IL-12 and TNF-alpha production may allow the dissemination of MAC. Further studies delineating the potential role of TNF-alpha in limiting the spread of MAC outside the lung are warranted.

Atypical teratoid/rhabdoid tumor mimicking tuberculous meningitis.

Atypical teratoid/rhabdoid tumor of the central nervous system is a highly malignant neoplasm in infants and young children. We report a 6 year-old girl with atypical teratoid/rhabdoid tumor. Based on cerebrospinal fluid examination MRI scan and family history of tuberculosis; we diagnosed tuberculous meningitis. There was inadequate response to the antituberculosis therapy; so we performed stereotactic brain biopsy. Pathologic result revealed high grade atypical teratoid/rhabdoid tumor.

Hypertrophic cranial pachymeningitis in countries endemic for tuberculosis: diagnostic and therapeutic dilemmas.

Hypertrophic cranial pachymeningitis (HCP) is an uncommon disorder with few studies correlating clinical, imaging and histopathological features. The aim of this study was to describe clinical and laboratory observations and therapeutic options of patients with HCP. Eleven patients with HCP (M:F 6:5; age range, 23-52 years) were evaluated over 10 years. Etiology was ascertained by MRI and laboratory tests and confirmed by biopsy of meninges and/or brain (7), nasal mucosa (1), mediastinal lymph node (1), muscle (2) or conjunctiva (2). Salient clinical features were headache (7), multiple cranial neuropathies (8), visual disturbances (6), seizures (2) and hemiparesis (2). Abnormal tests included: rapid erythrocyte sedimentation rate (3), positive serum venereal disease testing (1), chest CT abnormalities (4/6) and positive Mantoux test (2/5). Cerebrospinal fluid changes (10/11) revealed the following: cell count 0-47/mm(3); protein 14-95 mg/mL; and glucose of 44-79 mg/mL. Contrast MRI revealed a variable extent of thickened dura mater in all patients. Histopathology (n=11) confirmed chronic inflammation (100%) and provided specific etiology in six (vasculitis [2], sarcoidosis [2], tuberculosis [1], Wegener's granulomatosis [1]). Treatment included steroids only (4), anti-tubercular therapy with steroids (5), penicillin (1) and cyclophosphamide and plasmapheresis (1). During follow-up (27.0+/-26.3 months) there was significant recovery (9/9). On serial imaging (4), the lesion remained the same in three and resolved partially in one patient. HCP, despite frequently posing diagnostic and therapeutic challenges, has favorable outcome when treated appropriately.