Online newspaper of professor Yasser Metwally

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

December 31, 2008 — Recent advances in neuroimaging have resulted in a marked decrease in morbidity and death due to brain abscesses. The advent of computed tomography–guided stereotaxy has reduced morbidity in patients with deep-seated abscesses. Empirical therapy is best avoided in the present era, particularly given the availability of stereotactic techniques for aspiration and confirmation of diagnosis. Despite these advances, management of abscesses in patients with cyanotic heart disease and in immunosuppressed patients remains a formidable challenge. Unusual as well as more recently recognized pathogens are being isolated from abscesses in immunosuppressed patients. The authors provide an overview of the management of brain abscesses, highlighting their experience in managing these lesions in patients with cyanotic heart disease, stereotactic management of brain abscesses, and management of abscesses in immuno-suppressed patients.

By definition, a brain abscess is an intraparenchymal collection of pus. The incidence of brain abscesses is ~ 8% of intracranial masses in developing countries, whereas in the West the incidence is ~ 1–2%.[8,36,54] In this review we present an overview of the diagnosis and treatment options for brain abscesses, with specific reference to patients with cardiogenic brain abscess, the role of stereotaxy in the management of lesions, and management of brain abscesses in immunocompromised patients.

• Pathogenesis

Development of a brain abscess requires inoculation of an organism into the brain parenchyma in an area of devitalized brain tissue or in a region with poor microcirculation, and the lesion evolves from an early cerebritis stage to the stage of organization and capsule formation.[9,57] Winn et al.[63] developed a model of experimental brain abscess in rats and demonstrated that abscesses evolve from a stage of cerebritis and massive white matter edema to encapsulation. They observed several similarities between the abscesses in their model and those that occur in humans: 1) abscesses occurred in the white matter or at the junction of gray and white matter, migrating to the ventricle; and 2) the capsule was thickest toward the meninges and thinnest toward the ventricle. The mode of entry of organisms could be by contiguous spread, hematogenous dissemination, or following trauma.[36] The common predisposing causes of a brain abscess are chronic suppurative otitis media, congenital cyanotic heart disease, and paranasal sinusitis.[8,35,39,54,60] Immunosuppression due to disease or therapy is emerging as an important risk factor for development of brain abscess.

• Microbiological Spectrum

In the preantibiotic era, the most common organism isolated from a brain abscess was Staphylococcus aureus.[36] With the advent of penicillin and improved antibiotic therapy, Streptococcus spp have replaced Staphylococcus spp as the most common organisms.[18,36] Based on the site of origin, the organisms would be different. Table 1 shows the distribution of organisms depending on the site of origin of infection. De Louvois et al. isolated streptococci from abscesses of all types and at all sites, whereas Enterobacteriaceae and Bacteroides spp were isolated from otogenic temporal lobe abscesses, which had mixed cultures.[18] Streptococcus spp have been most commonly isolated from cardiogenic abscesses.[59] In neonates, the most common organisms are Proteus and Citrobacter spp. Anaerobes are one of the most common causative organisms in a brain abscess.[17] Polymicrobial infections are common, indicating the importance of using both aerobic and anaerobic cultures in diagnosis.[17,20] Occasionally, intracranial tuberculosis as well as fungal infections can present as an abscess.[16,32,43,44] Therefore, cultures for acid-fast bacilli and fungi should be done in all cases. Uncommon organisms reported include Listeria monocytogenes[13] and Burkholderia pseudomallei.[31]

• Clinical Presentation

Brain abscess occurs in the younger age groups-usually in the first three decades of life.[8,46,54,58] The most common presentation is that of headache and vomiting due to raised intracranial pressure. Seizures have been reported in up to 50% of cases.[4,8,54] Focal neurological deficits related to the site of the abscess may be present, depending on the size of the lesion. Altered sensorium with nuchal rigidity may occur in cases of increased mass effect resulting in herniation, or in cases of intraventricular rupture of brain abscess.[54,57]

• Diagnosis

A lumbar puncture is contraindicated in patients with a suspected brain abscess because it can result in transtentorial or transforaminal herniation and subsequent death.[61] Moreover, analysis of cerebrospinal fluid does not aid in diagnosis of an unruptured brain abscess. A CT scan of the brain obtained after administration of contrast material shows evidence of a ring-enhancing lesion in a well-defined abscess (Fig. 1) and features of cerebral edema in the stage of cerebritis. The rim of a brain abscess is usually thinner than that seen with neoplastic lesions (Fig. 2).[8] It aids in determining the location of the abscess, its size, number, mass effect, and shifts, and the presence of intraventricular rupture.[2,8,11,31] It also provides information with regard to the cause; the paranasal sinuses and mastoids are also imaged concomitantly. Although MR imaging obtained with diffusion weighting may be more sensitive in the differentiation of an abscess from other cystic brain lesions as well as in detection of the cerebritis stage, it may not be useful in an acutely ill patient and we do not recommend routine MR imaging for diagnosis in patients with a suspected brain abscess.[8,36] In children with an open anterior fontanelle, an ultrasonogram can be used to diagnose an abscess.

Figure 1. Axial Gd-enhanced MR image obtained in a 22-year-old man showing a large, multiloculated, ring-enhancing lesion with a thick wall in the left temporal lobe. The patient had a history of chronic discharge from his left ear and underwent cortical mastoidectomy. He developed headache 2 days after the procedure, at which time this MR image was obtained. He underwent craniotomy and excision of the abscess, followed by antibiotic therapy. Culture of the pus showed P. mirabilis. (Click to enlarge figure)

Figure 2. Axial contrast-enhanced CT scan obtained in a 33-year-old man who was inconsistent in taking his medications for tuberculous lymphadenitis. The scan demonstrates a hypodense right-sided parietal lesion with a thin enhancing capsule. The patient presented with altered sensorium and right hemiparesis of 1-day duration. He underwent excision of the abscess followed by intravenously administered antibiotics. Pus cultures showed nonhemolytic and anaerobic streptococci. Histopathological investigation of the abscess wall showed evidence of an organizing abscess with occasional granulomas, suggesting synchronous tuberculous and pyogenic infection. (Click to enlarge figure)

The definitive microbiological diagnosis is made by submission of the pus from the abscess for testing with aerobic and anaerobic cultures. Because fungal and tuberculous diseases can present as a brain abscess, pus should be submitted for both acid-fast bacilli and fungal cultures.[2,16,43,44] Pus from a brain abscess should be submitted for immediate microbiological studies because a delay could lead to negative cultures.[17,18] Screening investigations should be done in all cases to determine the source of the infection.

• Treatment

Treatment of a brain abscess involves aspiration of the pus or excision of the abscess, followed by parenteral antibiotic therapy.[1,2,8,36,42,49,54,60] Empirical medical therapy is best avoided and should be reserved for patients in whom a bacteriological diagnosis has been obtained from a systemic source or who are extremely ill; that is, too ill to undergo any form of intervention.[2,40,51] Small abscesses and lesions in the cerebritis stage respond well to medical therapy alone.[59] Multiple abscesses are best treated with aspiration of the largest one, followed by antibiotic therapy, which may be required for a longer duration of up to 3–6 months.[7,11,16] Most recent articles recommend aspiration followed by appropriate antibiotic therapy based on sensitivity of the causative organisms.[8,54] Weekly or biweekly CT scans to monitor the size of the abscess are, however, mandatory following aspiration, and repeated aspirations may be required.[54,63] The recommended duration of parenteral antibiotic therapy is 6–8 weeks following aspiration.

Craniotomy and excision is usually reserved for abscesses that enlarge after 2 weeks of antibiotic therapy or that fail to shrink after 3–4 weeks of antibiotics.[2,8,23,40,54,57] Craniotomy is also recommended for multiloculated abscesses and larger lesions with significant mass effect that are superficial and located in noneloquent regions of the brain. We also recommend excision of abscesses in the cerebellum, where recurrent pus collection following aspiration can lead to precipitous neurological worsening.[61] There are certain advantages to excision of a brain abscess in an otherwise neurologically intact patient. The risk of repeated collection of pus is almost completely eliminated, and hence the expense involved in repeated imaging is saved. The duration of hospitalization is also reduced. Furthermore, in patients with an otogenic brain abscess, the disease in the middle ear can also be surgically treated at the same sitting or soon thereafter.[32] This also reduces the likelihood of recurrence of the abscess.

The antibiotics of choice are crystalline penicillin, chloramphenicol, and metronidazole, followed by definitive therapy based on the sensitivity pattern of the causative organisms.[8,11,26,59] There is a recent trend toward the use of third-generation cephalosporins and avoidance of chloramphenicol.[8,59] If staphylococci are suspected, an antistaphylococcal penicillin should be used, with vancomycin being the alternative in cases of antibiotic resistance or patient intolerance to penicillin.[59] The source of the infection should be treated surgically or medically to prevent recurrence of the abscess.[33]

• Outcome

The cure rate for single or multiple abscesses reported in the literature is ~ 90% with surgical and medical therapy.[8,36,40,54] With the advent of the CT modality in the 1970s, there was a marked decrease in the morbidity and death due to brain abscesses, and this was a result of earlier diagnosis.[8,11,19,25,51,57,64] The mortality rate has decreased by nearly one third from that found in the pre-CT era.[57] Patients with nocardial and listerial brain abscesses have a threefold higher rate of mortality compared to those who die of other causes.[13,35,41] Intraventricular rupture of brain abscesses and a poor Glasgow Coma Scale score at presentation have been associated with worse outcomes.[40,57] Long-term sequelae include cognitive dysfunction and delayed onset of seizures as well as focal neurological deficits.

• Cyanotic Heart Disease and Brain Abscess

Patients with congenital cyanotic heart disease (with a right-to-left shunt) are at risk for developing a brain abscess.[3,4,8,14,20,22,29,37,39,49,57] Cyanotic heart disease accounts for 12.8–69.4% of all cases of brain abscesses with identified risk factors in several series, with the incidence being higher in children.[1,3,24,39,49] In most series of patients from developed countries, cyanotic heart disease is the most commonly identified risk factor for development of brain abscess in immunocompetent patients. The incidence of brain abscess in patients with cyanotic heart disease has been reported to range between 5 and 18.7%.[57] Tetralogy of Fallot is the most common cardiac anomaly associated with brain abscess.[12,23,57] Transposition of great vessels, tricuspid atresia, pulmonary stenosis, and double-outlet right ventricle have also been reported as predisposing factors.[12,56,57] Most of these abscesses are supratentorial in location.[23,49,56] Because most of these patients present only with headache, the threshold for performing a CT scan in a patient with cyanotic heart disease should be low.

In patients with cyanotic heart disease, there is a right-to-left shunt of venous blood in the heart, bypassing the pulmonary circulation. Thus, bacteria in the bloodstream are not filtered through the pulmonary circulation, where they would normally be removed by phagocytosis. Patients with cyanotic heart disease could have low-perfusion areas in the brain due to chronic severe hypoxemia and metabolic acidosis as well as increased viscosity of blood due to secondary polycythemia. These low-perfusion areas commonly occur in the junction of gray and white matter, and they are prone to seeding by microorganisms that may be present in the bloodstream.[28,56] The hematogenous mode of spread accounts for the subcortical location as well as the multiple number of abscesses often encountered in these patients.[7,12,22,57]

Streptococcus milleri was the most common organism isolated from the abscess in patients with cyanotic heart disease in one series.[3] Staphylococcus, other Streptococcus spp, and Haemophilus have also been isolated.[57] The isolation of gram-positive cocci is higher than that of gram-negative bacilli. With the advent of broad-spectrum antibiotic therapy, sterile cultures are being reported more often. Multiple organisms have also been isolated in some patients.[17,57]

Patients with cyanotic heart disease have compromised cardiopulmonary systems and exhibit a variety of coagulation defects, rendering them poor candidates for general anesthesia. Moreover, these abscesses are often deep seated in location, in proximity to the ventricular system (Fig. 3), and they are often multiple. The treatment of choice in these patients is thus aspiration of the abscess through a bur hole or twist-drill craniostomy performed after induction of local anesthesia.[1,22,49,57] Any coagulopathy, if present, should be corrected before the surgical intervention. In one series, the mortality rate following craniotomy and excision was as high as 71%.[27] Prusty[49] has reported that even with aspiration, nearly 17% of patients can develop cyanotic spells that could lead to life-threatening complications.

Figure 3. Axial contrast-enhanced CT scans obtained in a 17-year-old girl with tetralogy of Fallot who presented with fever that had lasted for 4 days and altered sensorium with right hemiparesis of 1-day duration. a: A right parietal subcortical ring-enhancing lesion abutting the ventricle wall is demonstrated. b: A CT scan obtained 10 days after antibiotic therapy, revealing persistence of the abscess with enhancement along both lateral ventricle walls, indicating ventriculitis. The patient was treated with external ventricular drainage and intravenous antibiotics for 1 month, after which a right ventriculoperitoneal shunt was inserted. The cerebrospinal fluid culture had shown peptostreptococci. She was asymptomatic after 1 year and could undergo surgery for her cardiac anomaly (Click to enlarge figure).

The recommended antibiotic therapy is penicillin with chloramphenicol,[8,22] although there has been a shift toward third-generation cephalosporins in recent years. Takeshita et al.[57] have suggested that intravenous antibiotics be administered for 6 weeks in these patients, with regular CT scans obtained to monitor the size of the abscess. Repeated aspirations may be required. Craniotomy should be restricted to patients with abscesses resistant to antibiotic therapy.[23,49,56,57]

The advent of CT scans and their use in the management of these abscesses has resulted in a fourfold decrease in the mortality rate in patients with brain abscesses secondary to cyanotic heart disease; from 40–60% in the pre-CT era to ~ 10%. This could be attributed to early detection, availability of image guidance for aspiration (particularly in small lesions), and better radiological follow-up during the course of the antibiotic therapy.[1,8,14,45,51,52,57] Intraventricular rupture of brain abscess has been reported to be a poor prognostic factor in these patients.[56,57] In our experience,[45,52] the advent of stereotaxy has aided in avoiding empirical therapy in patients with brain lesions, particularly so in patients with brain abscesses secondary to cyanotic heart disease. Stereotactic intervention can also help in obtaining a histological diagnosis of lesions mimicking a brain abscess in these patients. One of our patients with cyanotic heart disease and a ring-enhancing lesion in the brainstem was treated empirically at another institution with antibiotic therapy, with no clinical or radiological response. A stereotactic biopsy of the brainstem lesion revealed a tuberculoma, which responded to antituberculous drugs.[45]

• Role of Stereotaxy in Management of Brain Abscess

Sharma et al.[54] have highlighted the role of minimally invasive procedures like stereotactic aspiration or lavage with endoscopic stereotactic evacuation in the treatment of abscesses, even if the lesions are multiloculated. Several authors have recorded the utility of stereotactic techniques in the management of brain abscesses.[6,11,25,34,38,43,47,53,55,61,62] There are several advantages of stereotactic aspiration. Only stereotactic aspiration is appropriate for small, deep-seated abscesses or those located in eloquent regions of the brain, because it provides a direct and rapid access to the abscess through a predetermined route. Therefore, it is ideal for management of abscesses in the thalamus, basal ganglia, or brainstem.[21,38,45,48,52] Stereotactic aspiration also avoids the so-called leukotomy effect that can occur with a freehand aspiration technique. Finally, a biopsy of the wall of the abscess can also be obtained at the same time as the aspiration to confirm the diagnosis in case there is any doubt. Sometimes though, the penetration of a thick abscess wall with the blunt-tipped stereotactic probes can be difficult, and one may fail to enter the abscess. Impedance monitoring can avoid the “false-negative” result.[50]

Kondziolka et al.[30] have reported the use of a technique for drainage of abscesses for which a stereotactically guided catheter is placed in the cavity of abscesses > 3 cm. In their experience, factors associated with initial treatment failure following stereotactic aspiration include inadequate aspiration, lack of catheter drainage of larger abscesses, chronic immunosuppression, and insufficient antibiotic therapy. In almost three fourths of their patients, the lesions were successfully managed with a single stereotactic procedure. Itakura et al.[27] have reported good or excellent outcomes in > 90% of patients in whom external drainage of abscesses is in place for an average of ~ 2 weeks following stereotactic aspiration.

• Management of Brain Abscesses in The Immunocompromised Patient

Immunosuppression can predispose patients to the development of brain abscesses. Cunha[15] has reviewed the pathogenesis of central nervous system infections in immunocompromised patients. Compromised hosts with impaired T-lymphocyte or macrophage function are prone to developing infections with intracellular pathogens such as fungi (particularly Aspergillus spp) and bacteria like Nocardia spp. Brain abscesses caused by Aspergillus and Nocardia spp have been reported in immunosuppressed patients (Fig. 4).[10,16,35,41,43,44] Immunosuppression can result from illnesses like systemic or hematological malignancy or infections like human immunodeficiency virus, or it may be iatrogenic and due to long-term steroid medication, chemotherapy for malignancies, or immunosuppressive agents used in patients undergoing organ transplants. These patients are prone to the development of brain abscesses secondary to organisms that may not be seen in immuno-competent individuals, and because of this, empirical therapy in these patients should be avoided. Attention should be directed to obtaining a microbiological diagnosis so that appropriate antibiotic therapy can be initiated without delay. The imaging features of the abscess on CT or MR imaging studies do not help in arriving at a diagnosis of its cause. It is also important to subject the pus obtained from the abscess to microbiological examination for fungal elements and acid-fast bacilli besides the routine aerobic and anaerobic cultures. Arunkumar et al.[2] reported a series of 5 renal transplant recipients who developed brain abscesses secondary to chronic immunosuppression and whose lesions were managed with CT-guided stereotactic techniques. Each of their patients had a different causative organism, emphasizing the need for specific microbiological diagnosis in every immunocompromised patient with a brain abscess.

Figure 4. Axial contrast-enhanced CT scan obtained in a 12-year-old boy who presented with recurrent partial motor seizures and progressive loss of vision bilaterally, showing a ring-enhancing left-sided parietal lesion with multiple conglomerate smaller lesions adjacent to it. Note the extensive edema adjacent to the lesion and mass effect in the form of elevation of the craniotomy bone flap overlying it. The patient was receiving long-term steroid therapy for recurrent nephrotic syndrome, and his disease had been managed initially in another hospital with repeated aspiration of pus through a craniotomy over the past 9 months, along with prolonged courses of antibiotics. The pus had been sterile on routine cultures. Repeated exploration and excision of the abscess was performed, at which time the culture showed A. fumigatus. The patient is currently undergoing antifungal therapy.(Click to enlarge figure).

Table 1. Likely Pathogens in Brain Abscess Based on Predisposing Conditions.(Click to enlarge figure).

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The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

December 31, 2008 — Primary and secondary optic nerve sheath meningiomas (ONSMs) are neoplasms that account for a large proportion of optic nerve and orbital tumors. The diagnosis is not always straightforward and is based on the appropriate clinical findings and neuroimaging. Biopsy or surgical intervention may occasionally be necessary but is associated with significant morbidity. Issues related to clinical signs and symptoms, diagnosis, natural history, and treatment strategies are reviewed based on a review of published literature.

Diagnosis is usually based on radiographic and clinical findings. Biopsies are not obtained in most cases, thus adding further to the bias of possible misdiagnosis in all reported case series that do not have the benefit of histopathologic confirmation. Natural history typically shows inexorable progression in most cases, although long periods of stability are occasionally reported. Treatment options include observation, radiation alone, surgery alone, and combined radiation and surgery. The optimum timing of interventional therapy and radiation are evolving.

After serial examination documents new decline in acuity and/or visual field, fractionated radiotherapy appears most likely to preserve visual function and is a valid treatment approach for primary orbital ONSM. Tumor enlargement, as determined by serial imaging, may also provide an indication to begin radiotherapy.

• Epidemiology

  • Primary and Secondary Nerve Sheath Meningioma

Optic nerve sheath meningioma (ONSM) is a term applied to primary and secondary meningiomas of the optic nerve. According to a recent meta-analysis and subsequently reported large bi-institutional series, primary ONSMs accounts for approximately one third of primary optic nerve tumors and 5% to 10% of orbital tumors.[1-3] Since many reports and series fail to distinguish between primary and secondary tumors, determining the incidence of either with accuracy is difficult. The vast majority (90%) of optic nerve sheath tumors are secondary.[4]

Primary ONSM represents a neoplasia of meningothelial cap cells of arachnoid villi and can develop anywhere along the course of the optic nerve, from globe to prechiasmal intracisternal optic nerve.[5] Lesions may be unilateral, bilateral, or multifocal, with the latter two subgroups occurring most commonly in patients with type 2 neurofibromatosis. A meta-analysis of published cases indicated that tumors confined to the optic canal are more frequently (38%) bilateral compared with those in other locations (5%). Although rare, 65% of reported cases of bilateral ONSM are intracanalicular.[1] It is difficult to determine if these cases are truly multifocal in origin or if they represent midline or unilateral lesions, with dissemination across the clivus and planum sphenoidale.

Meningiomas extending from other locations and involving the optic nerve are secondary and may arise from the cavernous sinus, falciform ligament, clinoid, sphenoid wing, pituitary fossa, planum sphenoidale, frontal-parietal area, or olfactory groove.

•  Age and Sex Distribution

It is generally accepted that ONSM occurs more commonly in middle-aged women, but reports of the female:male distribution vary widely in the literature. Ratios as high as a 5:1 female predilection have been cited, but accurate estimates may be closer to a female preponderance of 61%, as determined by Dutton’s meta-analysis.[1] The overall mean age at presentation is cited as 40.8 years, varying from 36.1 years in men to 42.5 years in women.[1] ONSM has been diagnosed in a child as young as 2.5 years of age.[6] Moreover, bilateral cases appear to have an earlier mean age of onset of symptoms at 12.8 years.[1]

• Clinical Signs and Symptoms

Commonly reported clinical manifestations of ONSM include ipsilateral visual loss, afferent pupillary defect, color vision disturbance, visual field defect, proptosis, optic disc edema, motility disturbance, pain, and lower eyelid edema.[7] Patients have symptoms of gradual or rapid visual loss, diplopia, or gaze-evoked visual obscura-tions.[1,8,9] Ophthalmoscopic examination may reveal optic nerve head swelling, contiguous macular edema, nerve pallor, or choroidal folds. Optic disc swelling, accompanied by optic nerve pallor, also may be observed. As visual function declines, the optic disc edema may resolve, leaving a pale nerve head. Optociliary shunt vessels occasionally develop that represent the secondary dilation of preexisting retinal-to-choroidal shunting veins. Chronic optic nerve compression, caused by a variety of sources, prevents venous return of blood through the central retinal veins. Blood travels via these anastomotic vestigial circuits into the choroidal circulation and leaves the globe via vortex veins rather than the central retinal vein. The triad of visual loss, optic atrophy, and optociliary shunt veins was thought to be most commonly caused by ONSM.[10] The optic disc may be pale, with no prior swelling observed, when the meningioma is at the apex or within the optic canal.[11] However, posterior lesions may also present with optic disc swelling.[12]

• Radiologic Findings

  • Growth Patterns

The diagnosis of ONSM relies heavily on imaging findings. A recent article describing a retrospective review of 88 patients with ONSM at two institutions illustrated several radiographic growth patterns: tubular (diffuse, apical expansion, anterior expansion), globular, fusiform, and focal.[2] The tubular patterns, marked by widening along the length of the nerve sheath (Figure 1), were subdivided into diffuse expansion, apical expansion towards the orbital apex, or anterior nerve expansion towards the globe. Globular growth patterns were caused by exophytic expansion outside of the nerve sheath. Fusiform patterns were spindle shaped with tapers at the proximal and distal ends. This type was most likely to be confused with optic nerve glioma.[2] Focal exophytic lesions occasionally have been successfully resected.[2,13]

Figure 1. Tubular growth pattern of optic nerve sheath meningioma. A T1weighted, contrast-enhanced axial MRI shows diffuse enlargement and enhancement along the length of the left intraorbital (IO) and intracanalicular (IC) optic nerve sheath.(Click to enlarge figure)

•  Plain Film and Ultrasound Diagnosis

Prior to the advent of computed tomography (CT) and magnetic resonance imaging (MRI), clinicians depended on hyperostosis or optic canal enlargement on plain radiographic film studies. A- and B-modes of orbital ultrasonography were also useful. While orbital ultrasonography currently maintains a less definitive role than in the past, it remains widely available and in use in ophthalmic practices. With ultrasonography, the tumor typically is revealed as an enlargement of the nerve sheath signal, with medium to high internal reflectivity. In addition, the nerve sheath diameter remains constant when measured from the perpendicular and 30º angle to the visual axis. In contrast, a difference in the nerve sheath diameter, or “positive 30º test,” is detected with an increased cerebrospinal fluid space, typically accompanied by increased intracranial pressure.[14]

•  Computed Tomography

Thin CT scans (1.5-mm sections) may reveal regular or irregular thickening of the nerve sheath meninges. Tumors typically create a well-defined moderate to marked homogenous enhancement after intravenous contrast infusion. On thin section axial CT images, hyperdense enhancement of the meninges surrounding a hypodense nerve is suggestive in appearance of a “tram track.” Similarly, on noncontrast CT images, linear calcification of the nerve is also suggestive of a tram track. The optic nerve itself appears normal in size or of a smaller diameter within an area of thickened meninges, compared to the contralateral nerve at the same level. The smaller nerve size is the result of circumferential compression or atrophy and is a useful differential point. An intrinsically expanded nerve is more commonly seen in optic nerve glioma or other inflammatory lesions. Calcification may (1) surround the nerve and cause a tram-track appearance on axial and coronal CT scan, (2) maintain a punctate diffuse location, or (3) cause an en plaque signal along the optic canal, which may be difficult to distinguish from normal bone. Calcification may be masked by contrast agents and should be sought on precontrast soft tissue and bone-windowed images.

•  Magnetic Resonance Imaging

Although MRI is less sensitive than CT in the recognition of calcification, it currently remains the procedure of choice for diagnosis of ONSM. High (>/=1.5 tesla) field strength T1-weighted images of the brain and orbit, with fat suppression and gadolinium contrast, are used. ONSMs are typically isointense or slightly hypointense to brain and optic nerve tissue on T1-weighted images. ONSMs are typically hyperintense on T2-weighted images but may also be hypointense.

•  Radiographic Differential Diagnosis

It is not always possible to differentiate ONSM from other lesions involving the optic nerve and meninges. These other lesions include sarcoidosis, demyelinating optic neuritis or perineuritis, orbital inflammatory disease of the optic nerve, orbital schwannoma, lymphoma, hemangiopericytoma, and optic nerve metastasis.Accurate diagnosis depends on the clinical course and occasionally the biopsy.[15]

• Histopathologic Analysis

  • Growth Pattern: Primary and Secondary ONSM

Meningiomas typically grow along paths of least resistance, remaining confined to the subarachnoid or intradural space of the intraorbital optic nerve (Figure 2). The tumor, however, may invade dura, adjacent orbital tissue, muscle, bone, and globe. The neoplastic growth typically intermingles with the optic nerve blood supply from the pial vasculature. Orbital tumors may traverse the optic canal and affect the intracranial segment of the optic nerve or adjacent structures. Similarly, principally intracanalicular lesions (Figure 3) may expand proximally to the intracranial nerve or distally to the orbital segment. Theoretically, lesions may affect adjacent intracranial tissues and spread to the contralateral optic nerve.[16] Such an unusual clinical scenario has not been described in any recently published long-term case series of primary ONSM.[2,17,18]

Figure 2. Intradural optic nerve sheath meningioma. A T1-weighted, contrast-enhanced coronal MRI shows growth of the meningioma in a subdural pattern within the left nerve sheath partially surrounding the optic nerve within (arrow). (Click to enlarge figure)

Figure 3. Left intracanalicular optic nerve sheath meningioma. A T1-weighted, contrast-enhanced coronal MRI shows growth of the meningioma within the left optic canal (arrow). (Click to enlarge figure)

Additional patterns of growth more commonly associated with intracranial meningioma have been described in the orbit associated with secondary orbital spread from intracranial lesions (Figure 4). Large intracranial tumors with secondary extension from adjacent structures (cavernous sinus, falciform ligament, clinoid, sphenoid wing, pituitary fossa, planum sphenoidale, frontal-parietal area, or olfactory groove) more commonly affect both anterior visual pathways.

Figure 4. Secondary optic nerve sheath meningioma. A T1-weighted, contrast-enhanced coronal MRI illustrates enhancing mass affecting the planum sphenoidale (ps), left inferior orbital fissures (iof), and left optic nerve (on) secondarily. (Click to enlarge figure)

•  Histology

Orbital meningiomas have histologic features similar to those of intracranial meningioma. The majority of primary ONSMs are of the transitional type: concentric whorl formations of spindle or ovoid cells, meningothelial (syncytium) with sheets of polygonal cells separated by vascular trabeculae, or a mixture. Psammoma bodies are more common in the transitional pattern. Mitoses, architectural disruption, calcification, and MIB-1 staining are also described.[1,2] Primary orbital meningioma remote from the optic nerve is rare, and some authors maintain that there are diverse sites of origin (eg, ectopic orbital arachnoid, other intraorbital nerve sheaths, orbital mesenchymal cells, intracranial spread through orbital fissures, misdiagnosed lesions).[5,19-22]

• Prognosis

  • Clinical Course

Primary ONSMs are traditionally described as slow growing. Natural history has been extracted from various retrospective series and from published meta-analysis.[1,2,17,18] Data are necessarily plagued by biases of reporting, data acquisition, and dissimilar evaluators, all of which are common to retrospective multicenter studies. In addition, meta-analyses from multiple centers may be based at least partially on the same patient population, and study results should be carefully considered concerning this factor.[1,6,12,13,18,23,24] The location of ONSMs and the intricate relationship to the pial vascular supply have unavoidably contributed to the difficulty in histopathologic confirmation of ONSM. Since most lesions do not undergo biopsy, diagnosis is based solely on clinical findings. This may add further to the misdiagnosis bias in reported case series.

The worst clinical outcome with primary ONSM is ipsilateral blindness, severe proptosis necessitating enucleation or exenteration or, in rare cases, spread to the contralateral optic nerve or contiguous intracranial structures. Secondary ONSMs are more commonly associated with appreciable morbidity or mortality as correlated with the lesion and extent of the primary tumor. The morbidity and mortality related to treatment options must, of necessity, be weighed against these facts, especially in cases of primary ONSM.

•  Visual Outcome in Untreated and Treated Cases

The natural history of visual function in ONSM has only recently been elucidated. Most studies have documented slow, progressive visual loss and tumor growth over years in the affected eye. However, some patients remain stable for many years, while others develop “aggressive” periods with rapid visual loss with or without tumor enlargement. Occasionally, spontaneous improvement in visual function may occur.[17]

Turbin et al[18] studied 59 patients with better than no light perception at presentation. The patients were divided into 4 groups: 13 patients (group 1) were observed only, 12 patients (group 2) had surgery only (4 biopsy or partial resection, 8 total resection), 18 patients (group 3) received radiation alone, and 16 (group 4) had surgery and radiation (14 patients in this group had biopsy or partial resection and radiation, and 2 had total resection and radiation). Visual acuities at diagnosis were statistically similar across the 4 groups (P=.186), with overall distribution of visual acuities at diagnosis >/=20/40 in 56.3%, 20/50 to 20/400 in 12.5%, and <20/400 in 31.3%. At last follow-up, acuities were >/=20/40 in 28.1%, 20/50 to 20/400 in 15.6%, and <20/400 in 56.3% (mean of 150.2 months; range of 51 to 516 months), which worsened as a whole among the 4 groups (P=.004). Utilizing nonparametric analysis, all of the treatment groups showed statistically significant visual loss except the radiation-only group, which showed a trend for loss that was not statistically significant. Graphic representations of the results are presented in Figures 5 and 6.

Figure 5. Bar and whisker plots for nonparametric data. From Turbin RE, Thompson DR, Kennerdell JS, et al. A long-term visual outcome comparison in patients with optic nerve sheath meningioma managed with observation, surgery, radiotherapy, or surgery and radiotherapy. Ophthalmology. 2002; 109:890-899. Reprinted with permission from American Academy of Ophthalmology. (Click to enlarge figure)

Figure 6. Plot of visual acuity expressed as a decimal ratio according to treatment method at initial and final examination (20/20 = 1.0, 20/40 = 0.5, no light perception = 0). Bar and whisker plots for nonparametric data. From Turbin RE, Thompson DR, Kennerdell JS, et al. A long-term visual outcome comparison in patients with optic nerve sheath meningioma managed with observation, surgery, radiotherapy, or surgery and radiotherapy. Ophthalmology. 2002;109:890-899. Reprinted with permission from American Academy of Ophthalmology. (Click to enlarge figure)

Egan and Lessell[17] reported the natural history of 16 untreated patients. At diagnosis, 12 (75%) of the 16 patients had a visual acuity of >/=20/100. At last evaluation, 8 (50%) of the 16 patients had a visual acuity of >/=20/100 in the affected eye. Two patients maintained “stable” visual acuity but developed new visual field defects. Three patients had spontaneous mild improvement of visual acuity of 3 or fewer Snellen lines. In this study, 11 patients (69%) developed visual loss over a mean of 10.2 years. In the meta-analysis of cases prior to 1992, Dutton[1] reported 14% of observed patients maintained “stable vision,” although further details were lacking. Saeed and colleagues[2] found that 71% of 92 untreated and treated eyes maintained a visual acuity of 20/50 or better at a mean fol-low-up of 5.2 years. However, 27% of the eyes worsened to no light perception prior to intervention.

Although visual loss will generally occur in untreated eyes with ONSM, it typically occurs slowly, is limited to the affected eye, and is not associated with mortality. There-fore,treatments must take these natural history data and side effects into account when visual preservation is the primary goal.

•  Growth

In the series by Turbin et al,[18] radiographic progression was observed in 4 patients who were observed only, in 7 patients who had surgery alone, and in 8 patients who had surgery plus radiation. Two patients who had radiation alone demonstrated radiographic progression prior to treatment. Only 2 patients treated with radiation showed radiographic progression after radiotherapy, and both had had at least one surgical procedure prior to the radiotherapy.

Saeed et al[2] estimated annual growth in volume and length to be 3.38 mm3 and 0.12 mm, respectively, in calcified lesions and 23.45 mm3 and 0.6 mm in noncalcified lesions, respectively. However, other reported series have not confirmed risk factors for clinical progression.

Andrews et al[25] described a case series in which [111] Inoctreotide scintigraphy was used to track clinical activity following radiotherapy. These authors believed that octreotide single photon emission-computed tomography (SPECT) brain study provides a sensitive and quantitative assessment of tumor response after radiotherapy. They postulated that [111]In-octreotide scintigraphy “may also provide unambiguous data that allow investigators to differentiate treatment failure (eg, persistent or increasing tracer uptake with visual loss) from treatment-related morbidity (eg, decreasing tracer uptake with visual loss).”

•  Special Case Consideration

Although most meningiomas are histologically benign and slow-growing, aggressive behavior is seen occasionally, particularly in individuals 20 year of age or younger.[26] In some cases, a rapid growth phase is observed during pregnancy.[7,18,27] probably mediated by estrogen, progesterone, or androgen receptors.[28,29] As in other forms of meningioma, stable, known, or occult ONSMs may exhibit accelerated growth and cause visual decline during pregnancy. Finally, tumors documented by long-term clinical follow-up to be stable may occasionally cause rapid visual loss, even in the absence of radiographic enlargement.

• Treatment

For most patients with primary ONSM, fractionated radiation therapy is currently the technique most likely to achieve long-term preservation of visual function.[18] Although entrance criteria (minimum 50-month follow-up) selected for early strategies of fractionated radiothera-py,the study by Turbin and colleagues[18] provides the most comprehensive and durable evidence reported to date detailing the long-term efficacy of radiation therapy compared to other treatment regimens.[30,31] However, other extensive, modern case series provide strong evidence concerning the efficacy of more modern radiotherapy delivery techniques, albeit with shorter duration of follow-up (Table 1).[24,30,31,33]

Table 1. Summary of Treatment Statistics of Modern Conformal Fractionated Techniques (Click to enlarge figure)

•  Radiation Timing and Modality

Radiation therapy is now accepted as the appropriate vision-preserving therapy for the management of ONSM in nondiabetic patients with progressive visual loss.[2,18,23-25,31-39] Although there are no direct data concerning radiation therapy in diabetic patients with ONSM, there are theoretical concerns regarding increased susceptibility of diabetic patients to the vascular complications associated with radiation therapy.[18] The optimum timing of therapy (before, during, or after visual changes) and the optimum radiation strategy — lateral port external beam, fractionated conformal, fractionated stereotactic, intensity-modulated radiation therapy (IMRT) — remain evolving concepts.[2,18,23-25,31-39]

•  Effects of Radiation Treatment

Most radiation side effects are transient and self-limited. They include nausea, vomiting, focal alopecia, swelling, pain, and mild erythematous skin changes. Other side effects that are less frequent and often delayed include visual complications (radiation retinopathy, optic neuropathy, cataract formation, dry eye), cranial nerve dysfunction, pituitary dysfunction, brain necrosis, hearing loss, and new tumor induction (after decades).[31,40,41] Recent advances in achieving greater precision for delivering higher isodose levels to smaller volumes of tissue (thereby reducing the dosage to uninvolved tissue) should theoretically reduce side effects to surrounding tissues. In fact, in 94 patients presenting with vision better than no light perception treated with modern fractionated highly conformal techniques, few significant side effects have been reported (Table 1).[23,25,37-39,42] These data are not strictly comparable to those presented by Turbin et al,[18] which included patients treated with conventional external beam fractionated, conformal fractionated, or combination (fractionated radiotherapy and surgery). In that study, involving 34 patients treated with some form of fractionated radiotherapy with or without surgery, 6 eyes developed radiation retinopathy, 2 eyes developed persistent iritis, 1 patient developed temporal lobe atrophy, and none developed radiation optic neuropathy over a mean of 150 months (range 51 to 516 months). The duration of follow-up in published cases that detail new techniques is more limited, and the future side-effect incidence rate should be determined with longitudinal follow-up.

•  Surgical Role

Given its technical difficulties and trend toward postoperative blindness, surgery for ONSM has largely been replaced by radiation therapy. However, surgery retains its role in biopsy of atypical cases as well as extirpation in those cases in which complete tumor removal is necessary and visual preservation is not possible. The latter circumstance occurs more commonly in aggressive tumors in young patients. At present, microsurgical dissection for primary ONSM is not considered feasible due to the involvement of the pial blood supply to the nerve via neoplasm. Even subtotal resections often lead to blindness.[18] Furthermore, tumor may spread into the orbit and adjacent structures from a biopsy site.[3,18,26] However, authors from two treatment centers have described single cases in which focal tumor was removed, with subsequent improvement in postoperative visual function.[2,13] Although one tumor recurred after microscopic resection, the visual function remained stable.[2,18]

•  Role for Nerve Sheath Surgery

While the majority of patients undergoing surgical manipulation of nerve sheath meningiomas fare poorly, a rare subset of carefully selected patients may benefit from nerve sheath decompressive surgery under special conditions. Saeed et al[2] reported that of 10 patients who underwent nerve sheath decompression, only 1 sustained improved postoperative vision. However, none of these patients received adjuvant therapy. Wladis and colleagues[43] described 2 carefully selected patients, both with unilateral ONSM, who suffered progressive visual loss (20/200 and no light perception) and florid disc edema. The first had previously undergone stereotactic fractionated radiation therapy, and the second was subsequently treated with stereotactic fractionated radiotherapy after salvage surgery. After biopsy and fenestration, visual acuities in the first and second patients had improved to 20/25 and 20/200, respectively, coinciding with resolution of disc edema. Visual function for these patients remains stable at 6 and 2 years, respectively.[43] In these 2 cases, nerve sheath surgery was undertaken only after other treatment options were exhausted, and both required fractionated radiotherapy before or after surgery. However, this approach could ultimately result in orbital spread of the tumor from the fenestration site.[3,18,26]

• Future Direction

Discussions are limited regarding ONSM and alternative methods of management of progressive visual loss after radiation therapy, and no formal studies have been designed to deal with these sequelae. Radiation dose tolerance curves typically preclude radiation boost therapy to the optic nerves, if already treated with conventional radiotherapy doses. Some authors are proponents of chemotherapy (antimetabolites, receptor antagonists) to treat other forms of unresectable meningioma or to deal with failures of previous therapeutic attempts. Some agents (eg, hydroxyurea, mifepristone, interferon alpha, tamoxifen, cyclophosphamide, doxorubicin, vincristine, ifosfamide/mesna, and dacarbazine) may have a modest effect on other meningioma but have limited or no track record for ONSMs.[44-46] Moreover, numerous other agents (eg, STI 571, cilengitide, temozolomide, antineoplaston, SCH 66336, octreotide, erlotinib, gefitinib, imatinib) are in various stages of phase II and III trials involving meningioma with various indications. We have limited experience with these agents and would limit their use to formal rigorous experimental protocol or compassionate therapy until further supportive data are available.

• Conclusions

The diagnosis of ONSM is usually presumptive and based on the appropriate clinical picture supported by appropriate neuroimaging. Biopsy is not routinely advocated, as surgical intervention carries significant morbidity and mortality.

Historically, most patients were observed until vision was lost, tumor progression threatened intracranial invasion, involvement of the contralateral optic nerve occurred, or proptosis became unmanageable. At that point, the tumor would be completely excised, almost invariably leaving the patient blind in the affected eye. Our treatment strategy has included reassessment of patients with ONSM on a 3- to 6-month schedule, with serial neuroophthalmologic and visual field examination, unless progressive symptoms or unusual disease activity indicates sooner and more frequent evaluation. Patients often undergo reimaging at 3 months, and they are followed radiographically at 6- to 12-month intervals after the disease has stabilized.

Although at our institute treatment strategy is individualized, we currently recommend fractionated, highly conformal radiotherapy to patients as soon as serial examination documents a new decline in acuity and/or visual field. Tumor enlargement without loss of visual function, as determined by serial imaging, may also provide an indication for radiotherapy.

The appropriate treatment strategy for radiotherapy is an evolving concept; however, radiotherapy should be delivered via fractionated, 3-dimensional stereotactic techniques that provide the most precise conformal application of the dose to affected tissues. Theoretically, this approach should reduce the risk of side effects to surrounding radiosensitive ocular and neural tissues.

---

References

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16. Trobe JD, Glaser JS, Post JD, et al. Bilateral optic canal meningiomas: a case report. Neurosurgery. 1978;3:68-74.

17. Egan RA, Lessell S. A contribution to the natural history of optic nerve sheath meningiomas. Arch Ophthalmol. 2002;120:1505-1508.

18. Turbin RE, Thompson CR, Kennerdell JS, et al. A long-term visual outcome comparison in patients with optic nerve sheath meningioma managed with observation, surgery, radiotherapy, or surgery and radiotherapy. Ophthalmology. 2002;109:890-899.

19. D’Alena PR. Primary orbital meningioma. Arch Ophthlmol.1964; 1:832-833.

20. Tan KK, Lim AS. Primary extradural intra-orbital meningioma in a Chinese girl. Br J Ophthalmol. 1965;49:377-380.

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22. Benedict WL. Tumors and cysts arising near the apex of the orbit. Am J Ophthalmol. 1922;6:183-201.

23. Pitz S, Becker G, Schiefer U, et al. Stereotactic fractionated irradiation of optic nerve sheath meningioma: a new treatment alternative. Br J Ophthalmol. 2002;86:1265-1268.

24. Becker G, Jeremic B, Pitz S, et al. Stereotactic fractionated radiotherapy in patients with optic nerve sheath meningioma. Int J Radiat Oncol Biol Phys. 2002;54:1422-1429.

25. Andrews DW, Faroozan R, Yang BP, et al. Fractionated stereotactic radiotherapy for the treatment of optic nerve sheath meningiomas: preliminary observations of 33 optic nerves in 30 patients with historical comparison to observation with or without prior surgery. Neurosurgery. 2002;51:890-904.

26. Alper MG. Management of primary optic nerve meningiomas. Current status: therapy in controversy. J Clin Neuroophthalmol. 1981;1:101-117.

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29. Maxwell M, Galanopoulos T, Neville-Golden J, et al. Expression of androgen and progesterone receptors in primary human meningiomas. J Neurosurg. 1993;78:456-462.

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37. Narayan S, Cornblath WT, Sandler HM, et al. Preliminary visual outcomes after three-dimensional conformal radiation therapy for optic nerve sheath meningioma. Int J Radiat Oncol Biol Phys. 2003;56:537-543.

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43. Wladis EJ, Turbin RE, Langer PD, et al. Salvage therapy for ONSM. Presented at the American Academy of Ophthalmology; November 15-18, 2003; Anaheim, Calif.

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45. Kyritsis AP. Chemotherapy for meningiomas. J Neurooncol.1996; 29:269-272.

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The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

December 30, 2008 — Although the incidence of tuberculosis (TB) has decreased in the United States, this infection is a formidable force worldwide. TB can have an insidious presentation, affecting multiple organ systems, including the central nervous system (CNS). Although this may be a rare complication of TB, it can be a devastating omission for the patient. Therefore, it is imperative for health care providers to keep CNS TB in the differential when evaluating neurologic issues. The goal of this article is to enlighten the midlevel provider about the possible presentations of CNS TB, review diagnostic and laboratory studies, and explain treatment options.

Why should we care about tuberculosis (TB)? Recent reports have estimated that the incidence of TB has declined in the United States. Worldwide, it is estimated by the World Health Organization that each year, there are more than eight million new cases of TB, and three million people each year die of TB.[1] Overall, it is estimated that 19% to 43% of the world’s population has TB, including 15 to 30 million Americans. According to the Centers for Disease Control (CDC), 14,517 new cases of TB were reported in the United States during 2004, with foreign-born persons constituting 54%. The top five countries of origin of foreign-born persons with TB were Mexico, the Philippines, Vietnam, India, and China. Additionally, US-born blacks represented 45% of TB cases in the United States and more than 20% of all cases. Of note, Texas, California, and New York accounted for 42% of the overall cases reported in 2004.[2]

Although the overall incidence of TB has declined in the United States in recent years,[2] it is a formidable disease because of its highly infectious nature, insidious presentation, and propensity for latency. Health care workers in the United States need to be able to identify persons who are at risk of or who have contracted TB. As is well known, TB can affect multiple organ systems, the most common being pulmonary. However, research shows that as many as 10% of persons with pulmonary TB develop central nervous system (CNS) TB, which can manifest as meningitis or lesions of the brain or spine.[3,4,5] In addition, extrapulmonary TB, including miliary (disseminated) disease, is on the rise secondary to its increased prevalence in HIV-infected persons, medically underdeveloped populations, and alcohol and intravenous drug abusers.[1,6] For these reasons, it is imperative to maintain a high degree of suspicion when patients with TB risk factors present with neurologic complaints.

• Incidence

The incidence of TB is increasing worldwide.[6] Some reports keep TB as the “leading cause of death due to a single infectious agent” and the seventh leading cause of death and disability worldwide.[3,7] Many factors predispose a person to TB. Bayindir et al[8] state that 95% of their patients had low social, economic, and nutritional conditions. There are approximately 300 to 400 cases of TB meningitis in the United States each year.[9] CNS tuberculomas are seen in 0.55% to 15% of systemic TB cases, depending on the study reviewed.[3,8,10] Intracranial tuberculomas are seen in about 1% of all patients with TB,[6] whereas intradural spinal tuberculomas are reported to be 2% to 5% of CNS tuberculomas.[11]

• Pathogenesis

TB is an infectious disease caused by the obligate aerobic bacillus, Mycobacterium tuberculosis.[12] It is transmitted through inhalation of as few as 1 to 10 aerosolized droplets containing the bacteria. As the bacteria multiply in the alveoli and macrophages of the lung, the complex cell-mediated immune response generates a granulomatous reaction, resulting in a tubercle and caseating necrosis (a small rounded lesion with a necrosing center).[9] Its outer waxy capsule makes it more resistant to destruction. As a result, this bacterium can persist in old necrotic and calcified lesions and is capable of reinitiating growth. If the bacteria are not contained, the infection can be hematogenously spread to other sites.[9]

The location of TB spread to the CNS is directly related to the pattern of blood flow and usually spreads to the cerebral hemispheres and basal ganglia in adults and to the cerebellum in children. The ratio of intramedullary to intracranial lesions are found to relate to spinal cord versus brain weight, about 1:42.[10] Spinal lesions are most often found in the thoracic spine and often present as subacute cord compression.[12]

A tubercle that ruptures in the subarachnoid space results in TB meningitis, whereas deep lesions cause tuberculomas or abscesses. The tuberculoma capsule is composed of fibroblasts, lymphocytes, epithelioid cells, and Langhans giant cells, and its core is a necrotic caseous center.[13,14] When this core liquefies, the lesion becomes a tuberculous abscess, packed with AFB. Vascular inflammation, vasculitis, and edema, which can occur around the lesions, are products of the immune response and can cause additional clinical complications. TB meningitis is a result of an intense hypersensitivity reaction that gives rise to inflammatory changes involving cranial nerves. The inflammation can also affect blood vessels, resulting in vasculitis and subsequent thrombosis or infarction, causing strokelike syndromes. Communicating hydrocephalus can also occur secondary to impedance of cerebrospinal fluid (CSF) circulation and reabsorption.[1] (The arachnoid layer is the primary layer where CSF is reabsorbed.)

• Risk Factors

Only patients with pulmonary TB are infectious[1]; however, the risk factors for developing pulmonary and extrapulmonary TB are comparable.

• Presenting Signs And Symptoms

CNS TB presents in many different ways. A patient may be asymptomatic, have pulmonary symptoms, or have neurologic deficits alone. As one can see from the case studies, all of the patients had headaches, but one had vertigo and another fatigue. CNS TB usually has signs and symptoms of increased intracranial pressure or space-occupying lesions in the brain or spine.[15] Common complaints may include headache, stiff neck, fever, weight loss, blurry vision, confusion, lethargy, nausea, vomiting, and, for spinal cord lesions, lower extremity weakness or bowel or bladder symptoms. Signs of meningitis may include altered mental status, fever, seizure, cranial nerve deficits, papilledema, or meningismus. Patients with tuberculomas will have a physical examination that is consistent with the location in the brain of the space-occupying lesion, which may include cranial nerve deficits, altered mental status, visual changes, hemiparesis, or seizures. Patients with spinal cord lesions will have a physical examination consistent with the location of the lesion in the spinal cord.[8,15]

• Diagnostic Testing

• Imaging

A CT scan of the brain should be done if there is suspicion for intracranial or intramedullary TB. The CT scan should be done with and without contrast. Immature lesions are hypodense and nonenhancing. Mature lesions are isodense to hyperdense with solid, ring, or mixed enhancement. There is a typical target sign suggestive of TB. CT findings are similar to that of many other CNS lesions, including fungal infections, neurosarcoidosis, bacterial infections, and some metastatic disease.[16]

An MRI scan is more specific and sensitive than a CT scan and should be done with and without contrast. T1-weighted images show central isointensity. T2-weighted images show an isotense to hypertense core and a hyperintense rim, ring, or conglomerate of rings with enhancement.[3] MRI findings may also mimic several of the aforementioned lesions.

Figure 1. Brain stem tuberculoma. A, Axial T2 weighted image showing hypointense lesions in left pons. B, Axial T2 weighted image showing hypointense lesions in left midbrain. (Click to enlarge figure)

Figure 2. Brain stem tuberculoma. A, Conglomerate ring enhancing lesions in left pons on post contrast T1 weighted images. B, Conglomerate ring enhancing lesions in left midbrain on post contrast T1 weighted images.(Click to enlarge figure)

Figure3. Brain stem tuberculoma. A, Enhancing lesions in left perisylvian region on post contrast T1 weighted images. B, Post contrast T1 weighted images show ring enhancing lesions in suprasellar and interpeduncular cisterns.(Click to enlarge figure)

• Laboratory Tests

Laboratory results are not discussed much in the literature. Diagnosis is often made on history and physical, suspicion, and diagnostic imaging. Some laboratory findings are listed here.

Cerebrospinal Fluid. Lumbar punctures that remove 10 to 15 mL provide the best information. CSF studies may show normal findings[17] or have elevated protein, decreased glucose, or pleocytosis. Results of CSF polymerase chain reaction tests may be diagnostic.[15,16] Most patients will have an elevated opening pressure as well.[18]

Always get an AFB smear when testing CSF. Although there are a fair amount of false negatives, with serial AFB smears (up to 4) the diagnostic yield is 87%.[9]

Mantoux Tests. Mantoux tests may be positive or negative.

Other Blood Work. Sedimentation rate, C-reactive protein, and white blood cell count may also be elevated.

Biopsy of the lesion should be done if the diagnosis is unclear and the lesion is in an accessible area or if neurologic compromise is present. Histopathology may show a central necrosis, lymphocytes, Langerhans giant cells, or epithelioid cells.[8,11] Bacilli may or may not be present.

• Diagnostic Pathway

No definitive diagnostic pathway is available for CNS TB. Many times the diagnosis is discovered on biopsy. Often, the clinical diagnosis is neoplasm; therefore, it is appropriate to work up the lesion as a neoplasm.

When a patient has a history that is consistent with risk factors for TB, a Mantoux test is an appropriate place to start. If there are any signs of headache or neurologic deficit, CT scan, MRI scan, or both are important tests to order. Scans that reveal lesions should immediately be referred to a neurosurgery team for further workup and diagnosis. Once the diagnosis is finalized, it is important to use a multidisciplinary approach to patient care.

• Differential Diagnosis

Possible differential diagnoses include necrotic tumors, pyogenic abscess, toxoplasmosis, meningitis, lymphoma, and neoplasm.

• Treatment

Surgical intervention for intracranial tuberculomas is generally not recommended because prolonged pharmacologic therapy combined with corticosteroids is usually effective in treating these lesions. However, surgery may be warranted if immediate decompression is necessary or if biopsy is required for definitive diagnosis.[3]

CDC guidelines recommend a 9- to 12-month pharmacologic treatment regimen for CNS TB and offer four regimens for administering treatment. The initial phase of treatment in the first 2 months should include INH, rifampin (RIF), PZA, and EMB. The medications can be given daily throughout the first phase, daily for 2 weeks, and then twice weekly for 6 weeks, or three times weekly throughout. With differing administration schedules come differing doses of the drugs. If the organism’s drug susceptibilities are known, and it is fully susceptible, EMB need not be included in the initial phase. PZA should be avoided in severe liver disease, gout, and, perhaps, pregnancy. The continuation phase should consist of INH and RIF for 7 to 10 months, and this timeline should be prolonged if the patient was initially slow to respond to treatment.[15,19,20] When patients with intracranial tuberculomas experience increased intracranial pressure or neurologic symptoms, corticosteroids can be added to the regimen, although their value is still under investigation.[6,15,17]

Several cases of paradoxical enlargement of intracranial tuberculomas or development of new ones during treatment have been observed.[3,6,15,17] Initiation of steroids in these patients was helpful in many cases, often helping to prevent surgical intervention.[3] The development of intracranial TB lesions while on anti-TB therapy should not be considered a failure of treatment. Rather, treatment should be continued for a prolonged course, and high-dose corticosteroids added to the regimen. Repeat MRI scans should be done every few months to track the lesion or lesions.[3,21]

In addition, many special circumstances are considered when initiating treatment. Drug resistance or history of previous therapy may change the pharmacologic constituents and duration of treatment. In another example, the regimen for children is much the same as the regimen for adults; however, EMB is not frequently used because of its serious side effects of blurred vision, sudden changes in vision, and inability to see the colors red and green. In patients who are HIV positive, the once weekly dosing regimen for the continuation phase is not an option because of the development of resistance to RIF, and those with a CD4 count of less than 100 should receive daily or three times weekly dosing. Furthermore, anti-TB medications interact with antiretroviral agents; therefore, it is recommended that treatment of these patients be deferred to an HIV-related TB specialist. For patients with renal insufficiency or end-stage renal disease, special dosing considerations must be addressed. In the face of liver disease, prudent use of anti-TB drugs is recommended. INH, RIF, and PZA can cause hepatitis or worsen liver disease. However, because of the effectiveness of these drugs, their use is still recommended, depending on results of liver enzyme tests.

If serum aspartate transaminase is more than three times the normal level before initiation of treatment, the CDC offers several alternative regimens. In women who are pregnant or breastfeeding, streptomycin is the only drug that is documented to be harmful to the fetus, causing deafness. (Streptomycin is not commonly used in treatment because of high rates of resistance.) Women who are taking first-line anti-TB drugs can continue breastfeeding because the small concentrations of the drugs in the breast milk do not cause toxicity in the newborn.[19] Dosing and regimen specifics can be found at the CDC website, www.cdc.gov.

The CDC also recommends directly observed therapy for the following situations: pulmonary TB with positive sputum smears, treatment failure, drug resistance, relapse, HIV infection, previous treatment, current or prior substance abuse, psychiatric illness, memory impairment, previous nonadherence to therapy, and children and adolescents.[19]

Social issues that must be considered in successful TB treatment are language barriers, socioeconomic differences, access to resources (transportation, clinic, etc), insurance issues, child care, and housing.[19] As is commonly known, having an effective social support system is essential for successful treatment of most ailments.

• Prognosis

Prognosis varies depending on the studies that are examined. Bayindir et al[8] and Wang et al[4] believe that the outcome depends on the age and clinical stage of the patient. Both studies also suggest that prognosis is worse when there is a rapid deterioration in the patient’s neurologic status. However, Muthukumar et al[11] suggest that medical and surgical outcomes have had good results. Some researchers speculate that a treatment regimen involving surgery (depending on the superficiality of the lesion) and a regimen that is purely pharmacologic will both result in resolution of symptoms. However, it is possible that patients treated with drugs alone are more likely to return to baseline.[15]

• Summary

Although CNS TB is a rare complication of TB, it is a serious disease, and early recognition and treatment are imperative. Early diagnosis can prevent further deterioration and result in better prognosis. When a patient with known TB has neurologic complaints, immediate action must be taken to evaluate for CNS TB. In addition, this diagnosis should be on the differential for any patient seeking treatment with neurologic symptoms, whether or not the patient has been diagnosed with pulmonary TB. CSF studies, CT and MRI scans, the Mantoux test, and brain biopsy, if necessary, can aid in establishing a diagnosis of CNS TB. Although there are varying opinions as to duration of treatment, the addition of corticosteroids, and the role of surgery in treatment, it is generally agreed that the pharmacologic regimen is the mainstay of treatment.

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References

1. Leonard MK. (2002, 10/01/2002). Tuberculosis: forms of tuberculosis. 2002 Oct 1. Available at: www.medscape.com/viewarticle/534783?rssm Accessed May 25, 2006.

2. Centers for Disease Control and Prevention. Reported Tuberculosis in the United States, 2004. Atlanta, GA: US Department of Health and Human Services, CDC; September 2005;.

3. Wasay M, Kheleani BA, Moolani MK, et al.. Brain CT and MRI findings in 100 consecutive patients with intracranial tuberculoma. Neuroimaging. 2003;13(3):240-247.

4. Wang KC, Lin SM, Chen Y, Tseng SH. Multiple tuberculous brain abscesses. Scand J Infect Dis. 2002;34(12):931-934.

5. Skendros P, Kamaria F, Kontopoulos V, Tsitouridis I, Sidiropoulos L. Intradural, extramedullary tuberculoma of the spinal cord as a complication of tuberculous meningitis. Infection. 2003;31(2):115-117.

6. Bas NS, Guzey FK, Emel E, Alatas I, Sel B. Paradoxical intracranial tuberculoma requiring surgical treatment. Pediatr Neurosurg. 2005;41(4):201-205.

7. Akritidis N, Galiastsou E, Kakadellis J, Dimas K, Paparounas K. Brain tuberculomas due to miliary tuberculosis. South Med J. 2005;98(1):111-113.

8. Bayindir C, Mete O, Bilgic B. Retrospective study of 23 pathologically proven cases of central nervous system tuberculomas. Clin Neurol Neurosurg. 2006;108(4):353-357.

9. Porth CM, Kunert MP. Pathophysiology: Concepts of Altered Health States. Philadelphia, PA: Lippincott; 2002;.

10. Jaiswal AK, Jaisqal S, Gupta SK, Singh Gautam VK, Kumar S. Intramedullary tuberculoma of the conus. J Clin Neurosci. 2006;13(8):870-872.

11. Muthukumar N, Venkatesh G, Senthilbabu S, Rajbaskar R. Surgery for intramedullary tuberculoma of the spinal cord: report of 2 cases. Surg Neurol. 2006;66(1):69-74.

12. Citow JS, Ammirati M. Intramedullary tuberculoma of the spinal cord: case report. Neurosurgery. 1994;35(2):327-330.

13. Torii H, Takahashi T, Shimizu H, Watanabe M, Tominaga T. Intramedullary spinal tuberculoma. Neurol Med Chir (Tokyo). 2004;44(5):266-268.

14. Kim TK, Chang KH, Kim CJ, Goo JM, Kook MC, Han MH. Intracranial tuberculoma: comparison of MR with pathologic findings. Am J Neuroradiol. 1995;16(9):1903-1908.

15. Nicolls DJ, King M, Holland D, Bala J, del Rio C. Intracranial tuberculomas developing while on therapy for pulmonary tuberculosis. Lancet Infect Dis. 2005;5(12):795-801.

16. Corr PD. Tuberculosis, CNS. 2004 Nov 5. Available at: www.emedicine.com/radio/topic720.htm. Accessed November 18, 2005.

17. Chanet V, Baud O, Deffond D, Romaszko JP, Beytout J. Pseudotumor presentation of intracerebral tuberculomas. South Med J. 2005;98(4):489-491.

18. Unal S, Sutlas PN. Clinical and radiological features of symptomatic central nervous system tuberculomas. Eur J Neurol. 2005;12(10):797-804.

19. American Thoracic Society; CDC; Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep. 2003;52(RR-11):1-77. Available at: www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm. Accessed January 5, 2007.

20. Bajaj BK. Duration of therapy for tubercular meningitis. 2002 Dec 16. Available at: www.medscape.com/viewarticle/444649. Accessed January 10, 2007.

21. Dennison P, Rajakaruna G. Cerebral tuberculoma [case report]. Thorax. 2006;61(10):922.

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

December 30, 2008 — In L-dopa-naive patients with mild Parkinson’s disease (PD) and urinary urgency, a single dose of the drug increases bladder overactivity. However, after continual dosing, symptoms are reduced substantially, Italian investigators report in the May issue of Neurology.

Dr. Livia Brusa of the University of Rome Tor Vegata and colleagues studied bladder function in 26 patients with mild Parkinson’s disease. Urodynamic sessions were conducted before and 1 hour after administration of a single dose of carbidopa/L-dopa. The patients then went on to chronic L-dopa administration and the urodynamic tests were repeated 2 months later.

After the first administration of the drug, there was an increase in bladder filling sensation. However, after chronic administration, the researchers found a significant 86% improvement of filling sensation in comparison with basal values.

“Our results,” Dr. Brusa told Reuters Health, “strongly suggest that the different acute and chronic L-dopa effects could be due to the different synaptic concentrations obtained with the two modalities.”

Considering dopamine affinity for D1 receptors in comparison with that for D2, she continued, “we assume that after acute L-dopa administration the D2-mediated effect prevails over the D1 mediated effect.” This is in line with findings from animal studies.

“In conclusion,” said Dr. Brusa, “our study demonstrated that chronic L-dopa treatment ameliorated not only motor symptoms but also bladder function in Parkinson’s disease patients reporting urinary urgency.”

References

1. Neurology 2007;68:1455-1459.