A Phase 2A Trial of the Safety and Tolerability of Increased Dose Rifampicin and Adjunctive Linezolid, With or Without Aspirin, for Human Immunodeficiency Virus-Associated Tuberculous Meningitis: The LASER-TBM Trial.

BACKGROUND: Drug regimens that include intensified antibiotics alongside effective anti-inflammatory therapies may improve outcomes in tuberculous meningitis (TBM). Safety data on their use in combination and in the context of human immunodeficiency virus (HIV) are needed to inform clinical trial design. METHODS: We conducted a phase 2, open-label, parallel-design, randomized, controlled trial to assess the safety of high-dose rifampicin, linezolid, and high-dose aspirin in HIV-associated TBM. Participants were randomized (1.4:1:1) to 3 treatment arms (1, standard of care [SOC]; 2, SOC + additional rifampicin [up to 35 mg/kg/d] + linezolid 1200 mg/d reducing after 28 days to 600 mg/d; 3, as per arm 2 + aspirin 1000 mg/d) for 56 days, when the primary outcome of adverse events of special interest (AESI) or death was assessed. RESULTS: A total of 52 participants with HIV-associated TBM were randomized; 59% had mild disease (British Medical Research Council (MRC) grade 1) vs 39% (grade 2) vs 2% (grade 3). AESI or death occurred in 10 of 16 (63%; arm 3) vs 4 of 14 (29%; arm 2) vs 6 of 20 (30%; arm 1; P = .083). The cumulative proportion of AESI or death (Kaplan-Meier) demonstrated worse outcomes in arm 3 vs arm 1 (P = .04); however, only 1 event in arm 3 was attributable to aspirin and was mild. There was no difference in efficacy (modified Rankin scale) between arms. CONCLUSIONS: High-dose rifampicin and adjunctive linezolid can safely be added to the standard of care in HIV-associated TBM. Larger studies are required to determine whether potential toxicity associated with these interventions, particularly high-dose aspirin, is outweighed by mortality or morbidity benefit. CLINICAL TRIALS REGISTRATION: NCT03927313.

Effects of the Lubo cervical collar on airway patency in awake adults - A magnetic resonance imaging study.

INTRODUCTION: Intended for use by prehospital first responders, the Lubo TM cervical collar is an adjustable, radiolucent, single-use device that incorporates a mechanical jaw thrust mechanism. The combination enables non-invasive airway management in cases of trauma where cervical motion restriction is necessary. The potential benefits include use as an airway adjuvant maintaining upper airway patency, reducing provider task loading. The limited research on the device efficacy and safety requires further investigation. METHODS: A randomized, crossover, interventional study was performed to compare mean differences in airway patency at the level of the uvula, epiglottis, tongue and soft palate with and without the Lubo collar in awake volunteers using magnetic resonance imaging (MRI). Fourteen participants each underwent two MRI scans of the upper airway: A control scan with no Lubo collar, and an intervention scan with the Lubo collar applied and jaw thrust mechanism activated. Two independent radiologists measured anterior-posterior diameter of the airway at four anatomical levels on the resulting MRI images. RESULTS: There was no significant difference in mean airway diameter between the control and intervention measurements at any level. Mean (SD; 95% CI: p-value) differences were 0.9 mm (-2.38; 2.3 to 0.5; p=0.17) at the epiglottis, 0.5 mm (1.6; -0.5 to 1.4; p=0.29) at the soft palate, 0.2 mm (2.86; -1.4 to 1.9; p = 0.78) at the tongue, 0.4 mm (4.04; -1.9 to 2.7; p = 0.72) at the uvula. CONCLUSION: The Lubo TM airway collar did not show a significant change in upper airway patency at four anatomical levels measured in awake adult participants. Further research is required to investigate its clinical use in patients that are unable to maintain upper airway tone. Groups of interest would include trauma, obstructive sleep apnoea, obesity and patients under general anaesthesia.

Study protocol for a phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for HIV-associated tuberculous meningitis [LASER-TBM].

Background: Tuberculous meningitis (TBM) is the most lethal form of tuberculosis with a mortality of ~50% in those co-infected with HIV-1. Current antibiotic regimens are based on those known to be effective in pulmonary TB and do not account for the differing ability of the drugs to penetrate the central nervous system (CNS). The host immune response drives pathology in TBM, yet effective host-directed therapies are scarce. There is sufficient data to suggest that higher doses of rifampicin (RIF), additional linezolid (LZD) and adjunctive aspirin (ASA) will be beneficial in TBM yet rigorous investigation of the safety of these interventions in the context of HIV associated TBM is required. We hypothesise that increased dose RIF, LZD and ASA used in combination and in addition to standard of care for the first 56 days of treatment with be safe and tolerated in HIV-1 infected people with TBM. Methods: In an open-label randomised parallel study, up to 100 participants will receive either; i) standard of care (n=40, control arm), ii) standard of care plus increased dose RIF (35mg/kg) and LZD (1200mg OD for 28 days, 600mg OD for 28 days) (n=30, experimental arm 1), or iii) as per experimental arm 1 plus additional ASA 1000mg OD (n=30, experimental arm 2). After 56 days participants will continue standard treatment as per national guidelines. The primary endpoint is death and the occurrence of solicited treatment-related adverse events at 56 days. In a planned pharmacokinetic (PK) sub-study we aim to assess PK/pharmacodynamic (PD) of oral vs IV rifampicin, describe LZD and RIF PK and cerebrospinal fluid concentrations, explore PK/PD relationships, and investigate drug-drug interactions between LZD and RIF. Safety and pharmacokinetic data from this study will inform a planned phase III study of intensified therapy in TBM. Clinicaltrials.gov registration: NCT03927313 (25/04/2019).

Accuracy of plain radiographs in diagnosing biopsy-proven malignant bone lesions.

BACKGROUND: The diagnosis of primary bone tumours is a three-fold approach based on a combination of clinical, radiological and histopathological findings. Radiographs form an integral part in the initial diagnosis, staging and treatment planning for the management of aggressive/malignant bone lesions. Few studies have been performed where the radiologist's interpretation of radiographs is compared with the histopathological diagnosis. OBJECTIVES: The study aimed to determine the frequency of bone tumours at a tertiary hospital in South Africa, and, using a systematic approach, to determine the sensitivity and specificity of radiograph interpretation in the diagnosis of aggressive bone lesions, correlating with histopathology. We also determined the inter-observer agreement in radiograph interpretation, calculated the positive and negative predictive values for aggressive/malignant bone tumours and computed the cumulative effect of multiple radiological signs to determine the yield for malignant bone tumours. METHOD: A retrospective, descriptive and correlational study was performed, reviewing the histopathological reports of all biopsies performed on suspected aggressive bone lesions during a 3-year period from 2012 to 2014. The radiographs were interpreted by three radiologists using predetermined criteria. The sensitivity and specificity of the readers' interpretation of the radiograph as 'benign/non-aggressive' or 'aggressive/malignant' were calculated against the histology, and the inter-rater agreement of the readers was computed using the Fleiss kappa values. RESULTS: Of the 88 suspected 'aggressive or malignant' bone tumours that fulfilled the inclusion criteria, 43 were infective or malignant and 45 were benign lesions at histology. Reader sensitivity in the diagnosis of malignancy/infective bone lesions ranged from 93% to 98% with a specificity of 53% - 73%. The average kappa value of 0.43 showed moderate agreement between radiological interpretation and final histology results. The four radiological signs with the highest positive predictive values were an ill-defined border, wide zone of transition, cortical destruction and malignant periosteal reaction. The presence of all four signs on radiography had a 100% yield for a malignant bone tumour or infective lesion. CONCLUSION: The use of a systemic approach in the interpretation of bone lesions on radiographs yields high sensitivity but low specificity for malignancy and infection. The presence of benign bone lesions with an aggressive radiographic appearance necessitates continuation of the triple approach for the diagnosis of primary bone tumours.

Is computed tomography of the head justified in patients with minor head trauma presenting with Glasgow Coma Scale 15/15?

BACKGROUND: In keeping with radiology departments in tertiary referral hospitals in developing countries offering computed tomography (CT) head scan services, the radiology department at Groote Schuur Hospital (GSH) in the Western Cape of South Africa undertakes several such scans annually. Of these scans, many are undertaken for post-trauma patients with minor head injury (MHI). While there is agreement that MHI patients with Glasgow Coma Scale (GCS) scores of 13-14/15 may well benefit, there is doubt as to the clinical utility of routine CT head scanning in MHI patients with GCS scores of 15/15. OBJECTIVES: This retrospective descriptive study of patient records was undertaken to determine the frequency and clinical significance of any abnormalities found on CT head scans of 460 patients with MHI and GCS scores of 15/15, scanned at GSH between 2012 and 2014. METHOD: Ethical clearance was obtained and the records of 460 MHI patients with GCS scores of 15/15, loss of consciousness (LOC) and amnesia who underwent CT head scanning at GSH between 2012 and 2014 were then retrieved from the Philips picture archiving and communication system (PACS). Patient records, containing illegible referral forms or technically inadequate CT head scans, were excluded from the study. Patients' biographical, clinical and CT head scan data were entered into sequentially numbered data collection forms. These data were tabulated and summed as percentage distributions. Patients' CT head scan findings were reviewed and classified as either showing normal or abnormal features. Abnormalities detected on CT head scans were classified as being either clinically significant or clinically non-significant. RESULTS: Referral forms and CT scan reports were obtained for 460 MHI patients from a sample of 497 patients, calculated by using the equation for estimating a single proportion from a large sample (precision 1.5%). The sample obtained yielded an acceptable response rate of 460/497 (92.6%). Of 460 (100%) scan reports, 320 (69.6%) showed no abnormality, while 140 (30.4%) showed abnormality. Of the 140 abnormal scans, 107 (23.3%) showed clinically non-significant abnormality, while 33 (7.2%) revealed clinically significant abnormality. Twenty-two (4.8%) of these clinically significant scans showed brain contusion and 11(2.4%) showed skull fracture. No subdural or extradural haematoma, shift or herniation were reported and none of the 33 patients whose CT scans showed clinically significant abnormality underwent urgent neurosurgical intervention. CONCLUSION: Of the 460 CT head scans performed at GSH for MHI with LOC but normal GCS between 2012 and 2014, none required urgent neurosurgical intervention. This is in accordance with the 2012 Kimberley Hospital Rule (KHR), a management protocol which indicates that CT head scanning in patients with MHI and GCS scores of 15/15 can safely be delayed for 8 h. An audit of the records of patients excluded from this study coupled with an analysis of data from other Western Cape hospital CT head scan databases could help ensure that this scarce resource is used cost-beneficially for all head-injured patients in the Western Cape catchment area.

Is computed tomography of the head justified in patients with minor head trauma presenting with Glasgow Coma Scale 15/15?

Background: In keeping with radiology departments in tertiary referral hospitals in developing countries offering computed tomography (CT) head scan services, the radiology department at Groote Schuur Hospital (GSH) in the Western Cape of South Africa undertakes several such scans annually. Of these scans, many are undertaken for post-trauma patients with minor head injury (MHI). While there is agreement that MHI patients with Glasgow Coma Scale (GCS)scores of 13­14/15 may well benefit, there is doubt as to the clinical utility of routine CT head scanning in MHI patients with GCS scores of 15/15.Objectives: This retrospective descriptive study of patient records was undertaken to determine the frequency and clinical significance of any abnormalities found on CT head scans of 460 patients with MHI and GCS scores of 15/15, scanned at GSH between 2012 and 2014.Method: Ethical clearance was obtained and the records of 460 MHI patients with GCS scores of 15/15, loss of consciousness (LOC) and amnesia who underwent CT head scanning at GSH between 2012 and 2014 were then retrieved from the Philips picture archiving and communication system (PACS). Patient records, containing illegible referral forms or technically inadequate CT head scans, were excluded from the study. Patients' biographical, clinical and CT head scan data were entered into sequentially numbered data collection forms. These data were tabulated and summed as percentage distributions. Patients' CT head scan findings were reviewed and classified as either showing normal or abnormal features. Abnormalities detected on CT head scans were classified as being either clinically significant or clinically non-significant. Results: Referral forms and CT scan reports were obtained for 460 MHI patients from a sample of 497 patients, calculated by using the equation for estimating a single proportion from a large sample (precision 1.5%). The sample obtained yielded an acceptable response rate of 460/497 (92.6%). Of 460 (100%) scan reports, 320 (69.6%) showed no abnormality, while 140(30.4%) showed abnormality. Of the 140 abnormal scans, 107 (23.3%) showed clinically non-significant abnormality, while 33 (7.2%) revealed clinically significant abnormality. Twenty-two (4.8%) of these clinically significant scans showed brain contusion and 11(2.4%) showed skull fracture. No subdural or extradural haematoma, shift or herniation were reported and none of the 33 patients whose CT scans showed clinically significant abnormality underwent urgent neurosurgical intervention. Conclusion: Of the 460 CT head scans performed at GSH for MHI with LOC but normal GCS between 2012 and 2014, none required urgent neurosurgical intervention. This is in accordance with the 2012 Kimberley Hospital Rule (KHR), a management protocol which indicates that CT head scanning in patients with MHI and GCS scores of 15/15 can safely be delayed for 8 h. An audit of the records of patients excluded from this study coupled with an analysis of data from other Western Cape hospital CT head scan databases could help ensure that this scarce resource is used cost-beneficially for all head-injured patients in the Western Cape catchment area

Pediatric and adult spinal tuberculosis: imaging and pathophysiology.

The prevalence of tuberculosis (TB) has increased in developing and developed countries as a consequence of the AIDS epidemic, immigration, social deprivation, and inadequate TB control and screening programs. Spinal TB may be osseous or nonosseous. Classic findings of multiple contiguous vertebral body involvement, gibbus formation, and subligamentous spread with paravertebral abscesses are optimally evaluated with MR imaging. Nonspondylitic spinal TB is less well described in the literature, may develop in the absence of TB meningitis, and is often associated with meningovascular cord ischemia. Radiologists should be familiar with the spectrum of imaging findings, allowing early diagnosis and treatment of this serious condition.

Traumatic rupture of an intracranial dermoid cyst.

Intracranial dermoid cysts are congenital tumors of ectodermal origin. Rupture of these cysts can occur spontaneously, but rupture in association with trauma is reported infrequently. The diagnosis of rupture is made by the presence of lipid (cholesterol) droplets in the subarachnoid spaces and ventricles. Nonenhanced CT of the head demonstrates multiple foci of low attenuation that correspond with hyperintense signal on T1-weighted MRI. We present a case of an adult patient with rupture of an intracranial dermoid cyst, precipitated by minor trauma.

Reliability and diagnostic performance of CT imaging criteria in the diagnosis of tuberculous meningitis.

INTRODUCTION: Abnormalities on CT imaging may contribute to the diagnosis of tuberculous meningitis (TBM). Recently, an expert consensus case definition (CCD) and set of imaging criteria for diagnosing basal meningeal enhancement (BME) have been proposed. This study aimed to evaluate the sensitivity, specificity and reliability of these in a prospective cohort of adult meningitis patients. METHODS: Initial diagnoses were based on the CCD, classifying patients into: 'Definite TBM' (microbiological confirmation), 'Probable TBM' (diagnostic score ≥10), 'Possible TBM' (diagnostic score 6-9), 'Not TBM' (confirmation of an alternative diagnosis) or 'Uncertain' (diagnostic score of <6). CT images were evaluated independently on two occasions by four experienced reviewers. Intra-rater and inter-rater agreement were calculated using the kappa statistic. Sensitivities and specificities were calculated using both 'Definite TBM' and either 'Definite TBM' or 'Probable TBM' as gold standards. RESULTS: CT scan criteria for BME had good intra-rater agreement (κ range 0.35-0.78) and fair to moderate inter-rater agreement (κ range 0.20-0.52). Intra- and inter-rater agreement on the CCD components were good to fair (κ  =  ranges 0.47-0.81 and 0.21-0.63). Using 'Definite TBM' as a gold standard, the criteria for BME were very specific (61.5%-100%), but insensitive (5.9%-29.4%). Similarly, the imaging components of the CCD were highly specific (69.2-100%) but lacked sensitivity (0-56.7%). Similar values were found when using 'Definite TBM' or 'Probable TBM' as a gold standard. DISCUSSION: The fair to moderate inter-rater agreement and poor sensitivities of the criteria for BME suggest that little reliance should be placed in these features in isolation. While the presence of the CCD criteria of acute infarction or tuberculoma(s) appears useful as rule-in criteria, their absence is of little help in excluding TBM. The CCD and criteria for BME, as well as any new criteria, need to be standardized and validated in prospective cohort studies.

The complexity of HIV vasculopathy.

We present a case and discuss stroke related to human immunodeficiency virus (HIV) infection and the difficulties of reaching a firm diagnosis of the cause of the aneurysmal vasculopathy. In the absence of a clear aetiology we suggest looking for varicella zoster virus (VZV) replication in the cerebrospinal fluid (CSF) by polymerase chain reaction (PCR) and treating with intravenous acyclovir, aiming for HIV control with appropriate antiretroviral therapy and providing suitable antiplatelet agents. If there is a high index of suspicion of VZV, therapy with acyclovir may be prudent even if the CSF PCR is negative (as may occur after the first 2 weeks of reactivation of infection). Determination of a VZV plasma:CSF IgG ratio is not readily available and would only provide surrogate support for a previous VZV infection in the central nervous system compartment.

Rapidly progressive post-transplant lymphoproliferative disease following withdrawal of sirolimus.

Sirolimus, a potent inhibitor of B- and T-cell activation. is a commonly used immunosuppressant after renal transplantation. Withdrawal of sirolimus from the immunosuppression regimen may reduce B-cell surveillance. We present a case of rapidly progressive central nervous system (CNS) polymorphic Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disorder following the withdrawal of sirolimus.

Spinal tuberculosis: magnetic resonance imaging and neurological impairment.

STUDY DESIGN: Retrospective descriptive study. OBJECTIVE: To evaluate the preoperative magnetic resonance imaging (MRI) findings in spinal tuberculosis and identify features that correlate with the neurologic status and outcome. SUMMARY OF BACKGROUND DATA: MRI plays an important role in the diagnosis of spinal tuberculosis with a high specificity and sensitivity. It allows demonstration of bony, soft tissue and neural pathology; however, the clinical correlation is not clear. METHODS: MRI scans of 82 consecutively managed spinal tuberculosis patients over a 4-year period were studied. Data including age, gender, human immunodeficiency virus status, neurologic status were reviewed. This was correlated with preoperative MRI findings including level of involvement, percentage of vertebral body destruction, kyphotic angle, soft tissue involvement, cord size, and cord signal changes. RESULTS: Fifty-two percent of patients presented in a nonambulatory state, 21% mild neurologic deficit, and 27% were intact. Of those with neurologic deficit, significant recovery occurred in 92%, with 74% improving from nonambulatory to ambulatory status. The patients ambulant at presentation had a larger cord dimension than those who were not ambulatory. Cerebrospinal fluid persisting anterior to the cord at the apex of the deformity showed a trend to residual neurologic function. There was no significant correlation found between ambulatory status and the presence of an epidural abscess, kyphotic angle, or vertebral body destruction. There was no evidence of myelomalacia on the MRI scans, but cord signal changes on T2 images were present in 94% of patients presenting with neurologic deficit. CONCLUSION: There is correlation between residual cord size, cerebrospinal fluid remaining anterior to the cord, presence of cord signal changes in the T2-weighted images, and neurologic deficit; however, none were predictive of outcome. There was no significant correlation found between ambulatory status and the presence of an epidural abscess, kyphotic angle, or vertebral body destruction.

Stab injuries to the spinal cord: a retrospective study on clinical findings and magnetic resonance imaging changes.

OBJECTIVE: This study was undertaken to document changes on magnetic resonance imaging (MRI) scans after a stab to the spinal cord. The aim of the study was to determine if routine MRI scans for this type of injury would lead to a change in management. METHOD: All patients with a stab wound to the spinal cord sustained between November 2004 and July 2005 were retrospectively enrolled. All of the patients were examined, a data form was completed, and MRI was performed within 72 hours on arrival at Groote Schuur Hospital. RESULTS: Twenty-two patients were imaged during the study period. MRI results were reported by a neuroradiologist. The most common change seen on MRI scans was a spinal cord tract and cord signal change. Other imaging findings that were documented included cord swelling and extra-axial collections. Progressive neurological deficits developed in two patients, both as a result of sepsis. An intramedullary abscess was found on contrast follow-up imaging in only one of the two patients, and this was surgically drained. Five patients had extradural collections visible on MRI scans; however, all of these patients either had complete cord transection on MRI scans at the time of injury or in cases of incomplete injury (Brown Sequard syndrome), a tract was visibly affecting the hemicord that explained the injury and there was no mass effect from the extradural collection. CONCLUSION: Routine MRI scans performed on admission of patients with stab injuries to the spinal cord did not lead to surgical intervention unless there was progressive neurological deficit. In such cases, a contrast MRI scan should be performed to rule out sepsis as the most likely cause of deterioration.

Stroke in patients with human immunodeficiency virus infection.

OBJECTIVE: To report the nature of stroke in patients infected with human immunodeficiency virus (HIV) in a region with high HIV seroprevalence and describe HIV associated vasculopathy. METHODS: Patients with first ever stroke, infected with HIV and prospectively included in the stroke register of the Groote Schuur Hospital/University of Cape Town stroke unit were identified and reviewed. RESULTS: Between 2000 and 2006, 67 of the 1087 (6.1%) stroke patients were HIV infected. Of these, 91% (n = 61) were younger than 46 years. Cerebral infarction occurred in 96% (n = 64) of the HIV positive patients and intracerebral haemorrhage in 4% (n = 3). HIV infected young stroke patients did not demonstrate hypertension, diabetes, hyperlipidaemia or smoking as significant risk factors for ischaemic stroke. Infection as a risk factor for stroke was significantly more common in HIV positive patients (p = 0.018, OR 6.4, CI 3.1 to 13.2). In 52 (81%) patients with ischaemic stroke, an aetiology was determined. Primary aetiologies comprised infectious meningitides/vasculitides in 18 (28%) patients, coagulopathy in 12 (19%) patients and cardioembolism in nine (14%) patients. Multiple aetiologies were present in seven (11%) patients with ischaemic stroke. HIV associated vasculopathy was identified in 13 (20%) patients. The HIV associated vasculopathy manifested either extracranially (seven patients) as total or significant carotid occlusion or intracranially (six patients) as medium vessel occlusion, with or without fusiform aneurysmal dilation, stenosis and vessel calibre variation. CONCLUSION: Investigation of HIV infected patients presenting with stroke will determine an aetiology in the majority of patients. In our cohort, 20% of patients demonstrated evidence of an HIV associated vasculopathy.

Stroke caused by human immunodeficiency virus-associated intracranial large-vessel aneurysmal vasculopathy.

BACKGROUND: Intracranial aneurysms related to human immunodeficiency virus (HIV) infection have been well described in pediatric patients but not in adults. OBJECTIVE: To describe a case of intracranial large-vessel aneurysmal vasculopathy causing stroke in a 27-year-old HIV-infected woman. DESIGN: Comparison of clinical and histological data with previously published cases. SETTING: A referral hospital stroke unit. Patient A 27-year-old HIV-infected woman presenting with stroke; neuroimaging demonstrated fusiform aneurysmal dilation of the left internal carotid and the left middle cerebral artery and its branches. RESULTS: Autopsy showed degeneration of the elastic lamina, myxoid degeneration, and medial atrophy, causing consequent ectasia of the involved intracranial vessels. CONCLUSION: Aneurysmal dilation of the intracranial arteries occurs in HIV-infected adults, but the pathogenic role of HIV remains unknown.