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.

Craniocervical Junction and Cervical Spine Anatomy.

This is a detailed review of the embryologic derivation and anatomy of the craniocervical junction and subaxial cervical spine and the correlative radiological imaging anatomy.

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).

Venous sinus thrombosis in traumatic brain injury: a major trauma centre experience.

BACKGROUND: This study explores the presentation, management and outcomes of traumatic venous sinus thrombosis (VST) and identifies risk factors associated with poor outcomes. METHODS: This study is a retrospective review of all patients with VST secondary to trauma who presented to a major trauma centre, between April 2015 and January 2020. VST was confirmed by CT venogram and a consultant neuroradiologist. RESULTS: Forty-six patients were identified (38 male), mean age of 43 (range 12-78) and median follow-up 10.2 months (range 0.7-39.1). Fifty-two percent presented as a severe traumatic brain injury, and all had an associated skull fractures overlying the sinus. Ninety-six percent had cerebral contusions, 96% had an intracranial haematoma, 91% had traumatic subarachnoid haemorrhage (tSAH) and 22% had acute cerebral infarction. Thirty-seven percent of the VSTs were occlusive. Fifty-eight percent had sustained, unprovoked intracranial pressure (ICP) spikes (> 20 mmHg). Fifty percent underwent surgical intervention-20% external ventricular drain and 46% craniotomy/craniectomy. Nine percent were treated with anticoagulation and 4% with antiplatelets, at a median of 13.5 days and 9.5 days post-injury, with no additional complications. Age > 60 was associated with poor outcome (GOS of 3-5) (p = 0.0098). On follow-up CT, 52% of the VSTs remained unchanged, 29% re-canalised, 14% improved and 5% worsened, independent of treatment. CONCLUSIONS: This study demonstrated a higher incidence of VST in severe TBI and strong associations with skull fractures, cerebral contusions, tSAH, raised ICP and surgical intervention. Management was inconsistent, with no difference in outcome with or without anticoagulation. Larger, prospective cohort studies are needed to better understand this condition and establish evidence-based guidelines.

Radiological prediction of contralateral extradural haematoma following evacuation of traumatic acute subdural haematoma.

OBJECTIVES: To identify radiological predictors of contralateral extradural haematoma (CEDH) in patients undergoing evacuation of acute subdural haematoma (ASDH). DESIGN: Retrospective case-control study. SUBJECTS: Patients requiring evacuation of traumatic ASDH via craniotomy/craniectomy with contralateral skull fracture were analysed in two groups: those who developed CEDH postoperatively and those who did not. MATERIALS AND METHODS: Retrospective analysis of severe traumatic brain injury admissions over 24 months (2017-2019) at a major trauma centre. Pre- and post-operative CT scans were reviewed by a Consultant Neuroradiologist for initial fracture haematoma (FH) and specific contralateral skull fracture features (CLFF) comprising: complex petrous fracture, suture diastasis and fractures involving foramen spinosum or middle meningeal groove (MMG). RESULTS: 35 patients had ASDH evacuation (age: 11-74); 7 with craniotomy, 28 with craniectomy. 9/35 developed CEDH of whom 7 underwent bilateral craniotomy/craniectomy. 8/9 with CEDH had FH, 6/26 of those without CEDH had FH. All patients with CEDH had CLFF. 6/9 had >1 CLFF. CLFF was identified in 9/26 patients without CEDH and only 3/26 non-CEDH had >1 CLFF. Analysis using univariate logistic regression identified statistically significant factors for the development of CEDH which were: younger age, FH on initial CT, increasing number of CLFF and MMG involvement alone. After multivariate analysis, only younger age and FH were significant. CONCLUSIONS: FH and CLFF on CT enable prediction of CEDH in patients undergoing evacuation of traumatic ASDH. These features raise a high index of suspicion for this complication and may expedite investigation and management for CEDH.

Severe localised granulomatosis with polyangiitis (Wegener's granulomatosis) manifesting with extensive cranial nerve palsies and cranial diabetes insipidus: a case report and literature review.

BACKGROUND: Granulomatosis with polyangiitis (GPA, formerly Wegener's granulomatosis) is a multisystem vasculitis of small- to medium-sized blood vessels. Cranial involvement can result in cranial nerve palsies and, rarely, pituitary infiltration. CASE PRESENTATION: We describe the case of a 32 year-old woman with limited but severe GPA manifesting as progressive cranial nerve palsies and pituitary dysfunction. Our patient initially presented with localised ENT involvement, but despite treatment with methotrexate, she deteriorated. Granulomatous inflammatory tissue around the skull base resulted in cavernous sinus syndrome, facial nerve palsy, palsies of cranial nerves IX-XII (Collet-Sicard syndrome), and the rare complication of cranial diabetes insipidus due to pituitary infiltration. The glossopharyngeal, vagus and accessory nerve palsies resulted in severe dysphagia and she required nasogastric tube feeding. Her neurological deficits substantially improved with treatment including high dose corticosteroid, cyclophosphamide and rituximab. CONCLUSIONS: This case emphasises that serious morbidity can arise from localised cranial Wegener's granulomatosis in the absence of systemic disease. In such cases intensive induction immunosuppression is required. Analysis of previously reported cases of pituitary involvement in GPA reveals that this rare complication predominantly affects female patients.

Mobility shift of beta-dystroglycan as a marker of GMPPB gene-related muscular dystrophy.

BACKGROUND: Defects in glycosylation of alpha-dystroglycan (α-DG) cause autosomal-recessive disorders with wide clinical and genetic heterogeneity, with phenotypes ranging from congenital muscular dystrophies to milder limb girdle muscular dystrophies. Patients show variable reduction of immunoreactivity to antibodies specific for glycoepitopes of α-DG on a muscle biopsy. Recessive mutations in 18 genes, including guanosine diphosphate mannose pyrophosphorylase B (GMPPB), have been reported to date. With no specific clinical and pathological handles, diagnosis requires parallel or sequential analysis of all known genes. METHODS: We describe clinical, genetic and biochemical findings of 21 patients with GMPPB-associated dystroglycanopathy. RESULTS: We report eight novel mutations and further expand current knowledge on clinical and muscle MRI features of this condition. In addition, we report a consistent shift in the mobility of beta-dystroglycan (ß-DG) on Western blot analysis of all patients analysed by this mean. This was only observed in patients with GMPPB in our large dystroglycanopathy cohort. We further demonstrate that this mobility shift in patients with GMPPB was due to abnormal N-linked glycosylation of ß-DG. CONCLUSIONS: Our data demonstrate that a change in ß-DG electrophoretic mobility in patients with dystroglycanopathy is a distinctive marker of the molecular defect in GMPPB.

The craniocervical junction: embryology, anatomy, biomechanics and imaging in blunt trauma.

Imaging of the blunt traumatic injuries to the craniocervical junction can be challenging but central to improving morbidity and mortality related to such injury. The radiologist has a significant part to play in the appropriate management of patients who have suffered injury to this vital junction between the cranium and the spine. Knowledge of the embryology and normal anatomy as well as normal variant appearances avoids inappropriate investigations in these trauma patients. Osseous injury can be subtle while representing important radiological red flags for significant underlying ligamentous injury. An understanding of bony and ligamentous injury patterns can also give some idea of the biomechanics and degree of force required to inflict such trauma. This will assist greatly in predicting risk for other critical injuries related to vital neighbouring structures such as vasculature, brain stem, cranial nerves and spinal cord. The embryology and anatomy of the craniocervical junction will be outlined in this review and the relevant osseous and ligamentous injuries which can arise as a result of blunt trauma to this site described together. Appropriate secondary radiological imaging considerations related to potential complications of such trauma will also be discussed. TEACHING POINTS: • The craniocervical junction is a distinct osseo-ligamentous entity with specific functional demands. • Understanding the embryology of the craniocervical junction may prevent erroneous radiological interpretation. • In blunt trauma, the anatomical biomechanical demands of the ligaments warrant consideration. • Dedicated MRI sequences can provide accurate evaluation of ligamentous integrity and injury. • Injury of the craniocervical junction carries risk of blunt traumatic cerebrovascular injury.

Pineal and leptomeningeal metastases from a parotid carcinoma ex pleomorphic adenoma.

Carcinoma ex pleomorphic adenoma (CEPA) is an uncommon complication of an untreated pleomorphic adenoma (PA), but one that has a life-threatening significance. This case report documents the clinical, radiological and histopathological features of an extremely rare case of biopsy-proven pineal metastasis, with cerebellopontine and leptomeningeal spread, from CEPA of the parotid gland in spite of the patient having undergone parotidectomy, ipsilateral neck dissection and adjuvant radiotherapy. In spite of the current surgical and oncological treatment of CEPA, the rates of recurrence and distant metastases are high, with a subsequently poor prognostic outcome in most patients. Distant spread is usually to the bones and the lungs; however, more unusual locations have been documented. Our finding of pineal metastasis from CEPA has not previously been reported in the literature. Although this is a rare complication of an unusual condition, the aggressive behaviour of these malignancies warrants close clinical follow-up, with a low threshold for re-imaging and investigation if indicated.

Spectrum of imaging appearances of intracranial cryptococcal infection in HIV/AIDS patients in the anti-retroviral therapy era.

Cryptococcus neoformans infection is the most common fungal infection of the central nervous system (CNS) in advanced human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) patients, but remains a relatively uncommon CNS infection in both the immunocompromised and immunocompetent patient population, rendering it a somewhat elusive and frequently overlooked diagnosis. The morbidity and mortality associated with CNS cryptococcal infection can be significantly reduced by early recognition of the imaging appearances by the radiologist in order to focus and expedite clinical management and treatment. The emergence and evolution of anti-retroviral therapy have also impacted significantly on the imaging appearances, morbidity, and mortality of this neuro-infection. The constellation of varied imaging appearances associated with cryptococcal CNS infection in the HIV and AIDS population in the era of highly active anti-retroviral therapy (HAART) will be presented in this review.

Post-mortem CT and MRI: appropriate post-mortem imaging appearances and changes related to cardiopulmonary resuscitation.

Post-mortem cross-sectional imaging in the form of CT and, less frequently, MRI is an emerging facility in the evaluation of cause-of-death and human identification for the coronial service as well as in assisting the forensic investigation of suspicious deaths and homicide. There are marked differences between the radiological evaluation and interpretation of the CT and MRI features of the live patient (i.e. antemortem imaging) and the evaluation and interpretation of post-mortem CT and MRI appearances. In addition to the absence of frequently utilized tissue enhancement following intravenous contrast administration in antemortem imaging, there are a number of variable changes which occur in the tissues and organs of the body as a normal process following death, some of which are, in addition, affected significantly by environmental factors. Many patients and victims will also have undergone aggressive attempts at cardiopulmonary resuscitation in the perimortem period which will also significantly alter post-mortem CT and MRI appearances. It is paramount that the radiologist and pathologist engaged in the interpretation of such post-mortem imaging are familiar with the appropriate non-pathological imaging changes germane to death, the post-mortem interval and cardiopulmonary resuscitation in order to avoid erroneously attributing such changes to trauma or pathology. Some of the more frequently encountered radiological imaging considerations of this nature will be reviewed.

Branchial cleft anomalies: a pictorial review of embryological development and spectrum of imaging findings.

UNLABELLED: The branchial arches are the embryological precursors of the face, neck and pharynx. Anomalies of the branchial arches are the second most common congenital lesions of the head and neck in children, with second branchial arch anomalies by far the most common. Clinically, these congenital anomalies may present as cysts, sinus tracts, fistulae or cartilaginous remnants with typical clinical and radiological findings. We review the normal embryological development of the branchial arches and the anatomical structures of the head and neck that derive from each arch. The typical clinical and radiological appearances of both common and uncommon branchial arch abnormalities are discussed with an emphasis on branchial cleft anomalies. KEY POINTS: • Anomalies of the branchial arches usually present as cysts, sinuses or fistulae. • Second branchial arch anomalies account for approximately 95 % of cases. • There are no pathognomonic imaging features so diagnosis depends on a high index of suspicion and knowledge of typical locations. • Persistent cysts, fistulae or recurrent localised infection may be due to branchial arch anomalies. • Surgical excision of the cyst or tract is the most common curative option.

Is it time to target no evident disease activity (NEDA) in multiple sclerosis?

The management of multiple sclerosis is becoming increasingly complex with the emergence of new and more effective disease-modifying therapies (DMT). We propose a new treatment paradigm that individualises treatment based on a choice between two interchangeable therapeutic strategies of maintenance-escalation or induction therapy. We propose treating- to-target of no evident disease activity (NEDA) as defined using clinical and MRI criteria. This algorithm requires active monitoring with a rebaselining MRI, at a point in time after the specific DMT concerned has had sufficient time to work, and at least annual MRI studies to monitor for subclinical relapses. Disease activity on the maintenance-escalation therapy arm of the algorithm indicates a sub-optimal treatment response and should trigger a discussion about switching, or escalating, therapy or the consideration of switching to the induction therapy arm of the algorithm. In comparison, disease activity on an induction therapy arm would be an indication for retreatment or a switch to the maintenance-escalation therapy arm. We envisage the definition of NEDA evolving with time as new technological innovations are adopted into clinical practice, for example the normalisation of whole, or regional, brain atrophy rates and cerebrospinal fluid neurofilament levels.

Localization of parathyroid disease with 'sequential multiphase and dual-tracer' technique and comparison with neck ultrasound.

OBJECTIVE: The aim of the study was to evaluate the accuracy of the sequential multiphase and dual-tracer (SMADT) technique utilizing technetium-99m pertechnetate (99mTcO4) and dynamic technetium-99m-2-methoxyisobutylisonitrile (99mTc-MIBI) with single-photon emission computed tomography/computed tomography (SPECT/CT) for localization of hyperfunctioning parathyroid tissue and compare the results with ultrasound (US). MATERIALS AND METHODS: Sixty-four patients with hyperparathyroidism were scanned over 4 years. For the SMADT technique, 80 MBq 99mTcO4 was injected with dynamic thyroid image acquisition started at 20 min, followed by 900 MBq 99mTc-MIBI injection at 30 min; the dynamic imaging continued for 50 min. SPECT was acquired at 60 min, with SPECT/CT of the neck at 3 h. Subsequent subtraction and statistical difference analyses were performed. Neck US was carried out within 3 months. Findings for each parathyroid gland and thyroid were classified as positive or negative. The patients underwent surgical resection of parathyroid tissue on the basis of imaging results. SMADT and US findings were correlated with histology as the gold standard. RESULTS: Eighty-six histological samples were resected. The sensitivity of SMADT for localization to individual glands was 70.6% [95% confidence interval (CI)=58.1-80.7%] and that for neck US was 60.3% (95% CI=47.7-71.8%, P=0.26). Specificity was 94.4% (95% CI=70.6-99.7%) for SMADT and 72.2% (95% CI=46.4-89.2%) for neck US (P=0.13). Sensitivities in multigland disease were 63.6% (95% CI=31.6-87.6%) for SMADT and 36.4% (95% CI=12.4-68.4%) for US (P=0.37) and in nodular thyroid disease were 83.8% (95% CI=67.3-93.2%) and 66.7% (95% CI=48.9-80.9%), respectively (P=0.07). CONCLUSION: SMADT results in better localization of varying parathyroid pathologies and complements the role of US in patients with multigland disease and nodular thyroid.

A surprising cause of unilateral nasal obstruction and epistaxis: nasal septal schwannoma.

Schwannomas of the head and neck are the most common form of benign nerve sheath tumours, most commonly arising in the form of vestibular schwannomas. Schwannoma of the nasal cavity is an uncommon presentation of this pathology and specifically Schwannoma of the nasal septum is a rare presentation of this well understood disease process. We present the case of a 31-year-old Eastern European male who presented with unilateral nasal obstruction, congestion and epistaxis of 3 months duration. After imaging and biopsy, the diagnosis of nasal septal schwannoma was made on histological examination. This diagnosis of a unilateral nasal mass in a young man provides an opportunity to discuss the varied presentations of schwannoma as well as to examine to possible causes of nasal and septal masses in this demographic.

Imaging assessment of penetrating injury of the neck and face.

BACKGROUND: Penetrating trauma of the neck and face is a frequent presentation to acute emergency, trauma and critical care units. There remains a steady incidence of both gunshot penetrating injury to the neck and face as well as non-missile penetrating injury-largely, but not solely, knife-related. Optimal imaging assessment of such injuries therefore remains an on-going requirement of the general and specialised radiologist. METHODS: The anatomy of the neck and face-in particular, vascular, pharyngo-oesophageal, laryngo-tracheal and neural anatomy-demands a more specialised and selective management plan which incorporates specific imaging techniques. RESULTS: The current treatment protocol of injuries of the neck and face has seen a radical shift away from expectant surgical exploration in the management of such injuries, largely as a result of advances in the diagnostic capabilities of multi-detector computed tomography angiography (MDCTA), which is now the first-line imaging modality of choice in such cases. CONCLUSION: This review aims to highlight ballistic considerations, differing imaging modalities, including MDCTA, that might be utilised to assist in the accurate assessment of these injuries as well as the specific radiological features and patterns of specific organ-system injuries that should be considered and communicated to surgical and critical care teams. TEACHING POINTS : • MDCTA is the first-line imaging modality in penetrating trauma of the neck and, often, of the face • The inherent deformability of a bullet is a significant factor in its tissue-damaging capabilities • MDCTA can provide accurate assessment of visceral injury of the neck as well as vascular injury • Penetrating facial trauma warrants radiological assessment of key adjacent anatomical structures • In-driven fragments of native bone potentiate tissue damage in projectile penetrating facial trauma.