Five-Year Serial Brain MRI Analysis of Military Members Exposed to Chronic Sub-Concussive Overpressures.

BACKGROUND: The Canadian Special Operations Forces Command conducts explosives operations and training which exposes members to explosive charges at close proximity. This 5-year longitudinal trial was conducted in follow-up to our initial trial which examined military breachers with MRI and EEG pre and post blast exposure. PURPOSE: To examine brain MRI findings in military personnel exposed to multiple repeated blast exposures. STUDY TYPE: Five-year longitudinal prospective trial. POPULATION: Ninety-two males aged 23-42 with an average of 9.4 years of blast exposure. FIELD STRENGTH/SEQUENCE: 3 T brain MRI/T1-weighted 3D with reconstruction in three planes, T2-weighted, T2-weighted fluid attenuated inversion recovery (FLAIR) 3D with reconstruction in three planes, T2-weighted gradient spin echo (GRE), saturation weighted images, DWI and ADC maps, diffusion tensor imaging. ASSESSMENT: All MRI scans were interpreted by the two neuroradiologists and one neuroradiology Fellow in a blinded fashion using a customized neuroradiology reporting form. STATISTICAL TESTS: Matching parametric statistics represented the number of participants whose brain parameters improved or deteriorated over time. Odds ratio (OR) and 95% confidence intervals (CI) were computed using log regression modeling to determine volume loss, white matter lesions, hemosiderosis, gliosis, cystic changes and enlarged Virchow Robin (VR) spaces. A Kappa (κ) statistic with a 95% CI was calculated to determine rater variability between readers. RESULTS: A significant deterioration was observed in volume loss (OR = 1.083, 95% CI 0.678-1.731, permutation test), white matter changes (OR: 0.754, 95% CI 0.442-1.284, permutation test), and enlargement of VR spaces (OR: 0.775, 95% CI 0.513-1.171). Interrater reliability was low: κ = 0.283, 0.156, and 0.557 for volume loss, white matter changes, and enlargement of VR spaces, respectively. DATA CONCLUSION: There were significant changes in brain volume, white matter lesions, and enlargement of VR spaces. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Eagle jugular syndrome accompanied by de novo brainstem cavernous malformation: a case-based systematic review.

BACKGROUND: Eagle jugular syndrome (EJS), recently identified as a cause of cerebrovascular disease (CVD) due to venous obstruction by an elongated styloid process (SP), is reported here alongside a case of concurrent de novo cerebral cavernous malformation (CCM). This study aims to explore the potential causal relationship between EJS and de novo CCM through a comprehensive literature review. METHOD: Systematic literature reviews, spanning from 1995 to 2023, focused on EJS cases with definitive signs and symptoms and de novo CCM cases with detailed clinical characteristics. Data on the pathophysiology and clinical manifestations of EJS, as well as potential risk factors preceding de novo CCM, were collected to assess the relationship between the two conditions. RESULT: Among 14 patients from 11 articles on EJS, the most common presentation was increased intracranial hypertension (IIH), observed in 10 patients (71.4%), followed by dural sinus thrombosis in four patients (28.6%). In contrast, 30 patients from 28 articles were identified with de novo CCM, involving 37 lesions. In these cases, 13 patients developed CCM subsequent to developmental venous anomalies (43%), seven following dural arteriovenous fistula (dAVF) (23%), and two after sinus thrombosis (6%). In a specific case of de novo brainstem CCM, the development of an enlarged condylar emissary vein, indicative of venous congestion due to IJV compression by the elongated SP, was noted before the emergence of CCM. CONCLUSION: This study underscores that venous congestion, a primary result of symptomatic EJS, might lead to the development of de novo CCM. Thus, EJS could potentially be an indicator of CCM development. Further epidemiological and pathophysiological investigations focusing on venous circulation are necessary to clarify the causal relationship between EJS and CCM.

Quiz case: a clinical reasoning challenge in the emergency stroke setting.

A right-handed woman in her 80s was admitted to the emergency department 1 h after sudden-onset global aphasia and right-sided hemiparesis. Medical history included arterial hypertension, dyslipidemia, hyperuricemia, aortic stenosis, osteoporosis, and recent pulmonary embolism. Medication consisted of apixaban, bisoprolol, hydrochlorothiazide, allopurinol, fenofibrate, and vitamin D. Vital parameters (blood pressure, heart rate, body temperature, oxygen saturation) and glycemia were all within normal range. Electrocardiogram showed a first-degree atrioventricular block. The patient was promptly transported to the emergency computed tomography (CT) scanner. Non-contrast brain CT revealed a unilateral hyperdensity in the left caudate and lentiform nuclei. No other intracranial lesion was visualized. Laboratory studies were not yet available at the time of imaging. What is your diagnosis?

Angioarchitecture of the hemorrhagic developmental venous anomaly with stenosis of the collecting vein and cavernous malformation: a case report.

We herein report a case of developmental venous anomaly (DVA) with venous congestion caused by stenosis of the collecting vein that presented with intracerebral hemorrhage (ICH). A 74-year-old woman was referred to our hospital a few days after the onset of motor aphasia. Computed tomography (CT) and magnetic resonance imaging (MRI) showed ICH in the left frontal lobe. Angiography revealed DVA in the left frontal lobe in the late venous phase. Stenosis of the collecting vein of DVA at the entrance to the superior sagittal sinus was detected and accompanied by cavernous malformation (CM) beside DVA. Cone-beam CT revealed the absence of the left septal vein and hypoplastic transverse caudate veins. The patient was treated by blood pressure management and no additional neurological symptoms were detected. DVA develops to compensate for the absence of pial or deep venous systems, and generally benign and clinically asymptomatic. However, the outflow restriction of DVA causes chronic venous hypertension and the formation of CM. These abnormalities are considered to occur during post-natal life and may result in ICH. The risk of hemorrhage needs to be considered in cases of DVA with restricted venous outflow or CM.

Developmental venous anomaly with radiation-induced arteriovenous malformation.

Developmental venous anomaly (DVA) is considered a congenital vascular anatomic variation with normal draining function. Limited cases of DVA with arteriovenous malformation (AVM) in the territory of DVA have been reported, and the etiology of de novo AVM formation remains unknown and speculative. In this case, it is continuously observed that the inappropriate radiosurgery involving the DVA draining veins led to the disruption of DVA radicles and the secondary formation of de novo AVM and hemodynamic aneurysm. This sequential process exhibited in the present case verified that outflow disturbance underlay the potential etiology of AVM formation drained by adjoining DVA. Meanwhile, it also manifested the importance of preserving the integrity of the collecting veins when treating the DVA by any means.

Giant, symptomatic mixed vascular malformation containing a cavernoma, developmental venous anomaly, and capillary telangiectasia in a 19-month-old infant.

Intracranial mixed vascular malformations (MVMs) are defined as any combination of a developmental venous anomaly (DVA), cerebral cavernous malformation (CCM), capillary telangiectasia (CTG), or arteriovenous malformation (AVM) within a single, contiguous lesion. However, most MVMs described in the literature contain only 2 pathologically discrete malformations; juxtaposition of 3 or more abnormalities in a single lesion remains exceedingly rare. We present the case of a 19-month-old female with new onset focal seizures and a 4-cm right basal ganglia lesion initially believed to be an embryonal neoplasm. She subsequently underwent gross total resection (GTR) of the lesion via a transsylvian-transinsular approach. Intraoperatively, the lesion appeared to be heterogenous and highly vascular, with areas of purplish-gray friable tissue. Pathology confirmed the lesion to be a MVM containing a CCM, CTG, and a DVA. This appears to be the first reported case of such a lesion confirmed on pathology in the literature.

Infratentorial developmental venous anomaly concurrent with a cavernoma and dural arteriovenous fistula.

OBJECTIVES: While developmental venous anomaly (DVA) may be associated with cavernous malformation, mixed vascular malformation associated with dural arteriovenous fistula (dAVF) has not been previously reported. We observed a case with rare association of infratentorial DVA, cavernous malformation, and dAVF that presented with cerebellar ataxia. We report our endovascular treatment for this complex cerebrovascular condition. CASE PRESENTATION: A 32-year-old woman with ataxia had an infratentorial DVA associated with a cavernoma and dAVF. The dAVF had two shunting points. The dAVF was fed by the posterior meningeal arteries and drained through the sigmoid sinus into the transverse sinus. The dAVF was also fed by the occipital artery and retrogradely drained through the left jugular bulb into the dilated collecting vein of the DVA. Endovascular embolization was performed for the dAVF and dilated collecting vein of the DVA. Postoperative complications did not occur after embolization with no recurrence for three years. CONCLUSIONS: This is the first reported case of infratentorial DVA associated with a cavernoma and dAVF. Endovascular treatment was effective in treating this symptomatic complex cerebrovascular disorder.

Distant Recurrence of a Cerebral Cavernous Malformation in the Vicinity of a Developmental Venous Anomaly: Case Report of Local Oxy-Inflammatory Events.

BACKGROUND: Cerebral cavernous malformations (CCMs) are a major type of cerebrovascular lesions of proven genetic origin that occur in either sporadic (sCCM) or familial (fCCM) forms, the latter being inherited as an autosomal dominant condition linked to loss-of-function mutations in three known CCM genes. In contrast to fCCMs, sCCMs are rarely linked to mutations in CCM genes and are instead commonly and peculiarly associated with developmental venous anomalies (DVAs), suggesting distinct origins and common pathogenic mechanisms. CASE REPORT: A hemorrhagic sCCM in the right frontal lobe of the brain was surgically excised from a symptomatic 3 year old patient, preserving intact and pervious the associated DVA. MRI follow-up examination performed periodically up to 15 years after neurosurgery intervention demonstrated complete removal of the CCM lesion and no residual or relapse signs. However, 18 years after surgery, the patient experienced acute episodes of paresthesia due to a distant recurrence of a new hemorrhagic CCM lesion located within the same area as the previous one. A new surgical intervention was, therefore, necessary, which was again limited to the CCM without affecting the pre-existing DVA. Subsequent follow-up examination by contrast-enhanced MRI evidenced a persistent pattern of signal-intensity abnormalities in the bed of the DVA, including hyperintense gliotic areas, suggesting chronic inflammatory conditions. CONCLUSIONS: This case report highlights the possibility of long-term distant recurrence of hemorrhagic sCCMs associated with a DVA, suggesting that such recurrence is secondary to focal sterile inflammatory conditions generated by the DVA.

Crossed brainstem syndrome revealing bleeding brainstem cavernous malformation: an illustrative case.

BACKGROUND: Since the nineteenth century, a great variety of crossed brainstem syndromes (CBS) have been described in the medical literature. A CBS typically combines ipsilateral cranial nerves deficits to contralateral long tracts involvement such as hemiparesis or hemianesthesia. Classical CBS seem in fact not to be so clear-cut entities with up to 20% of patients showing different or unnamed combinations of crossed symptoms. In terms of etiologies, acute brainstem infarction predominates but CBS secondary to hemorrhage, neoplasm, abscess, and demyelination have been described. The aim of this study was to assess the proportion of CBS caused by a bleeding episode arising from a brainstem cavernous malformation (BCM) reported in the literature. CASE PRESENTATION: We present the case of a typical Foville syndrome in a 65-year-old man that was caused by a pontine BCM with extralesional bleeding. Following the first bleeding episode, a conservative management was decided but the patient had eventually to be operated on soon after the second bleeding event. DISCUSSION: A literature review was conducted focusing on the five most common CBS (Benedikt, Weber, Foville, Millard-Gubler, Wallenberg) on Medline database from inception to 2020. According to the literature, hemorrhagic BCM account for approximately 7 % of CBS. Microsurgical excision may be indicated after the second bleeding episode but needs to be carefully weighted up against the risks of the surgical procedure and openly discussed with the patient. CONCLUSIONS: In the setting of a CBS, neuroimaging work-up may not infrequently reveal a BCM requiring complex multidisciplinary team management including neurosurgical advice.

Prevalence and anatomical characteristics of developmental venous anomalies: an MRI study.

PURPOSE: Developmental venous anomalies (DVAs) are extreme anatomical venous variations formed by multiple radiating medullary veins, which converge centripetally into a single collecting vein. Their coexistence with symptomatic cavernous malformations (CMs) has been reported in the literature. The aim of this study was to assess the characteristics of DVAs using MRI. METHODS: A total of 6948 head MRIs of adult Caucasian patients were retrospectively analyzed to determine the number and locations of DVAs. We collected the data on the termination of the collecting vein, the prevalence of DVA-related CMs, and MRI FLAIR signal-hyperintensity corresponding to the location of the DVA. RESULTS: At least one DVA was identified in 7.46% of the patients. The prevalence decreased with age, with a Pearson correlation coefficient of - 0.7328. A total of 599 DVAs were identified. Multiple DVAs were found in 10.92% of the patients with DVAs. The DVAs were identified more often in the supratentorial region (73.12%, p < 0.0001), and the most common location was the frontal lobe (35.23%). The collecting vein usually drained into the superficial cerebral veins (68.78%). CMs were observed in 4.14% of the patients with DVAs, and the prevalence showed a positive correlation with age. Signal-intensity abnormalities were identified in the vicinity of 5.18% DVAs. CONCLUSION: Knowledge about characteristics of DVAs and associated anomalies is essential for neuroradiologists and neurosurgeons. The large number of currently available diagnostic studies enables us to assess anatomical variants on a great number of subjects.

Constitutional mismatch repair deficiency (CMMRD) presenting with high-grade glioma, multiple developmental venous anomalies and malformations of cortical development-a multidisciplinary/multicentre approach and neuroimaging clues to clinching the diagnosis.

Constitutional mismatch repair deficiency syndrome (CMMRD) is a rare cancer-predisposition syndrome associated with a high risk of developing a spectrum of malignancies in childhood and adolescence, including brain tumours. In this report, we present the case of an 8-year-old boy with acute headache, vomiting and an episode of unconsciousness in whom brain imaging revealed a high-grade glioma (HGG). The possibility of an underlying diagnosis of CMMRD was suspected radiologically on the basis of additional neuroimaging findings, specifically the presence of multiple supratentorial and infratentorial developmental venous anomalies (DVAs) and malformations of cortical development (MCD), namely, heterotopic grey matter. The tumour was debulked and confirmed to be a HGG on histopathology. The suspected diagnosis of CMMRD was confirmed on immunohistochemistry and genetic testing which revealed mutations in PMS2 and MSH6. The combination of a HGG, multiple DVAs and MCD in a paediatric or young adult patient should prompt the neuroradiologist to suggest an underlying diagnosis of CMMRD. A diagnosis of CMMRD has an important treatment and surveillance implications not only for the child but also the family in terms of genetic counselling.

Sinus pericranii with facial involvement-A great mimicker.

Sinus pericranii is a rare vascular anomaly characterized by an abnormal communication between the intra- and extracranial venous systems through a calvarial defect(s). We present three cases of congenital sinus pericranii with facial involvement, emphasizing its cutaneous presentation with diagnostic pitfalls and discuss the multidisciplinary management of this vascular anomaly.

Recurrent Transient Neurological Deficit Due to Intracerebral Steal Phenomenon in Association with a Developmental Venous Anomaly.

We report a symptomatic developmental venous anomaly (DVA) not causing parenchymal abnormality to provide a pathophysiologic clue in patients with recurrent transient neurologic deficit. A 32-year-old male presented with recurrent transient motor aphasia and headache in the left fronto-temporal region for three years. The symptoms usually lasted for one hour. Brain computed tomography (CT) angiography and magnetic resonance imaging using gradient recalled echo showed a prominent penetrating vein at the left frontal periventricular region. Brain CT perfusion imaging performed during the symptoms revealed increased perfusion in the corresponding area with relatively decreased perfusion in the left fronto-temporal cortices. Digital subtraction angiography revealed collecting venous blood from the left septal and thalamostriate veins draining into the left cavernous sinus without early arteriovenous shunting. In this patient, an inciting incident might have led to imbalance of the venous flow surrounding the DVA, causing venous hypertension and the intracerebral steal phenomenon in the surrounding area. The relatively hypoperfused cortical area adjacent to the DVA could be considered the cause of the transient motor aphasia, while venous hypertension could be the cause of the headache.

Cerebrofacial venous metameric syndrome-spectrum of imaging findings.

Cerebrofacial venous metameric syndrome (CVMS) is a complex craniofacial vascular malformation disorder in which patients have a constellation of venous vascular malformations affecting soft tissues, bone, dura, and neural structures including the eye and brain. It is hypothesized that a somatic mutation responsible for the venous abnormalities occurred prior to migration of the neural crest cells, and because of this, facial, osseous, and cerebral involvement typically follows a segmental or "metameric" distribution. The most commonly recognized form of CVMS is Sturge-Weber syndrome. However, a wide spectrum of CVMS phenotypical presentations exist with various metameric distributions of slow-flow vascular lesions including facial venous vascular malformations, developmental venous anomalies, venous angiomas, cavernous malformations (cavernomas), dural sinus malformations, and maybe even vascular tumors such as cavernous hemangiomas. Awareness of the various manifestations as described herewith is important for treatment and screening purposes.

A rupture risk analysis of cerebral cavernous malformation associated with developmental venous anomaly using susceptibility-weighted imaging.

PURPOSE: To search for the risk factors closely related to cerebral cavernous malformation associated with developmental venous anomaly (CCM-DVA) lesions rupture, laying foundations for the development of reasonable individual treatment plans for patients. METHODS: In this retrospective study, we collected CCM-DVA patients who met the inclusion criteria in our outpatient department from 2014 to 2017, MRI scans were performed including susceptibility-weighted imaging (SWI) and contrast-enhanced imaging, characteristics and basic clinical information were collected then statistically analyzed, CCM-DVA lesions were divided into 3 types according to the location and quantitative relationship between CCM and DVA. RESULTS: A total number of 319 adult patients were identified with 41.2±11.9 years on average, though univariate and multivariate regression analysis, ruptured presentations were more common in patients with prior hemorrhage (p=0.003), type III CCM-DVA lesions (p=0.001), lesions volume>1 cm3 (p<0.001), infratentorial lesions especially located in midbrain (p=0.019), pontine (p=0.007), medulla (p=0.015). Caplan-Meier curve shows a lower Hemorrhage-free survival rate on patients with type III CCM-DVA lesions (log-rank, p=0.0222), functional area lesions (log-rank, p<0.001), lesions volume>1 cm3 (log-rank, p<0.001), infratentorial lesions (log-rank, p=0.0002). CONCLUSION: The classification based on the relationship between CCM and DVA may be meaningful to predict the risk of lesion rupture and CCM lesions next to DVA distal branches showed a higher risk of rupture.

Paediatric developmental venous anomalies (DVAs): how often do they bleed and where?

INTRODUCTION: Developmental venous anomalies (DVAs) are anomalies of venous drainage and considered a low-flow malformation. Studies evaluating natural history and risk factors for intracranial haemorrhage in the paediatric population are rare. We evaluate clinical and radiological features, risk factors and outcomes of paediatric DVAs. METHODS: A retrospective study was conducted over a 10-year period between 2004 and 2014. Medical records, imaging and prospective databases were reviewed. Three-hundred-and-three radiological studies in total were evaluated. RESULTS: Fifty-two children (20 boys and 32 girls [median age: 6 years] were identified with DVAs. Their age distribution was as follows: 1.9% neonates (< 1 month), 11.5% infants (1 month to 1 year), 30.8% 1-5 years, 30.8% 5-12 years and 25% 12-16 years. The majority (92.3%) presented with asymptomatic DVAs identified incidentally. Overall, anatomical distribution revealed predilection for frontal region (42.3%) with other common sites being posterior fossa (17.3%) and basal ganglia (13.5%). Temporal (11.5%), parietal (9.6%) and occipital (5.8%) were the remainder. Associated cavernous malformations (CMs) were present in 3/52 (5.8%), and no DVAs were associated with aneurysms or arteriovenous malformations (AVMs). Three patients had more than one DVA. There were three deaths unrelated to DVAs over median follow-up of 3.8 years. Four patients (7.7%) suffered DVA-related intracranial haemorrhage presenting with neurological deficits. The ages of the children with DVA-related haemorrhages were 21 days, 2 years and 6 months, 7 years and 1 month and 11 years and 7 months. Left-sided DVA haemorrhages predominated (3/4, 75%). The relative risk of a cerebellar DVA haemorrhage compared to its supratentorial counterpart was 5.35 (OR 6.8, 95% CI 0.8-58). DISCUSSION: DVA-related haemorrhage is sevenfold greater in our paediatric cohort compared to adults and is significantly associated with cerebellar location and cavernous malformations. There were no haemorrhages over a median period of 3.8 years of prospective follow-up.

Symptomatic developmental venous anomalies.

Cerebral developmental venous anomalies (DVAs) are variations of venous vascular anatomy related to an underdevelopment of either the superficial or deep venous emissary system, resulting in a dilated transmedullary vein fed by multiple smaller venous radicles responsible for drainage of normal brain parenchyma. While typically benign and found incidentally on imaging studies, DVAs can rarely be symptomatic. The radiographic appearance of DVAs, as well as their symptomatic manifestations, is diverse. Herein, we will discuss the pathophysiology of symptomatic DVAs while providing illustrative case examples depicting each of their pathogenic mechanisms.

Focal limb dystonia caused by a complication of the cerebellar developmental venous anomaly: a case report.

BACKGROUND: There are no established theories regarding the role of the cerebellum in dystonia. We report a case of focal limb dystonia secondary to a vasogenic edema of the dentate nucleus caused by a symptomatic developmental venous anomaly. CASE PRESENTATION: A 44-year-old woman presented with sudden onset dystonia in her left arm for 1 week. Brain imaging revealed vasogenic edema in the deep white matter of the left cerebellar hemisphere, including the left dentate nucleus, secondary to a developmental venous anomaly. 18F-fluorodeoxyglucose positron emission tomography images showed hypometabolism in the corresponding cerebellar deep nuclei without the involvement of other brain regions. She was treated with a steroid. At the one-month follow-up, computed tomography scan demonstrated remission of the cerebellar edema, which was thought to be the cause of dystonia. CONCLUSIONS: This case demonstrates that the cerebellum has an important role in the development of dystonia. Further studies are needed to elucidate the relationship between dystonia and cerebellar dysfunction.

Developmental venous anomalies and brainstem cavernous malformations: a proposed physiological mechanism for haemorrhage.

The incidental diagnosis of both developmental venous anomalies (DVAs) and cavernous malformations (CMs) in the central nervous system is increasing with improved imaging techniques. While classically silent diseases, these cerebrovascular pathologies can follow an aggressive course, particularly when present in the brainstem. In the last decade, substantial research has focussed on KRIT1-mediated tight junction gene expression and their role in CM development. However, our understanding of the physiologic conditions precipitating symptomatic CM development or CM haemorrhage with and without concomitant DVAs, remains lacking. The only established risk factor for CM haemorrhage is a previous history of haemorrhage, and literature currently reports trauma as the only precipitant for symptomatic events. While plausible, this occurs in a minority, with many patients experiencing occult events. This manuscript presents a hypothesis for symptomatic CM events by first discussing the anatomical pathways for intracranial venous outflow via the internal jugular veins (IJV) and vertebral venous plexus (VVP), then exploring the role of venous flow diversion away from the IJVs under physiologic stress during dynamic postural shift. The resultant increase in intracranial venous pressure can exacerbate normal and pre-existing structural DVA pathologies, with repeated exposure causing symptomatic or CM-inducing events. This pathophysiological model is considered in the context of the role of the autonomic nervous system (ANS) in postural intracranial venous outflow diversion, and how this may increase the risk of DVA or CM events. It is hoped that this hypothesis invokes further investigation into precipitants for DVA or CM events and their sequela and, also, furthers the current knowledge on pathophysiological development of DVAs and CMs.

Successful Cesarean Section Deliveries in a Patient with a History of Developmental Venous Anomaly-Induced Hemorrhage.

While hemorrhage can occur because of developmental venous anomalies (DVAs), there is no established opinion concerning their association with pregnancy and childbirth. In the present report, we discuss the case of a now 39-year-old woman with DVA in whom pregnancy and childbirth were successful. When she was 28, she experienced disturbance of consciousness and paralysis on the left side of the body, and brain computed tomography revealed cerebral hemorrhage coupled with subarachnoid hemorrhage. Cerebral angiography revealed a DVA with an arteriovenous shunt, with superficial drainage surrounding the hematoma. No associated cavernous hemangiomas were observed, and the patient was diagnosed with DVA-induced hemorrhage and treated via conservative therapy. Later, at the ages of 32 and 35, she gave birth via Caesarean section under general anesthesia. At the age of 37, she experienced sudden headache and nausea, following which she was again diagnosed with DVA-induced hemorrhage. Fortunately, she experienced no exacerbation of symptoms such as paralysis. However, she currently has mild, residual paralysis on the left side of the body, and she regularly walks to the hospital using a cane for follow-up examinations.