Pan-European, open-label dose titration study of fentanyl buccal tablet in patients with breakthrough cancer pain.

BACKGROUND: Fentanyl buccal tablet (FBT), a rapid onset opioid used to treat breakthrough cancer pain, must be titrated to an effective dose that provides adequate analgesia and minimizes undesirable events. This open-label, randomized study compared the percentage of patients achieving an effective dose of FBT when starting titration at 100 or 200 µg. METHODS: Opioid-tolerant patients with chronic cancer-related pain who experienced up to four breakthrough pain episodes daily were randomized to a starting dose of 100 or 200 µg for the titration period. The dose was increased until an effective dose (100, 200, 400, 600 or 800 µg) providing adequate analgesia with acceptable adverse events was achieved. Patients achieving an effective dose entered a treatment period during which they treated up to eight breakthrough pain episodes with their effective dose. RESULTS: A total of 442 patients from 135 sites in seven European countries were screened. Non-inferiority was established with the percentage of patients achieving an effective dose starting titration at 200 µg (81.4%) compared with the 100-µg (75.2%) starting dose. The most common effective doses of FBT were 200 µg (39.6%) and 400 µg (26.9%). No new safety concerns were identified with use of FBT at doses up to 800 µg per episode. CONCLUSIONS: This study involving a real clinical practice setting showed a similar percentage of patients safely achieving an effective dose by titration starting with 100 versus 200 µg of FBT.

Stroke service: how can we improve and measure outcomes? Consensus summary from a global stroke forum.

The success of acute stroke treatment is first and foremost time-dependent, and the need for improvement in acute stroke management is demonstrated by the fact that only a minority of patients gain access to treatment - in particular, intravenous recombinant tissue plasminogen activator (IV tPA) - within the necessary time window. Standards of acute stroke care vary widely both regionally and nationally; consequently, various healthcare organizations have undertaken initiatives to measure and improve quality of care. To date, most quality measures have been process-based, focusing primarily on metrics of patient care in the acute hospital-based setting (e.g., time to recombinant tPA administration). Therefore, there remains a need for metrics designed to assess how improvements in process translate into patient outcomes. A global forum was convened to share best practice and provide consensus recommendations on core metrics for measuring improvements in access to care and patient outcomes. Recommendations for core metrics of patient outcomes include hospital-based outcomes (e.g., neurological status at 24 h, ambulatory status at discharge) and post-discharge outcomes (e.g., modified Rankin Scale score at 30 and/or 90 days). Recommendations for best practice relating to aspects of people, process, and technology involved in the stroke treatment pathway that may help provide improvements in these core outcome measures are also outlined.

Dynamic MR imaging patterns of cerebral fat embolism: a systematic review with illustrative cases.

Different MR imaging patterns of cerebral fat embolism have been reported in the literature without a systematic review. Our goal was to describe the patterns, explore the relationship between disease course and the imaging patterns, and discuss the underlying mechanism. We reveal 5 distinctive MR imaging patterns: 1) scattered embolic ischemia occurring dominantly at the acute stage; 2) confluent symmetric cytotoxic edema located at the cerebral white matter, which mainly occurs at the subacute stage; 3) vasogenic edematous lesions also occurring at the subacute stage; 4) petechial hemorrhage, which persists from the acute to the chronic stage; and 5) chronic sequelae, occurring at late stage, including cerebral atrophy, demyelinating change, and sequelae of infarction or necrosis. Underlying mechanisms of these imaging patterns are further discussed. Recognition of the 5 evolving MR imaging patterns of cerebral fat embolism may result in adjustment of the appropriate management and improve the outcome.

The ventriculocholecystic shunt: two case reports and a review of the literature.

We describe the re-siting of ventriculoperitoneal shunts to the gallbladder in two children. The first child had a rare case of hydrocephalus associated with plasminogen deficiency. She had had multiple VP shunt revisions due to non-absorption of CSF from the peritoneum. The second had craniopharyngioma-related hydrocephalus with once again a non-absorbing peritoneum. We report no surgical complications in the revisions for both the cases, and there has been a subsequent follow-up of 46 and 28 months, respectively, without incident. A review of the relevant literature describing the use and the performance of ventriculocholecystic shunts in comparison with other ventricular shunts is considered.

Hypertension-related cognitive decline: is the time right for intervention studies?

The importance of lowering blood pressure in hypertensive subjects is well known but the relationship between hypertension and cognitive function has been a subject of considerable controversy. Cross-sectional studies investigating the relationship between blood pressure and cognition have shown conflicting relationships whilst the majority of longitudinal studies have demonstrated elevated blood pressure to be associated with cognitive decline. Randomised studies have demonstrated heterogeneous and sometimes conflicting effects of blood pressure lowering on cognitive function and suggested reasons include multiple mechanisms by which hypertension affects the brain, the variety of cognitive instruments used for assessment and differences in antihypertensive treatments. Chronic hypertension accelerates arteriosclerotic changes in the brain with a disproportionate effect on subcortical circuits associated with cerebral small vessel disease. Randomised clinical trials assessing the cognitive consequences of blood pressure reduction in people with small vessel disease are lacking and many of the existing controversies on the cognitive consequences of blood pressure lowering, especially in older people, arise from the design limitations of studies. This article describes the methodological issues in designing such a trial and the results of a pilot evaluation to see if careful selection of subjects and measurements would make undertaking intervention studies feasible. Given the predicted upswing in people with cognitive impairments, the time is right for randomised clinical trials with specific cognitive end-points to examine the relationship between cognitive function and hypertension and guide practice.

Cerebrovascular reactivity and dynamic autoregulation in ischaemic subcortical white matter disease.

BACKGROUND: It has been suggested that impaired cerebral autoregulation and vasodilatory capacity may play in role in the pathogenesis of the leukoaraiosis seen in small vessel disease. Adequate perfusion of the deep white matter of the brain depends on the relationships between blood pressure (BP), cerebral vasoreactivity and autoregulation. METHODS: 24 h ambulatory BP measurement, quantitative volumetric MRI analysis of white matter lesion (WML) volume and transcranial Doppler ultrasound assessments of CO(2) reactivity in response to hypercapnia and dynamic cerebral autoregulatory index (ARI) were undertaken in 64 patients with cerebral small vessel disease. RESULTS: Subjects had mean 24 h BP 133/76 mm Hg (SD 13/9), median WML volume 7169 (IQR 20497) mm(3), mean CO(2) reactivity 83.6 (SD 37.4)% and mean ARI 5.6 (SD 1.4) (range 0-9). In multivariate models, after adjusting for age, gender, vascular risk profile and WML volume, ARI correlated with 24 h mean BP levels (R(2) = 0.127, t = 2.440, p = 0.019) and CO(2) reactivity correlated with duration of hypertension (R(2) = 0.085, t = -2.244, p = 0.029). In individuals with hypertension for more than 10 years, ARI also correlated with nocturnal BP dipping (r = 0.806, p = 0.002). ARI and CO(2) reactivity were unaffected by WML volumes, and ARI and CO(2) reactivity were unrelated. CONCLUSION: Cerebral autoregulation and CO(2) reactivity are two distinct processes which are not related to WML volume but are related to BP levels and duration of hypertension, respectively. Greater nocturnal dipping was associated with higher ARI values, suggesting preservation of autoregulation in patients with increased vulnerability to reduced cerebral perfusion.

Closed cranial meningocele with no communication to the CNS.

We present a case of two separate closed parietal meningoceles without communication to the CNS and not in the midline. This is the first such case reported in the literature.

Altered cortical activation during a motor task in ALS. Evidence for involvement of central pathways.

OBJECTIVE: To test the hypothesis that patients with amyotrophic lateral sclerosis (ALS) show increased cortical activation during a motor task compared to both healthy controls and patients with muscle weakness due to peripheral lesions. METHODS: Functional magnetic resonance imaging (fMRI) was used to measure activation during a block design paradigm contrasting right hand movements against rest in sixteen patients with ALS, seventeen healthy controls and nine patients with peripheral lesions. The groups were matched for age and gender and the two patient groups were matched for their degree of upper limb weakness. Analysis used a non-parametric approach to perform a 3 way hypothesis-driven comparison between the groups. RESULTS: During the motor task, patients with ALS showed increased cortical activation bilaterally, extending from the sensorimotor cortex [Brodmann areas (BA) 1, 2, 4] posteriorly into the inferior parietal lobule (BA 40) and inferiorly to the superior temporal gyrus (BA 22) when compared to peripheral lesion patients and controls. In addition, ALS patients showed reduced activation in the dorsolateral prefrontal cortex (DLPFC) extending to anterior and medial frontal cortex (BA 8, 9, 10, 32). CONCLUSIONS: We conclude that alterations in cortical function in ALS differ in sensorimotor and prefrontal regions. Importantly, we have shown that these changes do not reflect confounding by weakness or task difficulty, but are likely to be related to upper motor neuron pathology in ALS.

Measuring brain stem and cerebellar damage in parkinsonian syndromes using diffusion tensor MRI.

OBJECTIVE: To use diffusion tensor MRI to quantify and compare degeneration of the pons and cerebellar peduncles in multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and Parkinson disease (PD) and to relate changes in diffusion measures to clinical features and localized atrophy. METHODS: We used a region-of-interest approach to measure changes in fractional anisotropy and mean diffusivity in the middle cerebellar peduncles, decussation of the superior cerebellar peduncles, and pons in 17 patients with MSA, 17 with PSP, 12 with PD, and 12 healthy volunteers. We also evaluated atrophy of the cerebellar peduncles and pons on T2-weighted magnetic resonance images in patients with MSA and PSP. RESULTS: In MSA, fractional anisotropy was markedly reduced in the middle cerebellar peduncles, and mean diffusivity increased both here and in the pons compared with other groups, whereas in PSP, mean diffusivity was strikingly increased in the decussation of superior cerebellar peduncles. Cerebellar ataxia was related to mean diffusivity in the middle cerebellar peduncles (r = 0.71, p = 0.001) and pons (r = 0.60, p = 0.01) in MSA. Diffusion measures were related to localized atrophy in both MSA and PSP. CONCLUSIONS: Diffusion tensor MRI can be used to quantify neurodegenerative processes in different brain stem and cerebellar structures in multiple system atrophy and progressive supranuclear palsy during life, and may have diagnostic value. Larger studies of early, undifferentiated parkinsonian syndromes are indicated to provide estimates of the relative diagnostic value of diffusion measures, atrophy measures, and visual assessment of scans.

Is it worth pursuing surgery for epilepsy in patients with normal neuroimaging?

OBJECTIVE: To determine whether it is worth pursuing surgery for the treatment of epilepsy in patients with normal neuroimaging. METHODS: Two patient populations were studied: (1) 136 consecutive patients who were surgically treated; (2) 105 consecutive patients assessed with chronically implanted intracranial electrodes within the same period. Sixty patients belonged to both groups, and included all 21 patients who had normal neuroimaging. RESULTS: There were no differences in the proportion of patients with favourable outcome between those with normal and those with abnormal neuroimaging, irrespective of whether intracranial recordings were required. Among the 19 operated patients with normal neuroimaging, 74% had a favourable outcome (Engel's seizure outcome grades I and II), and among the 93 patients with abnormal neuroimaging, 73% had favourable outcome (p = 0.96). In patients with temporal resections, 92% of the 13 patients with normal neuroimaging had a favourable outcome, whereas among the 70 patients with abnormal neuroimaging, 80% had a favourable outcome (p = 0.44). In patients with extratemporal resections, two of the six patients with normal neuroimaging had a favourable outcome, while 12 of the 23 patients with abnormal neuroimaging had a favourable outcome (p = 0.65). Among the 105 patients studied with intracranial electrodes, five suffered transitory deficits as a result of implantation, and two suffered permanent deficits (one hemiplegia caused by haematoma and one mild dysphasia resulting from haemorrhage). CONCLUSIONS: It is worth pursuing surgery in patients with normal neuroimaging because it results in good seizure control and the incidence of permanent deficits associated with intracranial studies is low.

Islet isolation under cGMP conditions: replacing the coil.

INTRODUCTION: Clinical islet transplantation is increasingly regulated, with isolation standards defined under current good manufacturing practices (cGMPs). cGMP requires validation of equipment cleaning and sterilization. The automated process for islet isolation requires rapid thermal exchange during processing, manipulating a metal coil containing cellular product into and out of chilled/heated waterbaths. We recognize challenges of validating cleaning and sterilization of this coil and propose replacement with a disposable blood warming system. Our specific aims were to assess the system's ability to accommodate flow rates utilized during various phases of pancreatic digestion and to assess its efficiency of heat exchange and temperature control. METHODS: In a pancreas digestion circuit, heat exchange occurred via the coil in a digital water bath, or Warmflo blood warming bag in a digital warming unit. Temperature within the digestion chamber was assessed using an inserted thermocouple. Time to achieve 37 degrees C was measured for set heating element temperatures 38.5 degrees C to 41 degrees C. Circuit temperature maintenance characteristics were also recorded. RESULTS: The Warmflo bloodbag easily accommodated flows of 150 and 300 mL/min. At all set temperatures, the bag resulted in shorter or equivalent time to 37 degrees C than the coil. Maintenance of 37 degrees C was also equivalent. We have utilized this system for four human islet isolations with mean time to 37 degrees C of 5.5 minutes, without difference in digestion quality. CONCLUSIONS: Use of a disposable blood warming system in place of the coil during islet isolation provides adequate flow characteristics, heat exchange, and temperature control and may facilitate evolution of islet isolation toward cGMP compliance.

Patterns of cerebral blood flow reduction in patients with ischemic leukoaraiosis.

BACKGROUND: Ischemic leukoaraiosis (ILA) refers to diffuse T2-weighted white matter hyperintensity in the context of a previous clinical lacunar stroke. Reduced cerebral blood flow (CBF) in white matter has been demonstrated, but it is not known whether hypoperfusion is confined to lesions or extends into normal-appearing white matter. Demonstrating changes in normal-appearing white matter would provide clues to the importance of hypoperfusion in pathogenesis and would be an obvious target for therapies aimed at restoring white matter blood flow. METHODS: Twenty-one patients with ILA, and 16 age-matched control subjects, underwent exogenous contrast-based quantitative perfusion MRI. CBF was determined both within and outside areas of T2-weighted hyperintensity in both periventricular white matter and the centrum semiovale. RESULTS: CBF of normal-appearing white matter was reduced in periventricular regions (for patients with ILA, 17.9 +/- 5.6 mL/100 g/min; for controls, 21.6 +/- 5.1 mL/100 g/min; p = 0.046). CBF in gray matter and normal-appearing white matter of the centrum semiovale did not differ significantly between groups. In normal-appearing white matter in patients, CBF was higher in the centrum semiovale than periventricular white matter, with a similar trend in control subjects. CONCLUSIONS: Hypoperfusion may be an early feature in the development of periventricular lesions in ILA and may play a direct pathogenic role. Serial studies are now needed to determine whether these changes herald the appearance of new lesions and represent "at risk" white matter, and to determine whether pharmacological agents can restore perfusion of normal-appearing white matter.

Magnetic resonance imaging of cerebral venous sinus thrombosis.

Cerebral venous sinus thrombosis (CVST) represents a diagnostic challenge due to the diversity of clinical presentation. The radiologist should be aware of the common neurological features. Unenhanced CT may show the first indications of venous sinus occlusion. Confirmatory diagnostic imaging should be performed with magnetic resonance imaging (MRI) and magnetic resonance venography (MRV) or computed tomography (CT) venography. We illustrate the MRI and MRV features of the thrombosed venous sinus and venous oedema or infarction and discuss the diagnostic limitations of these techniques.

Alagille syndrome associated with angiographic moyamoya.

We describe the case of a 13-year-old boy with Alagille syndrome in whom intracranial imaging was performed following a seizure. The MRI and MRA revealed changes of angiographic moyamoya within both the anterior and posterior circulation. This very rare manifestation of the systemic vasculopathy in Alagille syndrome has not been previously documented in a patient without a focal neurological deficit. We discuss the potential role of routine intracranial imaging in patients with Alagille syndrome.

Preoperative and early postoperative magnetic resonance imaging in two cases of childhood choroid plexus carcinoma.

We present and illustrate the MRI appearances of two children with choroid plexus carcinoma. The MRI characteristics of these rare tumours are reviewed. Since total surgical resection is a significant prognostic factor, early postoperative MRI was performed in both cases to ensure surgical clearance. In one case a complete resection was documented and this patient remains well at short-term follow-up. Residual tumour was noted in the second case, but despite "second look" surgery there was subsequent local relapse.

MRI based diffusion and perfusion predictive model to estimate stroke evolution.

In this study we present a novel automated strategy for predicting infarct evolution, based on MR diffusion and perfusion images acquired in the acute stage of stroke. The validity of this methodology was tested on novel patient data including data acquired from an independent stroke clinic. Regions-of-interest (ROIs) defining the initial diffusion lesion and tissue with abnormal hemodynamic function as defined by the mean transit time (MTT) abnormality were automatically extracted from DWI/PI maps. Quantitative measures of cerebral blood flow (CBF) and volume (CBV) along with ratio measures defined relative to the contralateral hemisphere (r(a)CBF and r(a)CBV) were calculated for the MTT ROIs. A parametric normal classifier algorithm incorporating these measures was used to predict infarct growth. The mean r(a)CBF and r(a)CBV values for eventually infarcted MTT tissue were 0.70 +/- 0.19 and 1.20 +/- 0.36. For recovered tissue the mean values were 0.99 +/- 0.25 and 1.87 +/- 0.71, respectively. There was a significant difference between these two regions for both measures (p < 0.003 and p < 0.001, respectively). Mean absolute measures of CBF (ml/100g/min) and CBV (ml/100g) for the total infarcted territory were 33.9 +/- 9.7 and 4.2 +/- 1.9. For recovered MTT tissue, the mean values were 41.5 +/- 7.2 and 5.3 +/- 1.2, respectively. A significant difference was also found for these regions (p < 0.009 and p < 0.036, respectively). The mean measures of sensitivity, specificity, positive and negative predictive values for modeling infarct evolution for the validation patient data were 0.72 +/- 0.05, 0.97 +/- 0.02, 0.68 +/- 0.07 and 0.97 +/- 0.02. We propose that this automated strategy may allow possible guided therapeutic intervention to stroke patients and evaluation of efficacy of novel stroke compounds in clinical drug trials.

SPAMM, cine phase contrast imaging and fast spin-echo T2-weighted imaging in the study of intracranial cerebrospinal fluid (CSF) flow.

AIM: To compare the qualitative assessment of cerebrospinal fluid (CSF) flow using a SPAMM (spatial modulation of magnetization) technique with cine phase contrast images (cine PC) and fast spin echo (FSE) T2-weighted images. MATERIALS AND METHODS: SPAMM, PC and T2-weighted sequences were performed on 22 occasions in 19 patients. Eleven of the studies were performed following a neuroendoscopic third ventriculostomy (NTV), and in these cases, the success of the NTV was determined by clinical follow-up. Two observers used consensus to grade the presence of CSF flow at nine different sites for each study. RESULTS: At 14 of the 178 matched sites, which could be assessed by both SPAMM and cine PC, SPAMM CSF flow grade was higher than that of cine PC. At a further 14/178 matched sites, the cine PC grade was higher than that of SPAMM. There was definite CSF flow at 113/182 (62%) of all the cine PC sites assessed, and 110/181 (61%) of all SPAMM sites assessed whilst 108/198 (54%) of FSE T2-weighted image sites demonstrated flow voids. Cine PC grades were higher than SPAMM at the cerebral aqueduct (P < 0.05, Wilcoxon sign rank test). Definite CSF flow within the anterior third ventricle was present in 4/5 (SPAMM) and 3/5 (cine PC) successful NTVs, 0/2 (SPAMM and cine PC) unsuccessful NTVs and 1/10 (SPAMM and cine PC) patients without NTV. CONCLUSION: SPAMM provides a comparable assessment of intracranial CSF flow to that of cine phase contrast imaging at all CSF sites except the cerebral aqueduct.

Congenital midline cleft of the posterior arch of atlas: a rare cause of symptomatic cervical canal stenosis.

Developmental symptomatic C1 canal stenosis is very rare. We describe the computed tomography (CT) and magnetic resonance imaging (MRI) appearances in a 8-year-old child who presented with progressive upper and lower limb neurological symptoms and in whom imaging revealed the medial posterior hemiarches of a bifid C1 to be inturned and compressing the cervical cord. This particular configuration of the posterior arch of atlas is frequently associated with other craniocervical bony anomalies and presents with neurological symptoms early in life. Early CT or MRI examination of patients with symptomatic posterior arch of C1 defects is necessary, in order to detect such an appearance, since surgical treatment may prevent neurological deterioration.

The strange association of pneumosinus dilatans and arachnoid cyst: case report and review of the literature.

BACKGROUND: The authors present the case of a 71-year-old man with dramatic pneumosinus dilatans adjacent to a large, symptomatic, fronto-temporal arachnoid cyst. METHOD: The literature on pneumosinus dilatans and its association with arachnoid cyst is reviewed. FINDINGS: Pneumosinus dilatans may be either idiopathic, a reaction to an adjacent meningioma, or an 'ex-vacuo' response to cerebral volume loss and intracranial hypotension. It is also found with large arachnoid cysts and is probably under-recognised in this context. The co-existence of an expansile intradural lesion with changes in the skull base that tend to reduce the intracranial volume is puzzling, and has not yet been fully explained. Differences in the relative timing of paranasal sinus and arachnoid cyst growth, and the 'temporal agenesis' theory of arachnoid cyst formation have been proposed but do not account for all the features of this unusual association. INTERPRETATION: Pneumosinus dilatans is a useful and under-recognised indicator of the presence and chronicity of a variety of intracranial pathologies. Its association with arachnoid cyst is paradoxical, and a new explanation is offered as to how this may arise.