[Imaging pathologies of the corpus callosum]. / Pathologien des Corpus callosum in der Bildgebung.

The corpus callosum is the largest fiber bundle in the cerebral white matter in the human brain. A multitude of disorders including congenital malformations, acute and chronic traumatic lesions, ischemia, neoplasms, secondary manifestations of metabolic, toxic or degenerative diseases as well as chronic inflammatory and demyelinating diseases can primarily or secondarily affect the corpus callosum. This article presents magnetic resonance imaging (MRI) characteristics of the most relevant diseases affecting the corpus callosum.

[Imaging pathologies of the corpus callosum]. / Pathologien des Corpus callosum in der Bildgebung.

The corpus callosum is the largest fiber bundle in the cerebral white matter in the human brain. A multitude of disorders including congenital malformations, acute and chronic traumatic lesions, ischemia, neoplasms, secondary manifestations of metabolic, toxic or degenerative diseases as well as chronic inflammatory and demyelinating diseases can primarily or secondarily affect the corpus callosum. This article presents magnetic resonance imaging (MRI) characteristics of the most relevant diseases affecting the corpus callosum.

Improvement of functional outcome for patients with newly diagnosed grade 2 or 3 gliomas with co-deletion of 1p/19q - IMPROVE CODEL: the NOA-18 trial.

BACKGROUND: Given the young age of patients with CNS WHO grade 2 and 3 oligodendrogliomas and the relevant risk of neurocognitive, functional, and quality-of-life impairment with the current aggressive standard of care treatment, chemoradiation with PCV, of the tumour located in the brain optimizing care is the major challenge. METHODS: NOA-18 aims at improving qualified overall survival (qOS) for adult patients with CNS WHO grade 2 and 3 oligodendrogliomas by randomizing between standard chemoradiation with up to six six-weekly cycles with PCV and six six-weekly cycles with lomustine and temozolomide (CETEG) (n = 182 patients per group accrued over 4 years) thereby delaying radiotherapy and adding the chemoradiotherapy concept at progression after initial radiation-free chemotherapy, allowing for effective salvage treatment and delaying potentially deleterious side effects. QOS represents a new concept and is defined as OS without functional and/or cognitive and/or quality of life deterioration regardless of whether tumour progression or toxicity is the main cause. The primary objective is to show superiority of an initial CETEG treatment followed by partial brain radiotherapy (RT) plus PCV (RT-PCV) at progression over partial brain radiotherapy (RT) followed by procarbazine, lomustine, and vincristine (PCV) chemotherapy (RT-PCV) and best investigators choice (BIC) at progression for sustained qOS. An event concerning a sustained qOS is then defined as a functional and/or cognitive and/or quality of life deterioration after completion of primary therapy on two consecutive study visits with an interval of 3 months, tolerating a deviation of at most 1 month. Assessments are done with a 3-monthly MRI, assessment of the NANO scale, HRQoL, and KPS, and annual cognitive testing. Secondary objectives are evaluation and comparison of the two groups regarding secondary endpoints (short-term qOS, PFS, OS, complete and partial response rate). The trial is planned to be conducted at a minimum of 18 NOA study sites in Germany. DISCUSSION: qOS represents a new concept. The present NOA trial aims at showing the superiority of CETEG plus RT-PCV over RT-PCV plus BIC as determined at the level of OS without sustained functional deterioration for all patients with oligodendroglioma diagnosed according to the most recent WHO classification. TRIAL REGISTRATION: Clinicaltrials.gov NCT05331521 . EudraCT 2018-005027-16.

[Intracranial vascular malformations]. / Intrakranielle Gefäßmalformationen.

Intracranial vascular malformations range from incidental asymptomatic vascular alterations up to life-threatening vascular disorders. Arteriovenous malformations and dural arteriovenous fistulas are cerebral vascular malformations with arteriovenous shunting of blood. In the majority of cases they are accompanied by an elevated risk of intracerebral hemorrhage and can cause severe symptoms. They can be treated conservatively or interventionally via microneurosurgery, endovascular embolization and radiation therapy. Cavernous malformations, developmental venous anomalies (DVA) and capillary telangiectasia are cerebral vascular malformations without arteriovenous shunting. Cavernous malformations are rarely symptomatic in the form of cerebral hemorrhage, headache or seizures and in such cases an operative treatment can be indicated. The DVA and capillary telangiectasia are usually asymptomatic and do not require treatment.

Glioma imaging in Europe: A survey of 220 centres and recommendations for best clinical practice.

OBJECTIVES: At a European Society of Neuroradiology (ESNR) Annual Meeting 2015 workshop, commonalities in practice, current controversies and technical hurdles in glioma MRI were discussed. We aimed to formulate guidance on MRI of glioma and determine its feasibility, by seeking information on glioma imaging practices from the European Neuroradiology community. METHODS: Invitations to a structured survey were emailed to ESNR members (n=1,662) and associates (n=6,400), European national radiologists' societies and distributed via social media. RESULTS: Responses were received from 220 institutions (59% academic). Conventional imaging protocols generally include T2w, T2-FLAIR, DWI, and pre- and post-contrast T1w. Perfusion MRI is used widely (85.5%), while spectroscopy seems reserved for specific indications. Reasons for omitting advanced imaging modalities include lack of facility/software, time constraints and no requests. Early postoperative MRI is routinely carried out by 74% within 24-72 h, but only 17% report a percent measure of resection. For follow-up, most sites (60%) issue qualitative reports, while 27% report an assessment according to the RANO criteria. A minority of sites use a reporting template (23%). CONCLUSION: Clinical best practice recommendations for glioma imaging assessment are proposed and the current role of advanced MRI modalities in routine use is addressed. KEY POINTS: • We recommend the EORTC-NBTS protocol as the clinical standard glioma protocol. • Perfusion MRI is recommended for diagnosis and follow-up of glioma. • Use of advanced imaging could be promoted with increased education activities. • Most response assessment is currently performed qualitatively. • Reporting templates are not widely used, and could facilitate standardisation.

The Quest for more Research on Painful Diabetic Neuropathy.

A 62-year-old diabetologist diagnosed himself to have diabetes type-2, with an HbA1c of 9.5. Five months after lifestyle intervention and a multi-drug approach, HbA1c was 6.3, systolic blood pressure was below 135mmHg and BMI reduced to 27. But he suffered from severe painful diabetic neuropathy. Therefore he decided to visit his friend, a famous neuroscientist at an even more famous university. He asked him several plain questions: 1. What is the natural course of painful diabetic neuropathy? 2. Why do I have, despite almost normalizing HbA1c, more problems than before? 3. Are you sure my problems are due to diabetes or should we do a nerve biopsy? 4. Are there imaging techniques helpful for the diagnosis of this diabetic complication, starting in the distal nerve endings of the foot and slowly moving ahead? 5. Can you suggest any drug, specific and effective, for relieving painful diabetic neuropathy? This review will use the experts' answers to the questions of the diabetologist, not only to give a summary of the current knowledge, but even more to highlight areas of research needed for improving the fate of patients with painful diabetic neuropathy. Based on the unknowns, which exceed the knowns in diabetic neuropathy, a quest for more public support of research is made.

[Nerve injuries and traumatic lesions of the brachial plexus : Imaging diagnostics and therapeutic options]. / Nervenverletzungen und traumatische Läsionen des Plexus brachialis : Bildgebende Diagnostik und therapeutische Optionen.

CLINICAL/METHODICAL ISSUE: Traumatic lesions of peripheral nerves and the brachial plexus are feared complications because they frequently result in severe functional impairment. The prognosis is greatly dependent on the correct early diagnosis and the right choice of treatment regimen. It is important to distinguish between open and closed injuries. STANDARD RADIOLOGICAL METHODS: Initial imaging must critically evaluate or prove nerve continuity and is commonly achieved by high-resolution ultrasonography. During the further course, reactive soft tissue alterations, such as constrictive scarring or neuroma formation can be detected. In the case of deep nerve and plexus injuries this can be excellently achieved by dedicated magnetic resonance neurography (MRN) sequences. METHODICAL INNOVATIONS: The signal yield from brachial plexus imaging can be critically enhanced by the use of dedicated surface coil arrays. Furthermore, diffusion tensor imaging (DTI) may enable the regeneration potential of a nerve lesion to be recognized in the future. PERFORMANCE: Multiple reports have shown that neurosonography enables a precise evaluation of peripheral nerve structures (up to 90% sensitivity and 95% specificity in nerve transection) and that the method can critically impact on therapeutic decision-making in 60%. Currently, there are only few quantitative data on the exact performance of MRN in traumatic nerve lesions; however, individual reports indicate a high level of agreement with intraoperative findings. PRACTICAL RECOMMENDATIONS: In the initial work-up, especially in the case of peripheral, superficial and lesser nerve injuries, neurosonography is the preferred imaging approach to evaluate nerve integrity and the extent of nerve lesions. In the case of extensive nerve injury of proximal nerves and structures of the plexus as well as in the case of suspected root avulsion MRN is the method of choice.

Multicenter experience with the new SOFIA Plus catheter as a primary local aspiration catheter for acute stroke thrombectomy.

INTRODUCTION: The direct aspiration first pass technique (ADAPT) has been introduced as a rapid and safe endovascular treatment strategy in patients with ischemic stroke. OBJECTIVE: To determine the technical feasibility, safety, and functional outcome with ADAPT using the new large-bore 6F SOFIA Plus catheter. METHODS: A retrospective analysis of prospectively collected data from six university hospitals was performed. The following parameters of all acute stroke procedures (June 2015- January 2016) using the SOFIA Plus catheter were analyzed: accessibility of the thrombus with the catheter, recanalization success (Thrombolysis in Cerebral Infarction ≥2b), time to recanalization, procedure-related complications. Furthermore, National Institutes of Health Stroke Scale (NIHSS) scores at presentation and discharge and the modified Rankin scale (mRS) score at 90 days were recorded. RESULTS: 85 patients were treated using the SOFIA Plus catheter. The occlusion site was the anterior circulation in 94.1%. Median baseline NIHSS score was 18. In 64.7%, ADAPT alone was successful after a median procedure time of 21 min. With additional use of stent retrievers in the remaining cases, the recanalization rate was 96.5%. No catheter-related complications such as dissections were observed. Thrombus migration to a new vascular territory occurred in 4.7% and symptomatic hemorrhage in 4.7%. After 3 months, mRS 0-2 was achieved in 49.4%. Mortality rate was 20%. CONCLUSIONS: In the majority of cases, thrombus aspiration using the SOFIA Plus catheter results in successful recanalization after a short procedure time. With additional use of stent retrievers, a high recanalization rate can be achieved (96.5%). The complication rate was in line with those of previous publications.

Improved Brain Tumor Classification by Sodium MR Imaging: Prediction of IDH Mutation Status and Tumor Progression.

BACKGROUND AND PURPOSE: MR imaging in neuro-oncology is challenging due to inherent ambiguities in proton signal behavior. Sodium-MR imaging may substantially contribute to the characterization of tumors because it reflects the functional status of the sodium-potassium pump and sodium channels. MATERIALS AND METHODS: Sodium-MR imaging data of patients with treatment-naïve glioma WHO grades I-IV (n = 34; mean age, 51.29 ± 17.77 years) were acquired by using a 7T MR system. For acquisition of sodium-MR images, we applied density-adapted 3D radial projection reconstruction pulse sequences. Proton-MR imaging data were acquired by using a 3T whole-body system. RESULTS: We demonstrated that the initial sodium signal of a treatment-naïve brain tumor is a significant predictor of isocitrate dehydrogenase (IDH) mutation status (P < .001). Moreover, independent of this correlation, the Cox proportional hazards model confirmed the sodium signal of treatment-naïve brain tumors as a predictor of progression (P = .003). Compared with the molecular signature of IDH mutation status, information criteria of model comparison revealed that the sodium signal is even superior to IDH in progression prediction. In addition, sodium-MR imaging provides a new approach to noninvasive tumor classification. The sodium signal of contrast-enhancing tumor portions facilitates differentiation among most glioma types (P < .001). CONCLUSIONS: The information of sodium-MR imaging may help to classify neoplasias at an early stage, to reduce invasive tissue characterization such as stereotactic biopsy specimens, and overall to promote improved and individualized patient management in neuro-oncology by novel imaging signatures of brain tumors.

Mechanical Thrombectomy of Distal Occlusions in the Anterior Cerebral Artery: Recanalization Rates, Periprocedural Complications, and Clinical Outcome.

BACKGROUND AND PURPOSE: Patients with acute ischemic stroke in the anterior circulation are at risk for either primary or, following mechanical thrombectomy, secondary occlusion of the anterior cerebral artery. Because previous studies had only a limited informative value, we report our data concerning the frequency and location of distal anterior cerebral artery occlusions, recanalization rates, periprocedural complications, and clinical outcome. MATERIALS AND METHODS: We performed a retrospective analysis of prospectively collected data of patients with acute ischemic stroke undergoing mechanical thrombectomy in the anterior circulation between June 2010 and April 2015. RESULTS: Of 368 patients included in this analysis, we identified 30 (8.1%) with either primary (n = 17, 4.6%) or secondary (n = 13, 3.5%) embolic occlusion of the distal anterior cerebral artery. The recanalization rate after placement of a stent retriever was 88%. Periprocedural complications were rare and included vasospasms (n = 3, 10%) and dissection (n = 1, 3.3%). However, 16 (53.5%) patients sustained an (at least partial) infarction of the anterior cerebral artery territory. Ninety days after the ictus, clinical outcome according to the modified Rankin Scale score was the following: 0-2, n = 11 (36.6%); 3-4, n = 9 (30%); 5-6, n = 10 (33.3%). CONCLUSIONS: Occlusions of the distal anterior cerebral artery affect approximately 8% of patients with acute ischemic stroke in the anterior circulation receiving mechanical thrombectomy. Despite a high recanalization rate and a low complication rate, subsequent (partial) infarction in the anterior cerebral artery territory occurs in approximately half of patients. Fortunately, clinical outcome appears not to be predominately unfavorable.

Pulmonary and circulatory parameter guided anesthesia in patients with ischemic stroke undergoing endovascular recanalization.

BACKGROUND AND PURPOSE: Endovascular recanalization in ischemic stroke is often performed under general anesthesia. Some studies have shown a detrimental effect of general anesthesia. The reasons are unknown. METHODS: This was an observational study with retrospective and prospective phases. From 2008 to 2010, 60 patients treated by endovascular recanalization due to proximal vessel occlusion were analyzed with regard to ventilation parameters, blood gas values, blood pressure, and clinical parameters (pre-protocol phase). Subsequently, a protocol with target values for end-tidal CO2 (Petco2) and systolic blood pressure (SBP) was introduced and prospectively analyzed in 64 patients in 2012 (protocol phase). RESULTS: In the pre-protocol phase, significant hypocapnia (<30 mm Hg), a decrease in SBP after intervention (p<0.001), and an increase in SBP after extubation (p<0.001) were observed. After implementing the protocol in 2012, 63% of Petco2 values and 55% of SBP values (median) of the duration of intervention were within the predefined range. Severe hypocapnia and hypotension (SBP <100 mm Hg) after the intervention were significantly reduced. Longer duration of Petco2 values within 40-45 mm Hg, intracerebral hemorrhage, longer door to needle time, older age, unsuccessful recanalization, longer duration of endovascular treatment, and higher cumulative dose of norepinephrine were associated with an unfavorable outcome (modified Rankin Scale score >2). Intracerebral hemorrhage (OR 0.028, p=0.001), age (OR 0.9, p=0.013), and cumulative dose of norepinephrine (OR 0.142, p=0.003) were independent predictors of an unfavorable outcome. CONCLUSIONS: In patients receiving endovascular stroke treatment under general anesthesia, the cumulative dose of norepinephrine was an independent predictor of an unfavorable outcome. Further studies are needed to evaluate the optimal management of blood pressure in these patients, and whether avoidance of catecholamines could partly explain the improved outcomes for patients treated under conscious sedation in retrospective studies.

Advanced MR Imaging in Neuro-oncology.

The value of magnetic resonance (MR) imaging for the clinical management of brain tumour patients has greatly increased in recent years through the introduction of functional MR sequences. Previously, MR imaging for brain tumours relied for the most part on contrast-enhanced T1-weighted MR sequences but today with the help of advanced functional MR sequences, the pathophysiological aspects of tumour growth can be directly visualised and investigated. This article will present the pathophysiological background of the MR sequences relevant to neuro-oncological imaging as well as potential clinical applications. Ultimately, we take a look at possible future developments for ultra-high-field MR imaging.

[Cerebral MR imaging of malignant melanoma]. / Zerebrale MR-Bildgebung beim malignen Melanom.

CLINICAL/METHODICAL ISSUE: Melanoma is the third leading cancer entity to metastasize to the central nervous system (CNS) after lung and breast cancer. This is often an early event in the disease course and limits survival. Metastasis in the CNS is the cause of death in 10-40 % of melanoma patients and the incidence of brain metastasis is even higher (50-75 %). Cerebral metastases are commonly found in the subcortical white matter. The signal characteristics can vary substantially and may change over time due to hemorrhages or the accumulation of melanin and paramagnetic ions. It is not yet clear whether novel targeted therapies (e.g. immunotherapy and kinase inhibitors) alter imaging characteristics. Also immune-related side effects, such as hypophysitis (in approximately 5 % of patients receiving ipilimumab therapy) or granulomatous disease (neurosarcoid) can occur. STANDARD RADIOLOGICAL METHODS: Melanoma metastases are usually hyperdense in computed tomography (CT). In magnetic resonance imaging (MRI) T2-weighted (T2-w) fluid-attentuated inversion recovery (FLAIR) and T1-w sequences (with and without i.v. contrast) should be obtained. Coronal and axial imaging planes should be scanned to cross-correlate findings. METHODICAL INNOVATIONS: Susceptibility-weighted imaging is a new sensitive method to detect melanoma metastases. Approximately 66 % of melanoma metastases show intratumoral susceptibility signals (ITSS). This sets them apart from other metastases (e.g. lung and breast cancer show less ITSSs, specificity approximately 81-96 %). Diffusion imaging plays no major role in melanoma brain imaging. PERFORMANCE: Susceptibility-weighted imaging increases the sensitivity to detect metastases but lacks specificity. Differentiating metastases, microbleeding or calcification can be impossible. It is controversial how to interpret susceptibility signals without correlative signs on other sequences (differential diagnosis: metastasis, microbleeding and calcification). PRACTICAL RECOMMENDATIONS: CNS metastases are common in melanoma. MRI screening starting in stage IIc should be considered even in asymptomatic patients. Stage IV requires quarterly MRI examinations. Melanotic and amelanotic metastases show different MRI characteristics. The differentiation between metastasis and microbleeding can be impossible and might require a follow-up scan. Susceptibility-weighted imaging increases the sensitivity of metastases detection but lacks specificity. It can help to differentiate between different metastatic entities.

[Pituitary gland tumors]. / Hypophysentumoren.

BACKGROUND AND OBJECTIVES: This article gives an overview of the most common tumors of the pituitary gland and the differential diagnostics with special emphasis on radiological diagnostic criteria. MATERIAL AND METHODS: A selective search of the literature in PubMed was carried out. RESULTS: Pituitary adenomas constitute 10-15% of all intracranial tumors and are the most common tumors of the sellar region. Tumors smaller than 1 cm in diameter are called microadenomas while those larger than 1 cm in diameter are called macroadenomas. Approximately 65% of pituitary gland adenomas secrete hormones whereby approximately 50% secrete prolactin, 10% secrete growth hormone (somatotropin) and 6% secrete corticotropin. Other tumors located in the sella turcica can also cause endocrinological symptoms, such as an oversecretion of pituitary hormone or pituitary insufficiency by impinging on the pituitary gland or its stalk. When tumors spread into the space cranial to the sella turcica, they can impinge on the optic chiasm and cause visual disorders. A common differential diagnosis of a sellar tumor is a craniopharyngeoma. In children up to 10% of all intracranial tumors are craniopharyngeomas. Other differential diagnoses for sellar tumors are metastases, meningiomas, epidermoids and in rare cases astrocytomas, germinomas or Rathke cleft cysts CONCLUSION: As these tumors are located in an anatomically complex region of the skull base and are often very small, a highly focused imaging protocol is required. The currently favored modality is magnetic resonance imaging (MRI) with the administration of a contrast agent. The sellar region should be mapped in thin slices. In cases of suspected microadenoma the imaging protocol should also contain a sequence with dynamic contrast administration in order to assess the specific enhancement characteristics of the tumor and the pituitary gland.

Evaluation of microvascular permeability with dynamic contrast-enhanced MRI for the differentiation of primary CNS lymphoma and glioblastoma: radiologic-pathologic correlation.

BACKGROUND AND PURPOSE: Dynamic contrast-enhanced MR imaging can provide in vivo assessment of the microvasculature in intracranial tumors. The aim of the present study was to evaluate the diagnostic performance of dynamic contrast-enhanced MR imaging derived vascular permeability parameters, including the volume transfer constant, the volume of extravascular extracellular space, and the flux rate constant between the extravascular extracellular space and plasma, for the differentiation of primary CNS lymphoma and glioblastoma. MATERIALS AND METHODS: Sixty glioblastomas and 11 primary central nervous system lymphomas were included. Pretreatment T1-weighted dynamic contrast-enhanced MR imaging with a 3D T1-weighted spoiled gradient-echo sequence was performed on a 3T MR imaging scanner. Perfusion parameters (volume transfer constant, the volume of extravascular extracellular space, and the flux rate constant) were measured on the basis of the Tofts-Kernmode model. The Mann-Whitney U test and receiver operating characteristic analysis were used to compare those parameters between primary central nervous system lymphoma and glioblastoma. Histopathologic correlation of dynamic contrast-enhanced MR imaging findings was performed by using reticulin staining and CD31 immunohistochemistry. RESULTS: Median volume transfer constant and flux rate constant values were significantly higher in primary central nervous system lymphoma (0.145 ± 0.057 and 0.396 ± 0.088) than in glioblastoma (0.064 ± 0.021 and 0.230 ± 0.058) (P < .001, respectively). Median volume of extravascular extracellular space values did not differ significantly between primary central nervous system lymphoma (0.434 ± 0.165) and glioblastoma (0.319 ± 0.107). On receiver operating characteristic analysis, volume transfer constant had the best discriminative value for differentiating primary central nervous system lymphoma and glioblastoma (threshold, 0.093; sensitivity, 90.9%; specificity, 95.0%). Histopathologic evaluation revealed intact vascular integrity in glioblastoma despite endothelial proliferation, whereas primary central nervous system lymphoma demonstrated destroyed vessel architecture, thereby promoting vascular disintegrity. CONCLUSIONS: Primary central nervous system lymphoma demonstrated significantly higher volume transfer constant and flux rate constant values compared with glioblastoma, implying a higher vascular permeability in primary central nervous system lymphoma. These findings confirm initial observations from perfusion CT and dynamic contrast-enhanced MR imaging studies, correlating with underlying histopathologic features, and may be useful in distinguishing primary central nervous system lymphoma from glioblastoma.

Thoracic outlet syndrome in 3T MR neurography-fibrous bands causing discernible lesions of the lower brachial plexus.

OBJECTIVES: To investigate whether targeted magnetic resonance neurography (MRN) of the brachial plexus can visualise fibrous bands compressing the brachial plexus and directly detect injury in plexus nerve fascicles. METHODS: High-resolution MRN was employed in 30 patients with clinical suspicion of either true neurogenic thoracic outlet syndrome (TOS) or non-specific TOS. The protocol for the brachial plexus included a SPACE (3D turbo spin echo with variable flip angle) STIR (short tau inversion recovery), a sagittal-oblique T2-weighted (T2W) SPAIR (spectral adiabatic inversion recovery) and a 3D PDW (proton density weighted) SPACE. Images were evaluated for anatomical anomalies compressing the brachial plexus and for abnormal T2W signal within plexus elements. Patients with abnormal MR imaging findings underwent surgical exploration. RESULTS: Seven out of 30 patients were identified with unambiguous morphological correlates of TOS. These were verified by surgical exploration. Correlates included fibrous bands (n = 5) and pseudarthrosis or synostosis of ribs (n = 2). Increased T2W signal was detected within compressed plexus portion (C8 spinal nerve, inferior trunk, or medial cord) and confirmed the diagnosis. CONCLUSIONS: The clinical suspicion of TOS can be diagnostically confirmed by MRN. Entrapment of plexus structures by subtle anatomical anomalies such as fibrous bands can be visualised and relevant compression can be confirmed by increased T2W signal of compromised plexus elements. KEY POINTS: • MR neurography (MRN) can aid the diagnosis of thoracic outlet syndrome (TOS). • Identifiable causes of TOS in MRN include fibrous bands and bony anomalies. • Increased T2W signal within brachial plexus elements indicate relevant nerve compression. • High positive predictive value allows confident and targeted indication for surgery.

[Clinically isolated syndrome]. / Klinisch isoliertes Syndrom.

A clinically isolated syndrome (CIS) is a term which describes the first clinical onset of a potential multiple sclerosis (MS). It ought to be defined as an MS stage rather than a separate disease entity; however, with respect to the diagnostic work-up, differential diagnoses to be considered, prognostic factors for the development of a clinically confirmed MS and initiation of an immunomodulatory therapy, there are some important considerations supported by recent studies. These considerations as well as the current guidelines are critically discussed in this review article. Additionally, recommendations are given regarding the management of radiologically isolated syndrome (RIS) an imaging-based diagnosis of a potential preclinical stage of MS.

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment.

An essential mode of acquired resistance to radiotherapy (RT) appears to be promotion of tumor cell motility and invasiveness in various cancer types, including glioblastoma, a process resembling 'evasive resistance'. Hence, a logical advancement of RT would be to identify suitable complementary treatment strategies, ideally targeting cell motility. Here we report that the combination of focal RT and mammalian target of rapamycin (mTOR) inhibition using clinically relevant concentrations of temsirolimus (CCI-779) prolongs survival in a syngeneic mouse glioma model through additive cytostatic effects. In vitro, the mTOR inhibitor CCI-779 exerted marked anti-invasive effects, irrespective of the phosphatase and tensin homolog deleted on chromosome 10 status and counteracted the proinvasive effect of sublethal irradiation. Mechanistically, we identified regulator of G-protein signaling 4 (RGS4) as a novel target of mTOR inhibition and a key driver of glioblastoma invasiveness, sensitive to the anti-invasive properties of CCI-779. Notably, suppression of RGS4-dependent glioma cell invasion was signaled through both mTOR complexes, mTORC1 and mTORC2, in a concentration-dependent manner, indicating that high doses of CCI-779 may overcome tumor-cell resistance associated with the sole inhibition of mTORC1. We conclude that combined RT and mTOR inhibition is a promising therapeutic option that warrants further clinical investigation in upfront glioblastoma therapy.

Accumulation of non-compressive fascicular lesions underlies NF2 polyneuropathy.

A distinct polyneuropathy (PNP) syndrome affects up to 66 % of patients with neurofibromatosis II (NF2). Whether this is primarily a diffuse PNP or due to single, surgically amenable mass lesions has not yet been conclusively demonstrated. We aimed to solve this question by investigating the pathomorphological MR imaging correlate of this rare disorder. Eight patients with NF2-PNP were characterized by clinical examination, electrophysiological studies, and genetic analysis. All patients additionally underwent extended peripheral nerve imaging by a novel protocol of large-coverage high-resolution MRI. Quantitative analyses were performed by separately evaluating cross-sectional images, and by categorizing lesions into non-compressive fascicular microlesions (<2 mm), intermediate lesions (2-5 mm), and compressive macrolesions (>5 mm). The predominant imaging findings were non-compressive fascicular microlesions and intermediate lesions. Proximal-to-distal cumulative lesion burden of these lesions correlated strongly with the severity of clinical symptoms of NF2-PNP. In contrast, compressive macrolesions were not found at all in several symptomatic extremities. We conclude that proximal-to-distal accumulation of non-compressive fascicular lesions instead of compressive mass lesions predominantly underlies the clinical manifestation and severity of NF2-associated PNP. Diagnostic management may now be assisted by large-coverage high-resolution imaging of plexus and peripheral nerves. Additionally, the results underscore the feasibility of this new method, which may open up new diagnostic and investigative possibilities for other disseminated disorders of the peripheral nervous system.