Search

BACKGROUND Malignant peripheral nerve sheath tumors (MPNSTs) within the neuroaxis are rare, usually arising from peripheral and cranial nerves. Even more scarce are cranial subclassifications of MPNSTs termed “malignant intracerebral nerve sheath tumors” (MINSTs). These tumors are aggressive, with a strong tendency for metastasis. With this presentation, alongside resistance to adjunctive therapy, complete excision is the mainstay of treatment, although it is often insufficient, resulting in a high rate of mortality. OBSERVATIONS The authors report the case of an adult patient with a history of Noonan syndrome (NS) presenting with slowly progressive right-sided hemiparesis and right-sided focal motor seizures. Despite initial imaging and histology suggesting a left frontal lobe high-grade intrinsic tumor typical of a glioblastoma, subsequent molecular analysis confirmed a diagnosis of MINST. The patient’s neurological condition improved after gross-total resection and adjuvant chemo-radiation; he remains on follow-up. LESSONS MINSTs are rare neoplasms with a poor prognosis; management options are limited, with surgery being the cornerstone of treatment. Reports on rare tumors such as this will increase awareness of this particular pathology and disclose clinical experience. In this case, the authors were unable to establish a definite cause-and-effect relation between NS and MINST. Nevertheless, it remains the first reported case in the literature.

Amyloid-β (Aβ) is a peptide deposited in the brain parenchyma in Alzheimer’s disease and in cerebral blood vessels, causing cerebral amyloid angiopathy (CAA). Aβ pathology is transmissible experimentally in animals and through medical procedures in humans, such as contaminated growth hormone or dura mater transplantation in the context of iatrogenic prion disease. Here, we present four patients who underwent neurosurgical procedures during childhood or teenage years and presented with intracerebral haemorrhage approximately three decades later, caused by severe CAA. None of these patients carried pathogenic mutations associated with early Aβ pathology development. In addition, we identified in the literature four patients with a history of neurosurgical intervention and subsequent development of CAA. These findings raise the possibility that Aβ pathology may be transmissible, as prion disease is, through neurosurgical procedures. Electronic supplementary material The online version of this article (10.1007/s00401-018-1822-2) contains supplementary material, which is available to authorized users.

Background: Cardiovascular diseases remain the predominant cause of death worldwide, with the prevalence of heart failure continuing to increase. Despite increased knowledge of the metabolic alterations that occur in heart failure, novel therapies to treat the observed metabolic disturbances are still lacking. Methods: Mice were subjected to pressure overload by means of angiotensin-II infusion or transversal aortic constriction. MicroRNA-146a was either genetically or pharmacologically knocked out or genetically overexpressed in cardiomyocytes. Furthermore, overexpression of dihydrolipoyl succinyltransferase (DLST) in the murine heart was performed by means of an adeno-associated virus. Results: MicroRNA-146a was upregulated in whole heart tissue in multiple murine pressure overload models. Also, microRNA-146a levels were moderately increased in left ventricular biopsies of patients with aortic stenosis. Overexpression of microRNA-146a in cardiomyocytes provoked cardiac hypertrophy and left ventricular dysfunction in vivo, whereas genetic knockdown or pharmacological blockade of microRNA-146a blunted the hypertrophic response and attenuated cardiac dysfunction in vivo. Mechanistically, microRNA-146a reduced its target DLST—the E2 subcomponent of the α-ketoglutarate dehydrogenase complex, a rate-controlling tricarboxylic acid cycle enzyme. DLST protein levels significantly decreased on pressure overload in wild-type mice, paralleling a decreased oxidative metabolism, whereas DLST protein levels and hence oxidative metabolism were partially maintained in microRNA-146a knockout mice. Moreover, overexpression of DLST in wild-type mice protected against cardiac hypertrophy and dysfunction in vivo. Conclusions: Altogether we show that the microRNA-146a and its target DLST are important metabolic players in left ventricular dysfunction.

Patients with congestive myelopathy due to spinal dural arteriovenous fistula (SDAVF) typically present with progressive sensory and motor disturbance in association with sphincter dysfunction. Spinal MRI usually shows longitudinally extensive T2 signal change. Here, we report four patients with progressive myelopathy due to SDAVF who also presented with findings on cerebrospinal fluid (CSF) examination suggestive of an inflammatory aetiology. Such CSF findings in SDAVF are important to recognise, to avoid the erroneous diagnosis of an inflammatory myelitis and inappropriate treatment with immunosuppression. SDAVF can be difficult to detect and may require repeated investigation, with formal angiography as the gold standard.

ObjectivesHereditary Transthyretin (ATTR) amyloidosis is a genetic disorder where insoluble amyloid fibrils deposit in heart, nerves and various musculoskeletal tissues. Early recognition of TTR-FAP is important as new genetic therapies become available.DesignWe present one confirmed and one clinical case of ATTR deposition in ligamentum flavum causing lumbar canal stenosis.SubjectsThe first case is a 44-year-old female with TTR 184S heterozygous mutation who developed urinary urgency and bilateral leg pain exacerbated by walking. Neurological examination was normal. MRI lumbar spine showed a disc bulge in combination with ligamentum flavum thickening at L2/3 causing stenosis of the vertebral canal. She had a laminectomy of the L2/3 level. Histopathological analysis of the surgical tissue was positive on Congo red staining for amyloid and immunohistochemically identified as TTR type. The second case is a 68-year-old man with TTR V122I heterozygous mutation. He presented with paraesthesia from the knees to dorsum of the feet. On examination, power was normal and he had a length dependent neuropathy. A CT myelogram demonstrated spondylosis at L4/5 and L3/4 from disc bulge and marked flaval hypertrophy causing canal stenosis. He was placed on the waitlist for L4-5 decompression but unfortunately died prior to surgery.ConclusionsIdentifying ATTR in surgical specimens may diagnose hereditary amyloidosis in otherwise asymptomatic patients and in the future, provide early access to effective therapies.

ObjectivesIntraneural perineurioma is a rare, benign neoplasm of peripheral nerve. The histopathological features are well defined.DesignWe describe 5 cases of histologically confirmed perineuriomas and 14 cases diagnosed on clinical and radiological characteristics to highlight the features of this rare entity.MethodsWe identified cases from the imaging and histopathology database and conducted a retrospective case note review.ResultsThe subjects include 7 men and 12 women, with mean (standard deviation) age of 17.64 (13) years at onset of symptoms. 14 of the 15 lower limb cases were located in the sciatic nerve or its divisions. 1 each was identified in ulnar, median and radial nerves and 1 case was in a facial nerve. The MRI features were homogenous between the groups. The nerves biopsied included 1 tibial, 1 ulnar, 1 radial, 1 facial and 1 sciatic all showing classic pathology findings. 2 patients, interestingly, had coincidental intracranial meningioma, given the recent discovery of a potential shared pathogenesis (mutations in TRAF7) with intracranial meningiomas. 2 patients had ‘skip lesions’ within the same nerve and 3 patients had foraminal and extraforaminal involvement of lumbosacral nerve roots.ConclusionsOur unit now favours the clinicoradiological features for diagnosing perineuriomas rather than performing a biopsy on all patients. Also, the potential shared pathogenesis with meningiomas raises the clinical issue of screening in patients with perineuriomas but more clinical evidence is required.

Mutations in POLG are increasingly recognized as a cause of refractory occipital lobe epilepsy (OLE) and status epilepticus (SE). Our aim was to describe the epilepsy syndrome in seven patients with POLG mutations. We retrospectively reviewed the medical records of seven patients with POLG mutations and epilepsy. Mutation analysis was performed by direct sequencing of the coding exons of the POLG gene. Disease onset was at a median age of 18 years (range 12-26). Epilepsy was the presenting problem in six patients. All had focal seizures, with motor (n = 6) and visual (n = 6) phenomena. Six patients had secondarily generalized seizures and two patients had myoclonic seizures. Six patients had one or more episodes of refractory SE, including focal (n = 5), subtle (n = 4), myoclonic (n = 2) and convulsive (n = 3) SE. During or after SE, brain MRI showed lesions affecting the occipital lobe in all patients, probably due to continuous epileptic activity. Five of the six patients with SE died during treatment of SE, one due to valproate-induced hepatotoxicity. Associated clinical symptoms were ataxia (n = 6), polyneuropathy (n = 6), progressive external ophthalmoplegia (PEO) (n = 3) and migraine (n = 3). Epilepsy may be the first and dominant neurological problem caused by POLG mutations. The epilepsy may be severe and the condition of the patient may end in fatal SE. Refractory OLE and SE in a patient with polyneuropathy, ataxia, PEO or migraine warrant screening for POLG mutations. In this clinical setting, valproate should not be given in view of the risk of fatal hepatotoxicity.

Chloroquine (CQ) has been evaluated as an autophagy blocker for cancer treatment, but it is unknown if it acts solely by inhibiting cancer cell autophagy. We report that CQ reduced tumor growth but improved the tumor milieu. By normalizing tumor vessel structure and function and increasing perfusion, CQ reduced hypoxia, cancer cell invasion, and metastasis, while improving chemotherapy delivery and response. Inhibiting autophagy in cancer cells or endothelial cells (ECs) failed to induce such effects. CQ's vessel normalization activity relied mainly on alterations of endosomal Notch1 trafficking and signaling in ECs and was abrogated by Notch1 deletion in ECs in vivo. Thus, autophagy-independent vessel normalization by CQ restrains tumor invasion and metastasis while improving chemotherapy, supporting the use of CQ for anticancer treatment. publisher: Elsevier articletitle: Tumor Vessel Normalization by Chloroquine Independent of Autophagy journaltitle: Cancer Cell articlelink: http://dx.doi.org/10.1016/j.ccr.2014.06.025 content_type: article copyright: Copyright © 2014 Elsevier Inc. All rights reserved. ispartof: CANCER CELL vol:26 issue:2 pages:190-206 ispartof: location:United States status: published