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BACKGROUND: Observations in people with cerebral cavernous malformations, and in preclinical models of this disorder, suggest that the β-blocker propranolol might reduce the risk of intracerebral haemorrhage. We aimed to evaluate the safety and efficacy of prolonged treatment with propranolol to reduce the incidence of symptomatic intracerebral haemorrhage or focal neurological deficit in people with familial cerebral cavernous malformations.METHODS: We conducted a randomised, open-label, blinded-endpoint, phase 2 pilot trial (Treat_CCM) at six national reference centres for rare diseases in Italy. People aged 18 years or older with symptomatic familial cerebral cavernous malformation were eligible for enrolment. Participants were randomly assigned (2:1) to receive either oral propranolol (20-320 mg daily) plus standard care (intervention group), or standard care alone (control group), for 24 months. Participants, caregivers, and investigators were aware of treatment group assignment. Participants had clinical assessments and 3 T brain MRI at baseline and at 12 and 24 months. The primary outcome was new occurrence of symptomatic intracerebral haemorrhage or focal neurological deficit attributable to cerebral cavernous malformation over 24 months. Outcome assessors were masked to treatment group assignment. The primary analysis was done in the intention-to-treat population. Because of the pilot study design, we chose a one-sided 80% CI, which could either exclude a clinically meaningful effect or show a signal of efficacy. This trial is registered with EudraCT, 2017-003595-30, and ClinicalTrials.gov, NCT03589014, and is closed to recruitment.FINDINGS: Between April 11, 2018, and Dec 5, 2019, 95 people were assessed for eligibility and 83 were enrolled, of whom 57 were assigned to the propranolol plus standard care group and 26 to the standard care alone group. The mean age of participants was 46 years (SD 15); 48 (58%) were female and 35 (42%) were male. The incidence of symptomatic intracerebral haemorrhage or focal neurological deficit was 1·7 (95% CI 1·4-2·0) cases per 100 person-years (two [4%] of 57 participants) in the propranolol plus standard care group and 3·9 (3·1-4·7) per 100 person-years (two [8%] of 26) in the standard care alone group (univariable hazard ratio [HR] 0·43, 80% CI 0·18-0·98). The univariable HR showed a signal of efficacy, according to predefined criteria. The incidence of hospitalisation did not differ between groups (8·2 cases [95% CI 7·5-8·9] per 100 person-years in the propranolol plus standard care group vs 8·2 [95% CI 7·1-9·3] per 100 person-years in the standard care alone group). One participant in the standard care alone group died of sepsis. Three participants in the propranolol plus standard care group discontinued propranolol due to side-effects (two reported hypotension and one reported weakness).INTERPRETATION: Propranolol was safe and well tolerated in this population. Propranolol might be beneficial for reducing the incidence of clinical events in people with symptomatic familial cerebral cavernous malformations, although this trial was not designed to be adequately powered to investigate efficacy. A definitive phase 3 trial of propranolol in people with symptomatic familial cerebral cavernous malformations is justified.FUNDING: Italian Medicines Agency, Associazione Italiana per la Ricerca sul Cancro, Swedish Science Council, Knut and Alice Wallenberg Foundation, CARIPLO Foundation, Italian Ministry of Health.

OBJECTIVESome studies have highlighted psychological and neuropsychological difficulties and a potential reduction in health-related quality of life (HRQOL) in patients with pituitary tumors, despite hormone deficits or excess. To the authors’ knowledge, this study is the first prospective longitudinal case-control study with the aim of simultaneously testing whether HRQOL and psychiatric and neuropsychological disabilities are related to neural dysfunction due to hypercortisolism per se, or tumor mass and/or surgery in patients with Cushing’s disease (CD). The authors evaluated a homogeneous cohort of patients with CD and nonfunctioning pituitary adenomas (NFPAs) before and after neurosurgery and compared these patients with healthy controls.METHODSTwenty patients (10 with NFPA and 10 with CD) were evaluated using 3 validated questionnaires (SF-36, Beck Depression Inventory–II [BDI-II], and Minnesota Multiphasic Personality Inventory–II [MMPI-II]) to assess HRQOL and psychological status preoperatively and 12 months after neurosurgery. Neuropsychological tests were assessed preoperatively, 3–7 days postoperatively, and 12 months postoperatively. Twenty healthy matched controls were recruited.RESULTSPreoperatively, the NFPA and CD subgroups had worse HRQOL scores than controls on the basis of SF-36 scores, although the NFPA subgroup experienced significant recovery 12 months postoperatively. Preoperatively, CD patients had depressive symptoms according to the BDI-II and MMPI-II that persisted 12 months postoperatively, together with social introversion and hypochondriasis; NFPA patients were similar to controls except for hypochondriasis scores that were clinically significant at all timepoints. Preoperatively and 3–7 days postoperatively, both subgroups showed significant neuropsychological disabilities compared with controls, but only the CD subgroup did not completely recover over time.CONCLUSIONSHRQOL and neuropsychological impairments were observed in all patients at early timepoints, independent of hypercortisolism, tumor mass, and successful surgery. Over time, CD patients showed persistent changes in HRQOL, in particular in social activities. In this light, CD seems to have a strong impact on HRQOL and to be associated with more psychological and neuropsychological comorbidities than NFPA.

Introduction: Verbs and nouns can be selectively impaired, suggesting that they are processed, at least in part, by distinct neural structures. While several tests of object naming are available, tasks involving action verb naming with normative data are lacking. We report the construction and standardization of a new test for the assessment of picture naming of actions. Material and methods: The test includes 50 stimuli, strictly controlled for several confounding variables. Normative data on 290 Italian subjects pooled across homogenous subgroups for age, sex, and education are reported. Results: Multiple regression analyses revealed that age and education significantly correlated with the subject’s score. In particular, increasing age negatively affected performance, while the performance increased with a higher education. Conclusions: In the clinical practice, the availability of equivalent scores will help the comparison with performance in the picture naming of objects. This test allows investigating action naming deficits in aphasic patients, in Parkinson’s disease patients and in further neurodegenerative disorders, in which a specific impairment of action verbs is expected, filling a gap in the clinical neuropsychological assessment.

INTRODUCTION: Intra-operative neurophysiological monitoring and brain mapping techniques represent nowadays the gold standard for surgical resection of brain tumors. Brain mapping usually requires the exposure of a large area of brain cortex in order to identify the different eloquent sites (e.g. primary motor strip, speech arrest sites). Thus, relatively large classic fronto-temporal craniotomies are generally performed. Nevertheless, in recent years the use of small craniotomies targeted on the tumor has gained popularity thanks to Neuronavigation systems and to the low morbidity rates associated with shorter surgical procedures and reduced anesthestic drug administration. Aim of this study was to review our experience which combines extensive neurophysiological monitoring and small craniotomies. Length of surgical time, intra-operative and post-operative complications, length of stay, extent of resection rate and the neurological outcomes were assessed. PATIENTS AND METHODS: Eighty-five consecutive patients (54 Males, 31 Females; Median Age 55 years, range 12-77) underwent surgery with brain mapping and intra-operative neurophysiological monitoring for resection of a brain tumor in eloquent location under asleep-asleep (62 patients) or asleep-awake (23 patients) anesthesia. Pre- and post-operative assessment included in-depth neuropsychological evaluation and MRI. Tumor histologies were the following: 74 gliomas (60 HGG, 14 LGG), 6 metastases and 5 other tumor histologies (2 cavernomas, 2, meningiomas, 1 AVM). The bone flap was tailored to the size of the tumor; no cortex other than that which was strictly necessary for tumor resection was exposed. The intra-operative neurophysiological monitoring included: EEG, SSEP, transcranial MEP and/or cortical MEP, ECoG; direct electrical stimulation (DES) was performed using bipolar and monopolar probes. RESULTS: Median surgical time was 230 minutes (range 90-390). Intra-operative complications included 9 seizures (3 requiring pharmacological treatment, 6 regressing after cold irrigation) and 5 electrical seizure. Post-operative neurosurgical complications were the following: 8 seizures and 4 re-operation for hematoma. Seventy-three patients (86%) could be discharged home while 12 (14%) were transferred to rehabilitation. In only 3 patients (3.5%) a permanent new neurological deficit could be noted at 3-month follow-up. Median post-operative stay was 7 days (range 3-45). CONCLUSIONS: In our experience a small craniotomy supported by extensive neurophysiological monitoring and brain mapping permitted to achieve satisfactory results in terms of complications, hospitalization, and neurological outcomes.

Early and delayed cognitive dysfunctions are an understudied issue after aneurysmal subarachnoid hemorrhage (aSAH), irrespective of neurological outcome. The aim of this study was to describe early and delayed changes of cognitive functions, activities of everyday life, and quality of life in aSAH patients.

INTRODUCTION: The thalamus is a deep-seated and crucial structure for the sensory-motor system. It has been longly considered a surgically inaccessible area due to the morbidity associated with surgical resections. In fact, astrocytomas of the thalamus usually undergo bioptic procedures followed by adjuvant treatments (if indicated). Intra-operative neurophysiological monitoring (IONM) allows safe and satisfactory resections of lobar gliomas. Considering the need of reliable specimens for the pathological diagnosis and that the extent of resection is positively associated with overall survival, aim of this study was to review the feasibility and outcome of a small series of patients with thalamic astrocytomas operated with the aid of IONM. PATIENTS AND METHODS: Five patients with thalamic astrocytomas (1 grade I, 3 grade III, 1 grade IV) underwent surgical resection with IONM. Two astrocytomas were in the dominant hemisphere. All patients performed pre-operative and post-operative neuropsychological assessment. IONM consisted in transcranial MEP monitoring (4 patients), cortical MEP monitoring (2 patients), direct electrical stimulation (5 patients), EEG (5 patients) and ECoG monitoring (2 patients). Anesthesia was totally intra-venous (propofol + remifentanyl) for all patients; 1 patients was operated following an asleep-awake protocol, 4 following an asleep-asleep protocol. RESULTS: None of patients suffered from permanent motor deficits; 2 patients had a transient hemiparesis requiring rehabilitation; 1 patient suffered a transient aphasia, and 1 patient had permanent aphasia. None of the patients had intraoperative seizures, but 1 patient had a post-operative transient status epilepticus. Resection was total or subtotal in 3 cases and partial (with resection between 50 and 80% of the tumor volume) in the other 2 cases. CONCLUSIONS: Surgical resection of thalamic astrocytomas could be meaningful and relatively safe when guided by IONM. Larger series of patients are required to confirm this preliminary data.

Introduction Although it was a giant leap forward when it was introduced, the classic approach to the norming of neuropsychological tests (Capitani, 1987) has two main limitations: (i) it doesn’t consider possible interactions between covariates (e.g., age and education); (ii) working on by–subject percentages of correct responses, it cannot consider item covariates (e.g., frequency, length, imageability) that are known to affect performance substantially. Here we show how to overcome these limitations, and how this improves our diagnosis. Methods As a test case, we used the action–naming task devised by Crepaldi et al. (2006). 290 healthy Italian speakers (148 F and 142 M) made up our norming sample. They ranged 18 to 98 years in age (M=54.1) and 3 to 23 years in education (M=12.3). The test was standardized: (i) following the classic Capitani approach, based on regressing by–subject mean accuracy on gender, age and education; (ii) adding interactions between gender, age and education to the classic approach; (iii) using raw correct/incorrect scores thanks to mixed–effect models, thus being able to take under control also item variables (e.g., frequency, imageability) and any additional item– or subject–specific random variability (mixed–effects norming; Jaeger, 2008). Results We first contrasted the three approaches in terms of their amount of explained variance in the computation of expected scores, that is, their ability to “wash out” unwanted effects from expected scores. The classic Capitani norming explained 34.7% of the total variance; interaction norming went up to 43.7%; and mixed–effects norming ensured 73% of explained variance. A comparison between expected scores according to Capitani and mixed–effects norming in 2,600 combinations of age (20–85) and education values (3-22) revealed an overall correlation of .81. Differences were generally bigger with young age and low education, and with old age and high education; and typically showed higher expected scores by mixed–effects than Capitani norming (see Figure 1). Equivalent Scores (ES) were then computed for a simulated sample of around 80,000 patients ranging in age (20–85 years), education (3–22 years), gender (M–F) and raw scores (20–50 correct responses). They disagree 28% of the times according to the two approaches. The difference (in either direction) is 1.28 in mean, and ranges from 1 to 4. Mixed–effects ES is lower than Capitani ES in 61% of the cases. Among the 45070 simulated patients that would be classified as impaired at naming verbs (ES=0) according to Capitani norming, 5% would not be classified as such (ES>0) according to mixed–effects norming. These figures are closely replicated in a sample of 69 unselected aphasic patients. Discussion The data indicate that using a better statistical model to calculate expected scores is highly beneficial in terms of amount of explained variance, that is, we can gauge the true effects of subject (e.g., age) and item variables (e.g., frequency) much more precisely, thus enjoying higher–quality corrected scores. Critically, this reflects substantially into how (simulated and actual) patients are classified.

BACKGROUND: Patients with high grade gliomas (HGG) have a poor prognosis and experience cognitive deficits which depend on location, size, mass effect and edema of the tumor. Neuropsychological functioning (NPF) can be assessed by a battery of tests which objectivise the cognitive status of the patients. These tests are time-consuming and fatiguing for the patients, nevertheless could give relevant information about the course of the disease. Aim of our work was to describe overtime the NPF of patients affected by HGG and to correlate the NPF scores with tumor recurrence and survival. MATERIAL AND METHODS: We examined the NPF in 102 patients operated for HGG. Patients were followed longitudinally with the Milano-Bicocca Battery for neuropsychological assessment of low grade gliomas. Patients were evaluated before surgery and few days after surgery. Then, neuropsychological and neuro-oncological follow-up were performed every three months. We first explored the correlational structure of our neuropsychological variables through hierarchical clustering in the R package Hmisc. We then investigated the impact on patients’ outcome of the variables selected through hierarchical clustering via non-linear regression, with fixed/random effects. Time to tumor recurrence/death was selected as the main dependent variable. RESULTS: Sixty-seven males and 35 females (median age 59, range 18–81) were included. Starting from a battery of 27 neuropsychological tests, 10 tests could be selected from the statistical analysis (cluster structure, condition number K of 51.16) since they were strictly correlated with the other tests; thus, these 10 tests were used for the further statistical analysis. Pitting patients’ neuropsychological profiles against tumor relapse/death, 5 cognitive tests showed a significant correlation: Token test (p=0.003), Object Naming test (p=0.02), Digit Memory Span (p=0.001), Corsi Block test (p=0.004), Semantic Fluency test (p=0.003). A steep decline for all these tests emerged a few weeks before tumor relapse/death. Analyzing the NPF overtime, all the tests worsened immediately after surgery, recovered steadily within 2–3 months and then remained stable until progression. CONCLUSION: The tests which showed to be more informative about the patients NPF were Token test, Object Naming test, Digit Memory Span, Corsi Block test, Semantic Fluency test. These tests showed a significant decline few weeks before tumor relapse/death.