Prevalence of Poststroke Neurocognitive Disorders Using National Institute of Neurological Disorders and Stroke-Canadian Stroke Network, VASCOG Criteria (Vascular Behavioral and Cognitive Disorders), and Optimized Criteria of Cognitive Deficit.

BACKGROUND AND PURPOSE: The prevalence of poststroke neurocognitive disorder (NCD) has yet to be accurately determined. The primary objective of the present study was to optimize operationalization of the criterion for NCD by using an external validity criterion. METHODS: The GRECOG-VASC cohort (Groupe de Réflexion pour l'Évaluation Cognitive Vasculaire) of 404 stroke patients with cerebral infarct (91.3%) or hemorrhage (18.7%) was assessed 6 months poststroke and 1003 healthy controls, with the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network standardized battery. Three dimensions of the criterion for cognitive impairment were systematically examined by using the false-positive rate as an external validity criterion. Diagnosis of mild and major NCD was based on the VASCOG criteria (Vascular Behavioral and Cognitive Disorders). The mechanisms of functional decline were systematically assessed. RESULTS: The optimal criterion for cognitive impairment was the shortened summary score (ie, averaged performance for action speed, executive functions, and language) because it was associated with the highest (P=0.0001) corrected true-positive rate (43.5%) and a false-positive rate ≤5%. Using this criterion, the mean (95% confidence interval) prevalence of poststroke NCD was 49.5% (44.6-54.4), most of which corresponded to mild NCD (39.1%; 95% confidence interval, 34.4-43.9) rather than dementia (10.4%; 95% confidence interval, 7.4-13.4). CONCLUSIONS: This study is the first to have optimized the operationalization of the criterion for poststroke cognitive impairment. It documented the prevalence of poststroke NCD in the GRECOG-VASC cohort and showed that mild cognitive impairment accounts for 80% of the affected patients. Finally, the method developed in the present study offers a means of harmonizing the diagnosis of NCD. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01339195.

Phase I trial of bortezomib daily dose: safety, pharmacokinetic profile, biological effects and early clinical evaluation in patients with advanced solid tumors.

Purpose This phase I study investigated bortezomib in solid tumors used as a daily subcutaneous regimen. Previous regimens showed only modest activity in solid tumors which was potentially related to sub-optimal tumor penetration. We aimed at exploring if daily low dose administration of bortezomib may allow a greater and tolerable pharmacokinetic exposure which might be required for antitumor activity in solid tumors. Patients and methods This 3 + 3 design, dose escalation, monocentric study aimed at defining the maximum tolerated dose of daily low dose schedule of bortezomib. Tolerability, pharmacokinetics, pharmacodynamics, antitumor activity, biomarkers for proteasome inhibition, pre- and post-treatment tumor biopsies were also evaluated. Results A total of eighteen patients were dosed in 3 bortezomib cohorts (0.5, 0.6 and 0.7 mg/m2), with 3, 11 and 4 patients respectively. Three patients experienced dose-limiting toxicities: Grade (G) 3 Sweet's syndrome (at 0.6 mg/m2), G3 asthenia and anorexia or ataxia (2 patients at 0.7 mg/m2). The most common study drug-related adverse events (all grades) were thrombocytopenia (72%), fatigue (56%), neuropathy (50%), anorexia (44%) and rash (39%). Dose 0.6 mg/m2 of bortezomib was considered as the recommended phase II dose. A significant tumor shrinkage (-36% according to WHO criteria) was observed in one patient with heavily pre-treated GIST, and 2 minor responses (-20%) were recorded in two patients with melanoma and mesothelioma. Conclusion This daily subcutaneous regimen of bortezomib showed a dose dependent plasma exposure, evidence of target inhibition and preliminary signs of clinical activity. However, cumulative neurological toxicity of this dose-dense daily regimen might preclude its further clinical development.

New insights in radiation-induced leukoencephalopathy: a prospective cross-sectional study.

BACKGROUND: Radiation-induced leukoencephalopathy (RIL) is the most threatening delayed complication of cerebral radiotherapy (RT) and remains roughly defined by cognitive dysfunction associated with diffuse FLAIR MRI white matter hyperintensities after brain irradiation. We documented clinical, neuropsychological, and radiological aspects of RI in order to refine diagnostic criteria. METHODS: Patients referred to our center for deterioration in cognitive complaint at least 6 months after completing a focal or whole brain RT underwent a systematic cross-sectional assessment including clinical examination, neuropsychological tests, and a standardized MRI protocol. Patients with progressive tumor were excluded. RESULTS: Forty patients were prospectively enrolled. Of these, 26 had received a focal RT, median dose of 53 Gy (range 50 to 60), and 14 had received a whole brain RT, median dose of 30 Gy. Cognitive complaints, gait apraxia, and urinary troubles were reported in 100, 67, and 38% of cases, respectively. On neuropsychological examination, patients displayed a global and severe cognitive decline through a subcortical frontal mode. The cognitive changes observed were not hippocampic, but related to executive dysfunction. On MRI, 68% of the patients had extensive FLAIR hyperintensities with anterior predominance, 87% had brain atrophy, and 21% had intraparenchymal cysts. T2*-weighted MRI showed small asignal areas in 53% of the patients. These abnormalities are evocative of cerebral small vessel disease. Fractional anisotropy in the corpus callosum correlated with the cognitive evaluation. No differentiation in terms of cognitive and MRI features could be made between patients treated with focal brain RT (glioma) and patients treated with WBRT (for brain metastases or PCNSL). CONCLUSIONS: RIL can be defined by clinical symptoms (subcortical frontal decline, gait apraxia, urinary incontinence) and MRI criteria (cortico-subcortical atrophy, spread FLAIR HI, T2* asignals). This condition mimics a diffuse progressive cerebral small vessel disease triggered by RT, independent of RT protocol.

Quick, non-invasive and quantitative assessment of small fiber neuropathy in patients receiving chemotherapy.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common, potentially severe and dose-limiting adverse effect; however, it is poorly investigated at an early stage due to the lack of a simple assessment tool. As sweat glands are innervated by small autonomic C-fibers, sudomotor function testing has been suggested for early screening of peripheral neuropathy. This study aimed to evaluate Sudoscan, a non-invasive and quantitative method to assess sudomotor function, in the detection and follow-up of CIPN. Eighty-eight patients receiving at least two infusions of Oxaliplatin only (45.4%), Paclitaxel only (14.8%), another drug only (28.4%) or two drugs (11.4%) were enrolled in the study. At each chemotherapy infusion the accumulated dose of chemotherapy was calculated and the Total Neuropathy Score clinical version (TNSc) was carried out. Small fiber neuropathy was assessed using Sudoscan (a 3-min test). The device measures the Electrochemical Skin Conductance (ESC) of the hands and feet expressed in microSiemens (µS). For patients receiving Oxaliplatin mean hands ESC changed from 73 ± 2 to 63 ± 2 and feet ESC from 77 ± 2 to 66 ± 3 µS (p < 0.001) while TNSc changed from 2.9 ± 0.5 to 4.3 ± 0.4. Similar results were observed in patients receiving Paclitaxel or another neurotoxic chemotherapy. During the follow-up, ESC values of both hands and feet with a corresponding TNSc < 2 were 70 ± 2 and 73 ± 2 µS respectively while they were 59 ± 1.4 and 64 ± 1.5 µS with a corresponding TNSc ≥ 6 (p < 0.0001 and p = 0.0003 respectively). This preliminary study suggests that small fiber neuropathy could be screened and followed using Sudoscan in patients receiving chemotherapy.

Cognitive outcome after radiotherapy in brain tumor.

PURPOSE OF REVIEW: Survival of brain tumor patients has increased with improvements in cancer treatments. However, treatments like radiotherapy can be neurotoxic and thus new end-points in clinical trials, as well as in individual management, have appeared. This article reviews the cognitive outcomes after radiotherapy in brain tumor patients, focusing on radiation-induced impairments, and then discusses actual cognitive assessment limitations. RECENT FINDINGS: Although physiopathology of radiation-induced cognitive impairments remains elusive, a general course can be described as acute, early-delayed, and late-delayed effects corresponding to different processes. The last is of high interest because the related impairments are irreversible. In this context, a cognitive assessment should be performed as often as possible, but actual tools are unfortunately not developed. Nevertheless, with respect to neuro-oncologic specificities, new cognitive tools could be developed to overcome these limitations. SUMMARY: Improvements in neuropsychologic assessment for brain tumor patients are urgently needed. A dynamic vision of radiation-induced cognitive impairments appears inevitable and should lead to a change in actual considerations about neurotoxicity follow-up.

Severe meningo-radiculo-neuritis associated with ipilimumab.

PURPOSE: Ipilimumab is a T-cell-potentiating monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4) to promote antitumoural immunity. In phase III trials, ipilimumab was shown to be the first agent to improve survival in advanced melanoma patients, regardless of previous treatment. We report a case of severe neurologic disease after ipilimumab treatment. PATIENT AND METHODS: Neurologic symptoms including facial diplegia, tetraplegia, areflexia progressed with time a few days after the fourth monthly ipilimumab infusion. Analysis of the cerebro-spinal fluid showed elevated proteinorachy and lymphocytic meningitis. Despite high doses of steroids and symptomatic treatment, the symptoms worsened. RESULTS: Veinoglobulins were then infused and the patient began to improve and recovered almost normal activity two years later. CONCLUSION: The adverse event profile associated with ipilimumab was primarily immune-related. This is the first case in which such a severe event has been reported.

Brain damage from anticancer treatments in adults.

PURPOSE OF REVIEW: Treatment-induced brain toxicity remains a major cause of morbidity in adult patients with cancer. Contrasting with the 40-year-old unresolved controversy about the primary damaging event (vascular versus parenchymal) in the physiopathology, numerous prospective clinical trials have recently addressed the question of brain toxicity. Despite remarkable efforts in methodological design, they often only partially answer the questions of which treatment modalities are responsible, which brain functions are mainly impaired, how long the impairment duration is and which characteristics make patients vulnerable. RECENT FINDINGS: Real advances in the design of safer radiation procedures have been counterbalanced by a wider use of combined radiotherapy-chemotherapy regimens, the development of radiosurgery and the increasing number of long-term survivors. Although classic radionecrosis or chemonecrosis has become less common, more subtle changes such as progressive cognitive dysfunction are increasingly reported after radiotherapy (radiation-induced leukoencephalopathy) or chemotherapy, administered alone or in combination as reviewed here. The methodological aspects of published studies are questioned and suggestions are provided that may improve the design of future trials. SUMMARY: The abovementioned issue is of clinical importance given the number of patients treated for brain tumors, including patients with brain metastases, and the number of patients who are at high risk for brain metastasis who could benefit from prophylactic cranial irradiation. Moreover, drugs used in nonbrain tumors are now recognized to impair brain normal functioning.

Episodic Memory Impairments in Primary Brain Tumor Patients.

OBJECTIVE: Cognitive investigations in brain tumor patients have mostly explored episodic memory without differentiating between encoding, storage, and retrieval deficits. The aim of this study is to offer insight into the memory sub-processes affected in primary brain tumor patients and propose an appropriate assessment method. METHOD: We retrospectively reviewed the clinical and memory assessments of 158 patients with primary brain tumors who had presented to our departments with cognitive complaints and were investigated using the Free and Cued Selective Reminding Test. RESULTS: Retrieval was the process of episodic memory most frequently affected, with deficits in this domain detected in 92% of patients with episodic memory impairments. Storage and encoding deficits were less prevalent, with impairments, respectively, detected in 41% and 23% of memory-impaired patients. The pattern of episodic memory impairment was similar across different tumor histologies and treatment modalities. CONCLUSION: Although all processes of episodic memory were found to be impaired, retrieval was by far the most widely affected function. A thorough assessment of all three components of episodic memory should be part of the regular neuropsychological evaluation in patients with primary brain tumors.

Who should undergo a comprehensive cognitive assessment after a stroke? A cognitive risk score.

OBJECTIVE: To validate the ability of a specifically developed cognitive risk score to identify patients at risk of poststroke neurocognitive disorders (NCDs) who are eligible for a comprehensive cognitive assessment. METHODS: After assessing 404 patients (infarct 91.3%) in the Groupe de Réflexion pour l'Evaluation Cognitive VASCulaire (GRECogVASC) cross-sectional study with the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network battery 6 months after stroke, we used multivariable logistic regression and bootstrap analyses to determine factors associated with NCDs. Independent, internally validated factors were included in a cognitive risk score. RESULTS: Cognitive impairment was present in 170 of the 320 patients with a Rankin Scale score ≥1. The backward logistic regression selected 4 factors (≥73% of the permutations): NIH Stroke Scale score on admission ≥7 (odds ratio [OR] 2.73, 95% confidence interval [CI] 1.29-4.3, p = 0.005), multiple strokes (OR 3.78, 95% CI 1.6-8, p = 0.002), adjusted Mini-Mental State Examination (MMSEadj) score ≤27 (OR 6.69, 95% CI 3.9-11.6, p = 0.0001), and Fazekas score ≥2 (OR 2.34, 95% CI 1.3-4.2, p = 0.004). The cognitive risk score computed with these 4 factors provided good calibration, discrimination (overoptimism-corrected C = 0.793), and goodness of fit (Hosmer-Lemeshow test p = 0.99). A combination of Rankin Scale score ≥1, cognitive risk score ≥1, and MMSEadj score ≥21 selected 230 (56.9%) of the 404 patients for a comprehensive assessment. This procedure yielded good sensitivity (96.5%) and moderate specificity (43%; positive predictive value 0.66, negative predictive value 0.91) and was more accurate (p ≤ 0.03 for all) than the sole use of screening tests (MMSE or Montréal Cognitive Assessment). CONCLUSION: The GRECogVASC cognitive risk score comprises 4 easily documented factors; this procedure helps to identify patients at risk of poststroke NCDs who must therefore undergo a comprehensive assessment. CLINICALTRIALSGOV IDENTIFIER: NCT01339195.

Neurological manifestations and neuroradiological presentation of Erdheim-Chester disease: report of 6 cases and systematic review of the literature.

Erdheim-Chester disease (ECD) is a rare, non-Langerhans form of histiocytosis of unknown etiology that affects multiple organs. We report 6 cases of ECD with neurological involvement and neuroradiological abnormalities on brain MRI. A literature review revealed 60 other cases of ECD with neurological involvement. We therefore analyzed 66 ECD patients with neurological involvement. Cerebellar and pyramidal syndromes were the most frequent clinical manifestations (41% and 45% of cases), but seizures, headaches, neuropsychiatric or cognitive troubles, sensory disturbances, cranial nerve paralysis or asymptomatic lesions were also reported. Neurological manifestations were always associated with other organ involvement, especially of bones (at least 86%) and diabetes insipidus (47%). Neurological involvement was responsible for severe functional handicaps in almost all patients and was responsible for the death of 6 of the 66 patients (9%). Neuroradiological findings could be separated into three patterns: the infiltrative pattern (44%), with widespread lesions, nodules or intracerebral masses, the meningeal pattern (37%), with either thickening of the dura mater or meningioma-like tumors, and the composite pattern (19%), with both infiltrative and meningeal lesions.

[Single center experience with bevacizumab in a cohort of patients treated for a relapsing glioblastoma]. / Expérience monocentrique d'un traitement par bévacizumab dans la prise en charge des glioblastomes récidivant.

PURPOSE: Although there is no standard treatment for recurrent glioblastoma, prospective data in selected patients have suggested the usefulness of bevacizumab. We report our single center experience with bevacizumab in a cohort of patients treated for a relapsing glioblastoma. METHODS: We performed a retrospective analysis of consecutive patients treated with bevacizumab for a relapsed glioblastoma, between 2008 and 2013. Tumor responses, toxicities, time to progression and overall survival rates were analyzed. RESULTS: Thirty-five consecutive patients were identified. They were treated with bevacizumab 10mg/kg biweekly, associated with irinotecan (n=29; 84%), temozolomide (n=3; 9%) or as single agent (n=3; 9%) for a glioblastoma relapsing after chemoradiation (n=29) or after first line temozolomide only because of a poor general health status or because of multifocal tumor. Two (6%), 28 (80%) and five (14%) patients presented with Recursive Partitioning Analysis (RPA) III, IV and V-VI, respectively. After 2-3 months of treatment, median dose of prednisolone per patient was decreased three times. Clinical improvements or stability were reported in eight (23%) and 17 patients (49%). The best tumor response was partial response in 14 patients (40%), stable disease in nine patients (26%) and tumor progression in 11 patients (31%). Toxicities requiring treatment disruption were reported in five patients (14%). Median survival was 18.4 months (5-41 months). Median time interval between bevacizumab initiation and its disruption because of clinical/radiological progression and/or toxicity was 5.0 months (0.6-21.4 months). Median survival from bevacizumab initiation was 8.1 months (1.4-34 months). CONCLUSION: This single center retrospective experience suggests that bevacizumab is active for recurrent glioblastoma, in a series of poorly selected patients. Median survival times were in the range of those reported in therapeutic trials. This study questions the validity of usual predictive factors in the era of bevacizumab.

Prognostic value of health-related quality of life for death risk stratification in patients with unresectable glioblastoma.

Glioblastoma is the most common malignant brain tumor in adults. Baseline health-related quality of life (HRQoL) is a major subject of concern for these patients. We aimed to assess the independent prognostic value of HRQoL in unresectable glioblastoma (UGB) patients for death risk stratification. One hundred and thirty-four patients with UGB were enrolled from the TEMAVIR trial. HRQoL was evaluated at baseline using the EORTC QLQ-C30 and BN20 brain cancer module. Clinical and HRQoL parameters were evaluated in univariable and multivariable Cox analysis as prognostic factors for overall survival (OS). Performance assessment and internal validation of the final model were evaluated with Harrel's C-index, calibration plot, and bootstrap sample procedure. Two OS independent predictors were identified: future uncertainty and sensitivity deficit. The final model exhibited good calibration and acceptable discrimination (C statistic = 0.63). The internal validity of the model was verified with robust uncertainties around the hazard ratio. The prognostic score identified three groups of patients with distinctly different risk profiles with median OS estimated at 16.2, 9.2, and 4.5 months. We demonstrated the additional prognostic value of HRQoL in UGB for death risk stratification and provided a score that may help to guide clinical management and stratification in future clinical trials.

Abducens nerve palsy after schwannoma resection.

Tumors of the posterior mediastinum are mostly neurogenic and could involve the intervertebral foramen and the medullary canal. We describe the case of a patient who underwent surgery for a nerve sheet tumor originating at the level of the right second neural root. Resection was associated with an incidental dural tear and cerebrospinal fluid leak that was promptly repaired. One week after surgery, horizontal diplopia occurred. A palsy of the left abducens nerve secondary to intracranial hypotension was diagnosed. We present the pathogenic cascade leading to this ocular complication after posterior mediastinal surgery. The surgical techniques to prevent this complication are discussed.

[Psychological and neuropsychological problems in multiple sclerosis]. / Troubles psychiques et neuropsychologiques dans la sclérose en plaques.

Neuropsychological investigations have demonstrated that cognitive disorders are common (about 60%) in patients with multiple sclerosis. 22 patients and 22 controls participated in the study with a review of literature. The cognitive dysfunction may be termed a subcortical white matter dementia. The hallmarks are: forgetfulness, reduced speed of information processing, impaired attention and slowness of thought processes, impaired ability to manipulate acquired knowledge. Psychiatric disturbance have also high prevalence: emotional or personality changes, depression. Pathological laughing and crying are classical but not well understood. This intellectual and emotional changes in multiple sclerosis are studied by adapted psychometric psychiatric examination. Correlation of magnetic resonance imaging with neuropsychological testing is now demonstrated. Total lesion score is the best predictor of cognitive deficits, cerebral atrophy and lesions of the corpus collosium also. Neuropsychological rehabilitation techniques and symptomatic treatments must be applied to patients with multiple sclerosis.

[Brain metastasis: clinical and cognitive assessments]. / Métastases cérébrales intracrâniennes : signes cliniques et évaluations cognitives.

The incidence of brain metastases (BM) has increased due to the improvement of therapeutics and diagnostic imaging, but also to an aging population. The initial symptoms may develop suddenly or insidiously over weeks or months. The symptoms depend on the location of the BM and related complications (hydrocephalus, tumor hemorrhage, cerebral herniation). Headaches are the most frequent symptoms (50%); they are related to intracranial hypertension. Cognitive deficits are commonly described at diagnosis (67 to 90.5%). Cognitive assessment is essential because of its impact on patients' prognosis and quality of life. Nevertheless, these deficits remain underestimated. The Karnofsky Perfomance Scale and the Mini Mental State Examination (MMSE) seem inadequate. A short battery was proposed and internationally validated, assessing seven domains: attention (Digit Symbol Test WAIS-III), episodic memory (Hopkins Verbal Learning Test [HVLT]), working memory (Digit Span Test WAIS-III), verbal fluency (Controlled Oral Word Association Test [COWA]), fine motor dexterity (Grooved Pegboard Test), information processing speed (Trail Making Test [TMT] A) and executive functions (TMT B). This battery is relevant, feasible and associated with a good compliance. These cognitive tests are currently recommended to assess cognitive functions in patients with BM.

[Cognition and radiation therapy for brain metastases: a new paradigm to define]. / Cognition et radiothérapie dans les métastases cérébrales : un nouveau paradigme à définir.

Whole-brain radiation therapy is suspected of early and late neurocognitive impairment in long-surviving patients with brain metastases. This putative whole-brain radiation therapy neurotoxicity leads to its postponing in brain metastases management, despite its well-established benefit in the brain control of the illness especially when associated with surgery or stereotactic radiosurgery. The incidence of neurocognitive impairment in patients with brain metastases and their link with tumoral progression or radiation during time are discussed in the light of recent randomized controlled trials. Therefore, we will address various options that are under investigation - despite poor data on pathophysiologic mechanisms - in an attempt to circumvent these side effects.

[Central nervous system complications in patients undergoing cytotoxic chemotherapy and targeted therapies]. / Complications neurologiques centrales des chimiothérapies cytotoxiques et des thérapies ciblées.

Anti-cancer treatments (cytotoxic chemotherapies, targeted therapies and hormonotherapies) are known to induce early and delayed neurological toxicities. Acute encephalopathies and posterior reversible encephalopathies are better known and described, physiopathological hypotheses are emerging. It is difficult to discriminate what drug is causing the symptoms in patients treated with multiple cytotoxic drugs. Methotrexate and ifosfamide are responsible for acute encephalopathies. L-asparaginase and methotrexate or targeted therapies may induce cerebrovascular complications. As life expectancy increases and more complex regimen including innovative targeted therapies are developed, new toxicity profiles can be expected. To be able to provide an early diagnosis, prevention, and treatment (when existing) of these pathologies remains a tremendous challenge that would allow a good quality of life with social and professional life after their cancer is cured.

[Tremor/ataxia syndrome related to Fragile X premutation]. / Syndrome tremblement-ataxie lié à une prémutation de l'X fragile.

The FXTAS syndrome (Fragile X-associated tremor/ataxia syndrome) is a specific neurodegenerative syndrome affecting subjects carrying a premutation of the FMR1 (fragile X mental retardation 1) gene. It affects mainly men with the premutation and aged more than 50 years. This syndrome is separate and distinct from the fragile X syndrome. The FXTAS syndrome remains underestimated today. It should be considered in patients older than 50 years with tremors and cerebellar ataxia, especially when Parkinson disease or cognitive disorders are present or when there is a family history of infertility, early menopause, or mental retardation. In these patients, hyperintense signals of mid-cerebellar peduncle images on T2 and FLAIR MRI justify genetic testing for the FMR1 premutation.