Hervé Taillia

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.

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.

Neuropsychological assessment and cerebral vascular disease: the new standards.

Vascular cognitive impairment (VCI) includes vascular dementia (VaD), vascular mild cognitive impairment (VaMCI) and mixed dementia. In clinical practice, VCI concerns patients referred for clinical stroke or cognitive complaint. To improve the characterization of VCI and to refine its diagnostic criteria, an international group has elaborated a new standardized evaluation battery of clinical, cognitive, behavioral and neuroradiological data which now constitutes the reference battery. The adaption of the battery for French-speaking subjects is reported as well as preliminary results of the on-going validation study of the GRECOG-VASC group [Clinical Trial NCT01339195]. The diagnostic accuracy of various screening tests is reviewed and showed an overall sub-optimal sensitivity (<0.8). Thus, the general recommendation is to perform systematically a comprehensive assessment in stroke patients at risk of VCI. Furthermore,the use of a structured interview has been shown to increase the detection of dementia. In addition to the well known NINDS-AIREN criteria of VaD, criteria of VCI have been recently proposed which are based on the demonstration of a cognitive disorder by neuropsychological testing and either history of clinical stroke or presence of vascular lesion by neuroimaging suggestive of a link between cognitive impairment and vascular disease. A memory deficit is no longer required for the diagnosis of VaD as it is based on the cognitive decline concerning two or more domains that affect activities of daily living. Both VaMCI and VaD are classified as probable or possible. These new criteria have yet to be validated. Considerable uncertainties remain regarding the determinant of VCI, and especially the lesion amount inducing VCI and VaD. The interaction between lesion amount and its location is currently re-examined using recent techniques for the analysis of MRI data. The high frequency of associated Alzheimer pathology is now assessable in vivo using amyloid imaging. The first studies showed that about a third of patients with VaD due to small vessel disease or with poststroke dementia have amyloid PET imaging suggestive of AD. These new techniques will examine the interaction between vascular lesions and promotion of amyloid deposition. Although results of these on-going studies will be available in few years, these data indicate that efforts should be done in clinical practice to reduce underdiagnosis of VCI; VCI should be examined using a specific protocol which will be fully normalized soon for French-speaking patients; the sub-optimal sensitivity of screening tests prompts to use a structured interview to grade Rankin scale and to perform systematically a comprehensive assessment in stroke patients at risk of VCI; poststroke dementia occurring after 3 months poststroke may be preventable by treatment of modifiable vascular risk factors and secondary prevention of stroke recurrence according to recent recommendations.

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 (45.4xa0%), Paclitaxel only (14.8xa0%), another drug only (28.4xa0%) or two drugs (11.4xa0%) 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 73xa0±xa02 to 63xa0±xa02 and feet ESC from 77xa0±xa02 to 66xa0±xa03 µS (pxa0<xa00.001) while TNSc changed from 2.9xa0±xa00.5 to 4.3xa0±xa00.4. 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 TNScxa0<xa02 were 70xa0±xa02 and 73xa0±xa02 µS respectively while they were 59xa0±xa01.4 and 64xa0±xa01.5 µS with a corresponding TNScxa0≥xa06 (pxa0<xa00.0001 and pxa0=xa00.0003 respectively). This preliminary study suggests that small fiber neuropathy could be screened and followed using Sudoscan in patients receiving chemotherapy.

[Brain metastasis: clinical and cognitive assessments].

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.

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.

Episodic Memory Impairments in Primary Brain Tumor Patients

ObjectivenCognitive 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.nnnMethodnWe 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.nnnResultsnRetrieval 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.nnnConclusionnAlthough 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.

Vascular cognitive impairment: Advances and trends

The presence of vascular neurocognitive impairment (whatever the severity) is always associated with a functional impact and increased risk of dependency and institutionalization. However, vascular cognitive impairment remains underdiagnosed, and the mechanisms underlying post-stroke cognitive disorders are still poorly understood. However, the advent of new criteria and a standardized international neuropsychological battery is expected to lead to improved diagnosis and management, and the development of novel techniques (such as brain imaging and amyloid PET) should improve our understanding of the mechanisms underlying vascular cognitive impairment and help to identify potential targets for therapy.

Métastases cérébrales intracrâniennes : signes cliniques et évaluations cognitivesBrain metastasis: clinical and cognitive assessments

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.

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 lÉvaluation 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.