*IV – DIAGNOSIS

1 Clinical features

DLGGs are diagnosed most often in young patients (median age 35-40), who lead a normal family and socio-professional life. Following an asymptomatic period of several years (as evidenced by incidentally discovered DLGGs), partial or generalized seizures represent the presenting symptom in approximately 90% of patients, and appear to correlate with a better prognosis (62). They are drug resistant in about half the cases, particularly seizures originating from the rolandic, paralimbic, temporal and insular areas (33.66). Neurological examination is usually normal, deficits are infrequent and minimal if present. Intracranial hypertension itself is exceptional even with very large tumor volumes, reflecting the slow tumor progression. Indeed, the absence of neurologic deficit, in spite of frequent location of DLGGs in eloquent areas is explained by the very gradual growth and infiltration of glioma over several years before the first episode of seizure - giving the brain all the time to reorganize. These mechanisms of neuroplasticity are subtended by recruiting perilesional areas and / or areas remote to the glioma - within the ipsi-or contralateral hemisphere (16).

But while cognitive impairments have been underestimated for a long time they were frequently detected once an extensive neuropsychological assessment was performed at diagnosis. In fact while it has been traditionally considered that these patients had no neuropsychological deficit, many teams have recently demonstrated the existence of cognitive disturbances and stressed their (s) effect (s) on the quality of life - questioning the dogma of ’patient with a DLGG with normal examination’ (1).

These deficits, affecting mostly the processes of attention, working memory, executive function, learning or emotional and behavioral aspects, were found in approximately 90% of patients with brain tumor before treatment, supportive of the a negative impact of DLGG itself (41).

Thus, neurocognition is increasingly integrated as an evaluation criterion in clinical studies of patients with DLGGs. This is why systematic neuropsychological assessment together with rating scales of the quality of life are now recommended. This is for the following reasons:

(i) to search for possible subtle cognitive impairment missed during standard examination using appropriate assessment tools (e.g., the MMSE, although they are not quite exact when applied to patients with DLGGs because it was initially designed for screening of degenerative diseases in the elderly);

(ii) to develop the best individualized treatment strategy based on these results (eg, decision to resort to neoadjuvant chemotherapy rather than surgery first in highly infiltrating DLGG already with significant cognitive impairment);

(iii) to adapt the technique of any surgical procedure (for example, deciding to perform awake surgery with intraoperative mapping of language despite tumor location in the right hemisphere in a right-handed patient, because of discrete but objectives language disorders detected during evaluation, or to select intraoperative tasks on the basis of pre-surgical neuropsychological evaluation);

(iv) to determine a pretreatment cognitive baseline reference, crucial for longer term monitoring particularly post-operatively.

(v) and to plan for postoperative functional rehabilitation as surgery could have induced a transient neurocognitive impairment (25). Finally, note that the occurrence of high-order function impairment could be an early predictor of relapse in longitudinal neuropsychological studies.

In summary, in DLGGs, neuropsychological examination enables monitoring of neurological, cognitive and / or behavioral state, aids the therapeutic strategy and can potentially be an early indication of changes in tumor even before their detection by imaging.

2 imaging Features

Morphological Imaging

Although brain CT-scan can show a rather suggestive image (spontaneous hypodensity typically not enhanced after iodine injection, sometimes associated with calcifications), MRI of the brain is currently the gold standard in DLGGs. These tumors usually appear as poorly defined lesions, usually homogeneous, hypo-intense on T1 and hyper-intense signal T2 / FLAIR weighted images. On the contrary, although a typical DLGG doesn’t show enhancement, nearly 30% of these tumors may actually be enhanced with gadolinium (low intensity and / or punctiform). In fact, some ill-defined enhancements may remain stable over time. However, the appearance of contrast uptake, especially if nodular is often a sign of malignant transformation (52).

The volume of a DLGG is generally already large at diagnosis, estimated at an average of about 48 cc (8). These tumors are commonly located in functional areas, including frontal (especially at the supplementary motor area, ie just in front of the rolandic area) & insular - in contrast to glioblastomas, situated more posteriorly (28).

The plot of the growth curve of the tumor by comparing its mean diameter (calculated from its volume according to the formula d= on two consecutive MRI done at three months interval) is of significant importance at initial diagnosis, especially in detecting fast-growing gliomas behaving as a true malignancy.

Indeed, a direct statistical correlation was found between the evolving kinetics and the median survival in a subgroup of patients with DLGGs, with a median survival of 253, 210, 91 and 75 months for a growth rate of less than 4 mm / year, 4 to 8 mm / year, 8 to 12 mm / year and more than 12 mm / year, respectively (56).

It is worth noting that, if at the time of the first MRI, two disparaging criteria are met according to the ’ UCSF classification’ (based on the tumor location in a functional area, the Karnofsky index ≤ 80, age> 50 years, maximum diameter> 4cm) (10), the second MRI will be proposed earlier-six weeks from the first. This same calculation for tumor growth rate will be applicable throughout the follow up and to objectify any possible response to therapy (48,55).

Furthermore, successive MRIs show that; glial cells migrate along the axonal tract, tumor infiltration follow preferentially intrahemispheric white matter fibres (in particular uncinate, arcuate fascicles, and inferior fronto-occipital fascicle for paralimbic glioma) and / or interhemispheric white matter fibres according to their initial location, but also projection fibres such as the pyramidal tract (47).

However, conventional structural MRI is not able to show the boundaries of tumor infiltration. Indeed, it was demonstrated using staged biopsies that DLGGs invaded the parenchyma beyond the abnormal FLAIR signal, with tumor cells that could be found up to 2 cm around these anomalies (54). In fact, the use of new metabolic imaging techniques could be used to refine the diagnosis.