From Phineas Gage and Monsieur Leborgne to H.M.: Revisiting Disconnection Syndromes.

On the 50th anniversary of Norman Geschwind's seminal paper entitled 'Disconnexion syndrome in animal and man', we pay tribute to his ideas by applying contemporary tractography methods to understand white matter disconnection in 3 classic cases that made history in behavioral neurology. We first documented the locus and extent of the brain lesion from the computerized tomography of Phineas Gage's skull and the magnetic resonance images of Louis Victor Leborgne's brain, Broca's first patient, and Henry Gustave Molaison. We then applied the reconstructed lesions to an atlas of white matter connections obtained from diffusion tractography of 129 healthy adults. Our results showed that in all 3 patients, disruption extended to connections projecting to areas distant from the lesion. We confirmed that the damaged tracts link areas that in contemporary neuroscience are considered functionally engaged for tasks related to emotion and decision-making (Gage), language production (Leborgne), and declarative memory (Molaison). Our findings suggest that even historic cases should be reappraised within a disconnection framework whose principles were plainly established by the associationist schools in the last 2 centuries.

[Value of the functional neural tractography in the reconstruction of the visual pathways in DTMRI]. / Intérêt de la neurotractographie fonctionnelle dans la reconstruction des voies visuelles en IRMTD.

OBJECTIVE: This article shows that functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) are very useful in the in vivo description of the visual pathways using today's most advanced techniques and allowing fusion between fMRI and tractography. Two complementary techniques were combined: (1) DTI coupled with the tractography and (2) fMRI. MATERIALS AND METHODS: A group of 205 cases, normal and pathological, children and adults, were studied for tractographic reconstitution of visual pathways. In addition, 11 patients underwent an acquisition in fMRI (BOLD effect), with a stimulation of a black-and-white flickering checkerboard. Acquisition was carried out on a 3.0 Tesla GEHC MRI unit. Activated arrays of fMRI are overlaid with those of neurotractography (neural tractography) having like results a functional neurotractography. RESULTS AND DISCUSSION: The main components of the visual pathways were successfully reconstructed in tractography: the optic nerves, optic chiasm, optic tracts, and optic radiations. It was also possible to visualize fiber decussation within the chiasma (possible direct pathways to the hypothalamus and thalamus were also identified). CONCLUSIONS: The tensor of diffusion is increasingly used and is a promising technology to improve the diagnosis of neurological diseases. Sophisticated algorithms contribute a new vision of the anatomy, with the possibility of isolating distinct anatomical entities. With the software used, the charts of fMRI activation are overlaid on the anisotropy charts. The tractograms that link two regions of the same functional network thus provide information on subjacent structural connectivity. Consequently, one speaks about functional neurotractography.

[The results of MRI exploration of glaucoma patients: what are the benefits?]. / Que penser des résultats d'exploration par IRM des patients atteints de glaucome?

After 13 years of glaucoma exploration using MRI at 1.5 and 3 Tesla, we have deduced that there is no specific characteristic between the different forms of this disease, which is manifested by a slowly progressing degenerative optical neuropathy, predominant from front to back (with volume of the optic nerve head always greater than the distal portions of the 2nd neurone, chiasma, and optic tract), interspersed with clinical flare-ups that are recognized by an intense localized hypersignal (frequently from the apex progressing along the canal). Visual tract involvement is always bilateral, even in cases where symptoms are exclusively unilateral (asymmetry can be observed in these cases). The discordance between (i) the severity of axon reduction and (ii) the signs of injury already present at the time when MRI is performed and the relative preservation of visual function argues for encephalic disease with visual involvement. Its delayed discovery makes treatment, even with neuroprotectors, less effective and points toward the need for implementing directed genetic prevention studies, as a first step to more effectively assessing the therapies available.

[Differential diagnosis of retinoblastoma: a retrospective study of 486 cases]. / Diagnostic différentiel du rétinoblastome: étude rétrospective de 486 cas.

OBJECTIVES: Detail the most frequent problems encountered in the differential diagnosis of retinoblastoma. PATIENTS: and method: We conducted a retrospective study on the children referred to the Curie Institute for suspicion of retinoblastoma between 2000 and 2006. Diagnosis was made by fundus examination using the indirect ophthalmoscope, ultrasonography, and MRI. RESULTS: Of the 486 children seen during this period, 408 had unilateral or bilateral retinoblastoma and 78 (16%) had another lesion: Coats disease (20 children, 25%), congenital malformations (23 children, 30%; coloboma, PHPV, microphthalmia, isolated or associated with retinal dysplasia), other tumors (10 children, 13%; astrocytomas and medulloepithelioma), combined hamartomas (six children, 8%), inflammatory diseases (six children, 8%) (Toxocara canis, cat scratch eye disease, or toxoplasmosis), and other diseases (13 children, 16%; corneal opacities, congenital cataract, or retinal detachment). DISCUSSION: Compared to previous series, this study shows the proportion of erroneous diagnosis has lowered (16%) compared to earlier studies by Balmer (1986; 30%), and Shields (1991; 42%). No cases of retinopathy of prematurity were seen in our series, demonstrating that screening is good or of a lower frequency in France. The frequency of PHPV has dropped. Coats disease remains a frequent and sometimes difficult diagnosis to make, particularly in advanced stages of the disease.

Mutations in the AP1S2 gene encoding the sigma 2 subunit of the adaptor protein 1 complex are associated with syndromic X-linked mental retardation with hydrocephalus and calcifications in basal ganglia.

Fried syndrome, first described in 1972, is a rare X-linked mental retardation that has been mapped by linkage to Xp22. Clinical characteristics include mental retardation, mild facial dysmorphism, calcifications of basal ganglia and hydrocephalus. A large four-generation family in which the affected males have striking clinical features of Fried syndrome were investigated for linkage to X-chromosome markers; the results showed that the gene for this condition lies within the interval DXS7109-DXS7593 in Xp22.2. In total, 60 candidate genes located in this region, including AP1S2, which was recently shown to be involved in mental retardation, were screened for mutations. A mutation in the third intron of AP1S2 was found in all affected male subjects in this large French family. The mutation resulted in skipping of exon 3, predicting a protein with three novel amino-acids and with termination at codon 64. In addition, the first known large Scottish family affected by Fried syndrome was reinvestigated, and a new nonsense mutation, p.Gln66X, was found in exon 3. Using CT, both affected patients from the French family who were analysed had marked calcifications of the basal ganglia, as previously observed in the first Scottish family, suggesting that the presence of distinctive basal ganglia calcification is an essential parameter to recognise this syndromic disorder. It may be possible to use this feature to identify families with X-linked mental retardation that should be screened for mutations in AP1S2.

Paul Broca's historic cases: high resolution MR imaging of the brains of Leborgne and Lelong.

In 1861, the French surgeon, Pierre Paul Broca, described two patients who had lost the ability to speak after injury to the posterior inferior frontal gyrus of the brain. Since that time, an infinite number of clinical and functional imaging studies have relied on this brain-behaviour relationship as their anchor for the localization of speech functions. Clinical studies of Broca's aphasia often assume that the deficits in these patients are due entirely to dysfunction in Broca's area, thereby attributing all aspects of the disorder to this one brain region. Moreover, functional imaging studies often rely on activation in Broca's area as verification that tasks have successfully tapped speech centres. Despite these strong assumptions, the range of locations ascribed to Broca's area varies broadly across studies. In addition, recent findings with language-impaired patients have suggested that other regions also play a role in speech production, some of which are medial to the area originally described by Broca on the lateral surface of the brain. Given the historical significance of Broca's original patients and the increasing reliance on Broca's area as a major speech centre, we thought it important to re-inspect these brains to determine the precise location of their lesions as well as other possible areas of damage. Here we describe the results of high resolution magnetic resonance imaging of the preserved brains of Broca's two historic patients. We found that both patients' lesions extended significantly into medial regions of the brain, in addition to the surface lesions observed by Broca. Results also indicate inconsistencies between the area originally identified by Broca and what is now called Broca's area, a finding with significant ramifications for both lesion and functional neuroimaging studies of this well-known brain area.

[Functional amblyopia: a functional MRI evaluation of the visual cortex response after treatment]. / Amblyopie fonctionnelle : évaluation en IRM fonctionnelle de la réponse corticale visuelle après traitement.

PURPOSE: Functional MRI evaluation of the cortical response in treated amblyopic patients. MATERIAL AND METHODS: Clinical and functional MRI exploration of ten patients, seven men and three women aged from 21 to 59 years, with strabismus management during childhood. Functional evaluations were performed on a 1.5 Tesla MR device, with four monocular functional sessions, two stimulations per eye. Alternating rest and active phases displayed still and flickering black and white checkerboards with spatial and temporal frequencies of 1 degree/8Hz and 15'/4Hz. Anatomical realignment and statistical analysis were performed using SPM99 (Statistical Parametric Mapping) to compare the four sessions in individuals. RESULTS AND DISCUSSION: In patients presenting a visual acuity of the amblyopic eye less than 0.7, stimulation of this eye induced lower response in V1, V3, and V5 in comparison with the contralateral eye stimulation. Unexpectedly, in patients recovering normal or subnormal acuity, the amblyopic eye gave comparable or enhanced response in these areas. Additional response was found in the secondary visual cortex, the cuneus, the lingual gyrus, and in parietal, frontal, and orbitofrontal areas. These results suggest a variation in cortical response depending on the efficacy of the treatment. Recovered amblyopic eye, even with acuity less than the contralateral eye, may induce a reinforced cortical sensitivity to visual stimulus. Secondary visual areas may contribute to an attentional process in image perception and analysis. Cortical plasticity may be observed several years after amblyopia treatment. CONCLUSION: Our study substantiates the importance of an effective and early treatment of functional amblyopia, inducing cortical plasticity with reinforced attention and sensitivity to visual perception.

[Arteriovenous malformation of the brain revealed through a visual blur and Adie's pupil]. / Tumeur vasculaire cérébrale révélée par un flou visuel concomitant à la découverte d'une pupille d'Adie.

INTRODUCTION: Arteriovenous malformations of the brain (BAVMs) are a relatively rare group involving intracranial vascular lesions (telangiectasia, cavernous malformation, venous anomaly). We report the case of a patient who presented an atypical visual symptomatology revealing a BAVM. OBSERVATION: A 48-year-old woman consulted for a recent bilateral visual blur. In darkness, discrete anisocoria appeared on the left eye. At the biomicroscopy light examination, we found areflexic semi-mydriasis (direct and consensual) on the left eye; the light reflex (direct and consensual) on the right eye was normal. During the accommodative reflex test the left pupil contracted. We propose the diagnosis of Adie's pupil, which was confirmed by the pilocarpine test (0.125%). We decided to examine the visual field because the symptomatology of the visual blur remained unexplained. The visual field showed a left homonymous inferior lateral scotoma. MRI showed a right occipital arteriovenous malformation. DISCUSSION: A quick examination could confuse painless anisocoria with a compression of the IIIrd intrinsic left nerve. This recent scotoma revealed BAVM progression. The natural history of BAVMs shows that the essential risk of these injuries is the onset of an intracranial hemorrhage. To reach a radical therapeutic decision, a cerebral arteriography clarifying the afferent and efferent vascularity of the nidus was carried out. CONCLUSION: This case is original in that it associates the concomitant discovery of a BAVM and Adie's pupil. Symptomatic BAVMs are extremely serious. Planning their treatment requires multidisciplinary cooperation in order to reduce the risk of mortality.

MR tractography with diffusion tensor imaging in clinical routine.

Using MRI, we demonstrated that the depiction of the cerebral white matter fiber tracts has become a routine procedure. Diffusion tensor (DT) sequences may be analyzed with combined volume analysis and tractography extraction software, giving indirect visualization of white matter connections. We obtained DT data from 20 subjects with normal MR imaging and five patients presenting cerebral diseases such as brain tumors, multiple sclerosis and stroke, with five patients explored on two different MR scanners. Data were transferred to dedicated workstations for anatomical realignment, determination of voxel eigenvectors and calculation of fiber tract orientations in a region of interest. In all subjects, axonal directions underlying the main neuronal pathways could be delineated. Comparisons between diseased regions and contralateral areas demonstrated changes in voxel anisotropy in injured regions, revealing possible preferential fiber orientations within diffuse T2 hyperintensities. Rapid data processing allows imaging of the normal and diseased fiber pathways as part of the routine MRI examination. Therefore, it appears that whenever white matter disease is suspected a tractography can be performed with this fast and simple method that we proved to be reliable and reproducible.

[Cortical response in age-related macular degeneration (part I). Methodology and subject specificities]. / Réponse corticale dans la DMLA (Première partie). Méthodologie et spécificités des sujets.

PURPOSE: To evaluate the cortical response to visual stimulation in patients with age-related macular degeneration (ARMD). MATERIAL AND METHODS: We conducted a prospective functional MRI study at 1.5 Testa in ten patients presenting with unilateral or bilateral ARMD and five age-matched controls. The visual stimulus was a sequence of resting phase (presentation of a fixation point on a black background) followed by an activation phase (flashes at 2 Hz). Functional data were recorded with anatomy; significant hemodynamic response secondary to neuronal activation was statistically determined using the SPM 99 software. RESULTS: The first objective was to estimate the feasibility of a functional study in the elderly. Controls and patients complained about the duration of the examination, although each of the two active functional sessions lasted only 4.5 min. The central point fixation was impaired for the patients; some deviated their gaze to center the fixation point on a perimacular retinal area. Because of substantial movement during MRI acquisitions, the data from two patients and one control were withdrawn from statistic processing. DISCUSSION AND CONCLUSION: This study is one of the few evaluations reported on functional MRI in the elderly, because of technical constraints, patient fragility and their ophthalmologic pathology. Optimizing the visual stimulus and the paradigm of stimulation, repeating patient information and support have helped demonstrate significant cortical hemodynamic response in most subjects, even in the most affected patients. Evaluation of the visual cortex by functional MRI appears feasible in the ophthalmologic pathology of the elderly, providing an adapted management of the subject's conditions.

[Cortical response to age-related macular degeneration (Part II). Functional MRI study]. / Réponse corticale dans la DMLA (Deuxième partie). Etude en IRM fonctionnelle.

UNLABELLED: PURPOSE AND MATERIALS: To evaluate the cortical response to visual stimulation in patients with age-related macular degeneration (ARMD), we conducted a functional MRI study in ten patients presenting unilateral or bilateral ARMD and five age-matched controls, using white flashes during activation phases (see Part I). RESULTS: After anatomical conformation, eight patients and four controls showed significant cortical hemodynamic response to monocular stimulations. Individual analysis was preferred to group evaluation, because of the differences in visual loss in a small number of patients. In controls, we observed cortical response in the primary visual cortex, especially at occipital poles corresponding to the macula. Patients showed a qualitative and quantitative restriction in cortical response and exclusion of occipital poles after stimulation of the affected eye, whereas activation was found in the peripheral striate and peristriate cortex. Cortical response showed hemispheric asymmetry in some patients. DISCUSSION: Our study demonstrated an activation defect in the macular projected striate cortex, corresponding to visual impairment in ARMD patients. Nevertheless, at a given visual acuity, cortical response may vary among subjects. Patients' subjective apprehension may account for such variations, as well as objective visual capacity stemming from residual functional retinal areas within the affected macula. The hemispheric asymmetry in cortical activation may result from gaze deviation onto the new fixation area in the perimacular retina, thus altering the global visual field. Enhancement in the peripheral striate and peristriate areas suggests changes in cortical interactions, possibly by a lowering of the feedback from macular projected V1. Finally, cortical evaluations must take into account degenerative phenomena delaying the hemodynamic response in the elderly. CONCLUSION: Aiming at a specific population of weakened patients with a serious visual impairment, we obtained significant results concerning cortical plasticity for visual perception in central vision deletion. Our preliminary findings must be confirmed in a larger population and correlated with other techniques exploring vision, in particular with multifocal electroretinography for retinal evaluation.

[Tractography of the visual pathways: routine examination in magnetic resonance imaging]. / Tractographie des voies visuelles: évaluation en routine en imagerie par résonance magnétique.

Water diffusion analysis in magnetic resonance imaging (MRI) provides an elective visualization of fiber tract orientations in cerebral white matter, especially for optic tracts. We explored 25 patients from 18 to 45 years of age, with normal MRI in 20 subjects, and radiological anomalies in five. On a 1.5 Tesla MRI apparatus, diffusion tensor acquisitions were performed in 5 minutes 58 seconds with an EPI Single Shot sequence covering the entire brain. Image displacements were precluded by patient information and adequate fixation, then digitally corrected on workstations. Volume merging and fiber tract extraction were achieved using dedicated software (Volume-One and dTV). A directional depiction was obtained for all areas in the white matter, in particular for white matter junctions. Coming from the lateral geniculate body, the optic tracts were directed posteriorly toward the occipital cortex, with numerous connections to extrastriate associative areas, and through the corpus callosum and the fornix. Diffusion tractography requires optimization of volume displacements, before and secondary to MRI acquisitions. Our diffusion tensor acquisition, with image optimization in a short-duration sequence can be routinely applied to all patients, for a specific analysis of functional connections between cortical areas of cerebral white matter.

[Acute optic neuritis in children: clinical features and treatment. A study of 28 eyes in 20 children]. / Les neuropathies optiques aiguës de l'enfant: particularités cliniques et thérapeutiques. A propos de 28 yeux chez 20 enfants.

PURPOSE: Analyzing a personal series of children with acute optic neuritis (AON), we studied MATERIAL AND METHODS: A retrospective study of 28 eyes in 20 patients (mean age: 10;7 years), examined between 1982 and 1997, with a follow-up ranging from 6 months to 15 years (mean: 5;5 years). We recorded etiologic factors, clinical features (ocular and extra ocular), biological results, and neuroimaging findings. RESULTS: Initial involvement was uni- or bilateral with poor visual acuity (under 20/200 in 22 eyes of 28). Intracerebral inflammation was present in 9 of 13 cases where MRI was performed. We found a cause in only 7 cases (5 viral diseases and 2 recent vaccinations against hepatitis B). Visual recovery was good (over 20/25 in 20 eyes of 28) whatever the treatment, but AON recurred in 5 children. Four children later developed multiple sclerosis. CONCLUSIONS: The cause of AON is rarely found. After eliminating an infection, we retained viral disease, complication of a recent vaccination against hepatitis B, and neurological diseases. MRI was the imaging study of choice. Development of multiple sclerosis occurred in 4 cases of 20, the same frequency as in the literature. The risk of later development of multiple sclerosis was 20%. Progression of AON was often excellent. Nevertheless, corticotherapy was added, in form of intravenous boluses followed by decreasing oral therapy for one month.

[The anatomy collections of the Paris V University: their role in medical teaching for two centuries]. / Les collections d'anatomie de l'université Paris V: leur rôle dans l'enseignement de la médecine depuis deux siècles.

The Museum of anatomy of the University Paris V exhibits a collection of ancient and high quality dissections and waxworks, very well preserved, which were used for teaching anatomy and have been classified historic monument since 1992.

["Idiopathic" acute optic neuropathies in children]. / Les neuropathies optiques aiguës "idiopathiques" de l'enfant.

We reported a retrospective study of 27 children (mean age = 10 years), who presented a loss of vision due to an acute optic neuritis, between 1982 and 1997. The symptoms ar more likely bilateral in children, and frequently associated with systemic viral infection or hepatitis B vaccination. Multiple sclerosis occurs approximately in 20 p. cent of the cases, i.e. less frequently than by adults. Magnetic resonance imaging is now systematic: in 20 children hyperintense nodular abnormalities in a various distribution was demonstrated by 9 children. During the follow-up, 23 eyes of 27 have an excellent recovery of vision, but 4 patients have developed multiple sclerosis. Corticotherapy was uses in 23 cases, in the form of methylprednisolone intravenous flashes in 14 cases.

[CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy): clinical features and neuroimaging]. / CADASIL (artériopathie cérébrale autosomique dominante avec infarctus sous-corticaux et leucoencéphalopathie): clinique et neuroimagerie.

Recently identified in a french family, CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a generalised disease of small arteries, largely predominating in the brain. Its clinical manifestations start during mid-adulthood and include recurrent ischaemic subcortical events, attacks of migraine with aura, severe mood disorders, subcortical dementia, and, at magnetic resonance imaging, widespread leuko-encephalopathy. There is so far no specific treatment and the mean duration of the disease is 20 years. CADASIL is most frequently a familial disorder with an autosomal dominant mode of transmission. Its responsible gene, Notch 3, is located on Chromosome 19. By the identification of its gene, CADASIL, (which is now known to affect over 400 families worldwide) is a unique variety of cerebro-vascular disease, affecting mainly the subcortical white matter.

Normal-appearing white matter in optic neuritis and multiple sclerosis: a comparative proton spectroscopy study.

We investigated neurochemical abnormalities in the normal-appearing white matter (NAWM) on MRI of patients with optic neuritis (ON) and compared them to those of patients with multiple sclerosis (MS). Patients with ON (42) were classified into three groups according to abnormalities on brain MRI. Patients with MS (55) were divided in two groups: relapsing remitting MS (RRMS) and secondary progressive MS (SPMS). All patients underwent MRI of the brain and localised proton magnetic resonance spectroscopy (MRS) of NAWM. The results were compared to those of 15 controls. Patients with MS had significant abnormalities compared with controls and with patients with ON. Patients with RRMS and those with ON had comparable MRS parameters, while patients with SPMS had significant spectroscopic abnormalities in comparison with controls, but also with patients with RRMS. These changes consisted of a decrease in N -acetylaspartate, a neuronal marker, which may reflect axonal dysfunction and/or loss. MRS abnormalities were detected in 14 patients with ON (27 %). The main abnormalities consisted of a decrease in N -acetylaspartate, an increase in choline-containing compounds at long echo times, and the presence of free lipid peaks at short echo times. MRS of the NAWM on MRI may prove useful for detecting neurochemical brain abnormalities in ON not visible on MRI.

Encephalitis after hepatitis B vaccination: recurrent disseminated encephalitis or MS?

OBJECTIVE: To describe clinical and MRI features of patients with a disease suggestive of CNS inflammation after hepatitis B vaccination. METHODS: Eight patients with confirmed CNS inflammation occurring less than 10 weeks after hepatitis B vaccination are described. They received follow-up clinically and on MRI for a mean period of 18 months. RESULTS: Clinical and MRI findings were compatible with acute disseminated encephalomyelitis. However, clinical follow-up, repeated MRI, or both showed the persistence of inflammatory activity, which makes this encephalitis more suggestive of MS than of acute disseminated encephalomyelitis. CONCLUSION: The persistent inflammatory activity observed clinically and on MRI in these patients is comparable with that usually observed in MS. Epidemiologic studies are currently testing the hypothesis of a triggering role of hepatitis B vaccination in CNS demyelination.

[Fronto-naso-ethmoido-sphenoido-maxillo-orbital mucocele with ophthalmologic presentation]. / Mucocèle fronto-naso-ethmoïdo-sphénoïdo-maxillo-orbitaire à révélation ophtalmologique.

PURPOSE: We present a case of a large mucocele pressing the orbit forward and compared our findings with those reported by others. CASE REPORT: A 23-year-old woman was examined for an inflammatory tumor of the internal canthus. She had a 6/10 vision loss of the left eye, diplopia, and non-axial exophthalmos. CT scan and magnetic resonance imaging evidenced a huge sinus mucocele behind the orbit. Surgery using the paralateronasal approach was performed. Pathology confirmed the diagnosis of mucocele. DISCUSSION: Ophthalmic complications of mucoceles result from tumor growth leading to compressive optic neuropathy or even compression of the chiasma. A sinus mucocele should be suspected upon indirect clinical signs and lead to neuroradiological explorations. Magnetic resonance imaging reveals iso- or high signals on T1-weighted sequences and high signal on T2-weighted sequences. MRI evidences intracranial or orbital extension. CT scan reveal the degree of bone erosion. Prognosis is favorable after surgical treatment. It is important to correctly diagnose mucocele on the basis of clinical and neuroradiological findings in order to propose early surgery and prevent permanent visual loss by compressive optic neuropathy.