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.

Shape and volume of craniofacial cavities in intentional skull deformations.

Intentional cranial deformations (ICD) have been observed worldwide but are especially prevalent in preColombian cultures. The purpose of this study was to assess the consequences of ICD on three cranial cavities (intracranial cavity, orbits, and maxillary sinuses) and on cranial vault thickness, in order to screen for morphological changes due to the external constraints exerted by the deformation device. We acquired CT-scans for 39 deformed and 19 control skulls. We studied the thickness of the skull vault using qualitative and quantitative methods. We computed the volumes of the orbits, of the maxillary sinuses, and of the intracranial cavity using haptic-aided semi-automatic segmentation. We finally defined 3D distances and angles within orbits and maxillary sinuses based on 27 anatomical landmarks and measured these features on the 58 skulls. Our results show specific bone thickness patterns in some types of ICD, with localized thinning in regions subjected to increased pressure and thickening in other regions. Our findings confirm that volumes of the cranial cavities are not affected by ICDs but that the shapes of the orbits and of the maxillary sinuses are modified in circumferential deformations. We conclude that ICDs can modify the shape of the cranial cavities and the thickness of their walls but conserve their volumes. These results provide new insights into the morphological effects associated with ICDs and call for similar investigations in subjects with deformational plagiocephalies and craniosynostoses.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) has been recently reported as a cause of stroke. It is characterized, in the absence of hypertension, by recurrent subcortical ischaemic strokes, starting in early or midadulthood and leading in some patients to dementia. Magnetic resonance imaging and pathological examination show numerous small subcortical infarcts and a diffuse leukoencephalopathy underlaid by a non-arteriosclerotic, non-amyloid angiopathy. We performed genetic linkage analysis in two unrelated families and assigned the disease locus to chromosome 19q12. Multilocus analysis with the location scores method established the best estimate for the location of the affected gene within a 14 centimorgan interval bracketed by D19S221 and D19S222 loci.

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.

[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.

Localized proton magnetic resonance spectroscopy in patients with adult adrenoleukodystrophy. Increase of choline compounds in normal appearing white matter.

OBJECTIVES: To describe the changes in the results of magnetic resonance imaging and spectroscopy occurring in the normal-appearing white matter of patients with adult adrenoleukodystrophy and to present evidence of a particular change that may serve as a marker for the follow-up of the disease. DESIGN: Neurologic, magnetic resonance imaging, and localized proton spectroscopic examinations were performed in 11 patients with adult adrenoleukodystrophy and compared with 11 sex- and age-matched controls. PATIENTS: Eleven patients with adult adrenoleukodystrophy participated in a trial of dietary therapy with glyceryl trioleate and glyceryl trierucate (Lorenzo's oil) in the Fédération de Neurologie and the Institut National de la Santé et de la Recherche Médicale, Unité 134, at the Hôpital de la Salpêtrière in Paris, France. RESULTS: The results of magnetic resonance imaging of the white matter were normal in 2 patients and showed areas of mild symmetrical hypersignals on T2-weighted images and fluid attenuated inversion recovery sequences, localized in the posterior white matter in 9 patients. The results of spectroscopy indicated that the peak of the area of choline-containing compounds was increased at long echo times in patients with adult adrenoleukodystrophy, which may reflect very long-chain fatty acid accumulation in this disease. The peak of the area of myo-inositol-containing compounds was increased at short echo times in patients with adult adrenoleukodystrophy, which may indicate a rise in this metabolite concentration. The N-acetylaspartate-creatine amplitude ratio was significantly decreased in patients with motor deficit. The significance of this finding remains to be established. CONCLUSIONS: The results of localized proton magnetic resonance spectroscopy show abnormalities in the cerebral white matter of patients with adult adrenoleukodystrophy, which may contribute to the understanding of the pathophysiologic characteristics of the disease. Although changes in the results of spectroscopy found in this disease are not specific, the increase of choline-containing compounds may reflect the accumulation of very long-chain fatty acids in the central nervous system. Localized proton magnetic resonance spectroscopy may prove a valuable technique, in addition to magnetic resonance imaging, for noninvasive investigation of patients with adult adrenoleukodystrophy undergoing future clinical trials.

Localized proton magnetic resonance spectroscopy in relapsing remitting versus secondary progressive multiple sclerosis.

OBJECTIVE: To determine the efficacy of MRS in discriminating between relapsing remitting (RR) and secondary progressive (SP) MS. METHODS: MRS at long and short echo times was carried out in 104 patients with MS stratified for clinical course (RR or SP), and the results were compared with those of 15 control subjects. Normal-appearing white matter (NAWM) was studied in 55 patients, and a high-T2-signal area on MRI in 49 others. RESULTS: At long echo times, there was a highly significant decrease in the ratios N-acetyl-aspartate/creatine (NAA/Cr) and NAA/ choline (Cho) in high-T2-signal areas and in the NAWM in patients with an SP course compared with control subjects and patients with an RR course. There was a significant negative correlation between these ratios and clinical disability measured by Expanded Disability Status Scale score, which was independent of disease duration. Discriminant values between patients with RR and SP courses were found in the NAWM (NAA/Cr = 1.75 and NAA/Cho = 1.5), but not in high-T2-signal areas. At short echo times, there was a significant increase in the ratio myoinositol/Cr in high-signal areas of patients with an SP course compared with control subjects, and the presence of abnormal resonances in the lesions and NAWM for free amino acids and lipids (in 30% and 8%, respectively) and GLX complex (glutamine, glutamate, gamma-aminobutyric acid; 16% and 20%, respectively). CONCLUSIONS: Studying normal-appearing white matter on MRI with MRS allows discrimination between relapsing remitting and secondary progressive patients. In the NAWM of patients with MS and an SP course, severe axonal loss/dysfunction is negatively correlated to clinical disability and independent of the duration of the disease.

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.

Clinical and spectroscopic improvement in HIV-associated cognitive impairment.

To assess the impact of highly active antiretroviral therapy (HAART) on AIDS-associated cognitive impairment, 22 patients with AIDS with (n = 11) and without (n = 11) cognitive deficit were evaluated clinically and by MRS every 3 months for 9 months. Nineteen patients were on HAART at study entry, 21 after 2 months. Cognitively impaired patients presented with a subcorticofrontal deficit and decreased N-acetyl-aspartate in frontal white matter. These clinical and metabolic abnormalities reversed partially on HAART, whereas they remained within normal limits in cognitively unimpaired patients.

Notch3 mutations in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a mendelian condition causing stroke and vascular dementia.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited condition whose key features include recurrent subcortical ischemic events, migraine attacks and vascular dementia in association with diffuse white-matter abnormalities seen on neuroimaging. Pathologic examination shows multiple small deep cerebral infarcts, a leukoencephalopathy and a nonatherosclerotic nonamyloid angiopathy involving mainly the media of small cerebral arteries. To progress in understanding the pathophysiological mechanisms of this condition, we undertook the identification of the mutated gene. We mapped the CADASIL gene on chromosome 19p13.1. More than 120 families have been referred to our lab. Genetic linkage analysis of 33 of these families allowed us to reduce the size of the genetic interval to less than 1 cM and to demonstrate the genetic homogeneity of this condition. In the absence of any candidate gene, we undertook positional cloning of this gene. We identified, within the CADASIL critical region, the human Notch3 gene, whose sequence analysis revealed deleterious mutations in CADASIL families co-segregating with the affected phenotype. These data establish that this gene causes CADASIL. Identification of the CADASIL gene will provide a valuable diagnostic tool for clinicians and could be used to estimate the prevalence of this underdiagnosed condition. It should help in the understanding of pathophysiological mechanisms of CADASIL and vascular dementia.

The cerebellar second homunculus remains silent during passive bimanual movements.

In a previous study, we showed that the second homunculus in lobule VIII of the cerebellum is activated during bilateral out-of-phase index finger-thumb opposition, implying a role in motor coordination. However, several recent studies indicate that the cerebellum could be more actively involved in sensory information processing during movement. Therefore, as lobule VIII activation could involve either a motor or a proprioceptive component, these two components must be distinguished and their relative contribution must be determined. Using functional imaging, we studied cerebellar activation of the same region during passively induced index finger-thumb opposition of both hands in in-phase and out-of-phase modes, thereby excluding the voluntary movement component. No significant activation was detected in lobule VIII. Intense activation of lobule VIII, obtained during active, out-of-phase bimanual movements, therefore does not involve a significant sensory component related to direct proprioceptive feedback. This result is strongly in favour of the specific recruitment of lobule VIII during out-of-phase movements related more to complex motor timing than to sensory function.

Specific neocerebellar activation during out-of-phase bimanual movements.

We used fMRI to study cerebellar activation during index finger-thumb opposition of the right hand and index finger-thumb opposition of both hands in in-phase and out-of-phase modes. The right hand movement activates the contralateral anterior lobe of the cerebellum. During bimanual in-phase movements, this activity pattern becomes bilateral. More interestingly, bilateral out-of-phase movements recruit the cerebellar posterior lobe VIII, which likely corresponds to the second homunculus. As out-of-phase movements differ from the in-phase movements only by their temporal complexity and their attentional awareness, this study demonstrates the preferential involvement of the cerebellar second homunculus in the control of complex movements.

Preliminary results of a magnetic resonance imaging (MRI) study of the pig brain placed in stereotaxic conditions.

Magnetic resonance imaging (MRI) of two pig brains was realized. The animals were placed in the stereotaxic conditions currently used in experiments. To allow the positioning of the animal in the MRI instrument, landmarks were previously traced on the snout of the pig. To avoid movements, animals were deeply anesthetized. MRI were taken in frontal, horizontal and sagittal directions. Afterwards, the brains of the pigs were frozen and cut into sections, frontal for one animal and sagittal for the other. Histologic and MR images were compared. The usefulness of this technique is discussed.

Comparison study of CT and positron emission tomographic data in recent cerebral infarction.

To better understand the pathophysiologic correlates of the computed tomographic (CT) scan changes seen in recent cerebral infarction, 17 patients (20 studies) underwent both x-ray transmission and positron emission CT investigations within 18 days after clinical onset of complicated ischemic stroke in the internal carotid artery territory. The density changes before and after contrast study measured within the CT lesion were correlated to the local cerebral blood flow (CBF), oxygen utilization (CMRO2), and oxygen extraction fraction (OEF) measured with the oxygen-15 steady-state positron technique. Statistically significant linear correlations were found between hypodensity and CBF, hypodensity and CMRO2, and contrast enhancement and CBF, such that the more CBF and CMRO2 were depressed, the more marked was the hypodensity; and the more CBF was elevated, the more marked was the contrast enhancement. Although marked contrast enhancement was associated with decreased OEF (luxury perfusion), it was only rarely associated with increased CBF. Various hypotheses are discussed to explain these findings.

Minimal surface: a useful paradigm to describe the deeper part of the corpus callosum?

The aim of this magnetic resonance imaging study was to find a geometrical characterization of the deeper part of the corpus callosum. Its shape was studied in 12 middle-aged persons free of white matter pathology. Profiles of curvatures were measured showing that this surface was close to a minimal one, especially at the genu and near the splenium. To assess the effect of a white matter pathology on these geometrical features, the same measurements were performed in an extra group of nine patients with definite multiple sclerosis. The hypothesis of curvatures profiles parallelism for the two groups could be rejected at the 0.05 confidence level for the mean curvatures but not for the Gaussian ones. Curvatures profiles may give indications on balance between the cortex and the fiber bundles growth rates during the development and on large scale modifications co-occurring with multilocular white matter pathologies.

Post-pneumonectomy evaluation of the chest: a prospective comparative study of MRI with CT.

A comparative study of 11 pneumonectomized patients was undertaken in order to evaluate the respective advantages and drawbacks of MRI and CT in post-operative follow-up. Nine patients were healthy at the time of the study and two presented with tumor recurrence. MR examination included 500/40 ms axial, and frontal 800/40-80 ms or 1300/60-120 ms nongated spin echo sequences. MRI was slightly more efficient in identifying vascular stump and main nodal stations, and detected better than CT tumoral and metastatic spread in cancer recurrences. It was as informative as CT in evaluating postpneumonectomy space and bronchial stump. It was noncontributory in the detection of calcifications. Although clips were visible with MRI, their location was less definite than with CT, a potential pitfall when radiotherapy is planned.

MRI in the pre-operative assessment of tracheal cylindroma. Case report.

Compared with malignant neoplasms of the chest, benign tumours are quite rare; cylindroma (or salivary gland adenoma) is exceptional. The apparent histological benignancy belies its high potential for invasiveness. This can, in some cases, lead to extensive, non-conservative surgery. By a different approach in the imaging of the chest, Magnetic Resonance Imaging in this condition may provide an accurate pre-operative assessment. We present a case in which MRI provided the information necessary for the surgical approach, and describe its accuracy and the results obtained.

[Study with localized proton magnetic resonance spectroscopy of 31 multiple sclerosis lesions: correlations with clinical and MRI features]. / Etude en spectroscopie protonique localisée de 31 lésions de SEP: corrélations avec les données cliniques et en IRM.

We have analyzed with localized proton magnetic resonance spectroscopy (MRS) 31 lesions in 28 patients with multiple sclerosis (MS). The course of the disease was either relapsing remitting, secondary progressive, or primary progressive. Four patients had an isolated neurological syndrome suggestive of MS. The decrease in the NAA/Cre ratio and the raise of the Cho/Cre ratio were more pronounced in patients with an acute isolated neurological syndrome, suggesting the predominance of an inflammatory process, and the presence of an axonal dysfunction in the initial course of the lesion. The NAA/Cre ratio was negatively correlated with clinical disability and thus could be used as an index of disease activity. Patients with a secondary progressive course exhibited a significant increase in the Myo/Cre ratio compared to those with a relapsing remitting course. Thus, there may be an association between the evolution towards a progressive disease and axonal loss or the development of gliosis. The isointense lesions to the cerebrospinal fluid on MRI T1 weighted sequences were characterized by a sharp raise in the Cho/Cre ratio suggesting demyelination and/or intense inflammation. Gadolinium enhanced lesions were not characterized by a specific neurochemical profile.

[Magnetic resonance spectroscopy in multiple sclerosis]. / Spectroscopie par résonance magnétique et sclérose en plaques.

Magnetic resonance spectroscopy allows in vivo neurochemical exploration of multiple sclerosis (MS) lesions and normal appearing white matter on MRI. It gives insights into pathophysiology: inflammation (increase of choline), recent demyelination (increase in lipids and choline), axonal dysfunction (decrease of NAA), gliosis (increase of myoinositol). The spectroscopic profile of lesions is not specific to MS. Therefore MRI remains the first investigation to perform when MS is suspected. However, spectroscopy is a sensitive, reproducible, non invasive tool which may provide an index of activity. In the future, spectroscopy may contribute in homogenizing patient selection for clinical trials and might be used, in association with MRI, to evaluate therapeutic efficiency. Spectroscopy might also influence therapeutic choices by identifying the prevailing lesional mechanism: inflammation, demyelination, axonal destruction, or gliosis.

[Cerebral blood flow and oxygen extraction in lacunar hemiplegia. Semi-quantitative study using oxygen 15 and emission tomography]. / Débit sanguin cérébral et extraction d'oxygène dans les hémiplégies lacunaires. Etude semi-quantitative par l'oxygène 15 et la tomographie d'émission.

The oxygen 15 non invasive continuous inhalation technique coupled with positron emission tomography (P.E.T.) allows the local study of cerebral blood flow and oxygen metabolism. Recent P.E.T. studies have demonstrated the frequent occurrence of widespread metabolic depression remote from the site of middle cerebral artery territory infarct per se, especially over the cortical mantle and thalamus ipsilaterally, and over the cerebellar hemisphere contralaterally. These phenomena have been taken as indicative of transneural depression (i.e. diaschisis). We thought it interesting to study the possible occurrence of such abnormalities in patients with lacunar syndromes. We have applied the (15)0 technique to six patients (2 with pure motor hemiplegia, 4 with ataxic hemiparesis) for whom no large causal ischemic lesion could be demonstrated on CT scans; in only one patient was a lacunar lesion, presumably responsible for the clinical deficit demonstrated. Compared to a set of 19 patients without brain disease, the semi-quantitative results (analyzed in terms of asymmetry indices between homologous brain regions) in our patients did not disclose any pathophysiologically significant abnormality. More specifically, no evidence of physiological dysfunction similar to that reported in internal carotid artery territory infarcts, was detected over the cerebral or cerebellar cortices. These findings are commented upon in view of the presumably small size and the uncertain topography of the causal lesion.