Heightened activation of embryonic megakaryocytes causes aneurysms in the developing brain of mice lacking podoplanin.

During early embryonic development in mammals, including humans and mice, megakaryocytes (Mks) first originate from primitive hematopoiesis in the yolk sac. These embryonic Mks (eMks) circulate in the vasculature with unclear function. Herein, we report that podoplanin (PDPN), the ligand of C-type lectin-like receptor (CLEC-2) on Mks/platelets, is temporarily expressed in neural tissue during midgestation in mice. Loss of PDPN or CLEC-2 resulted in aneurysms and spontaneous hemorrhage, specifically in the lower diencephalon during midgestation. Surprisingly, more eMks/platelets had enhanced granule release and localized to the lower diencephalon in mutant mouse embryos than in wild-type littermates before hemorrhage. We found that PDPN counteracted the collagen-1-induced secretion of angiopoietin-1 from fetal Mks, which coincided with enhanced TIE-2 activation in aneurysm-like sprouts of PDPN-deficient embryos. Blocking platelet activation prevented the PDPN-deficient embryo from developing vascular defects. Our data reveal a new role for PDPN in regulating eMk function during midgestation.

[Functional and morphological changes of the diencephalon vascular endothelium of rats in experimental ischemia-reperfusion injury and diabetes mellitus].

We have studied the influence of bilateral carotid ischemia-reperfusion on the indices of the functional and morphological condition of the vascular endothelium of the brain hypothalamolimbic complex. It has been established that a decrease of the density of endothelial location in an early ischemic-reperfusion period in the control rats has a relative characterstipulated by edema of cells whereas on the 12-th day of observation an increase of the absolute density of cells takes place. During both periods of observation there is an increased content of the tjtal RNA in the capillary endotheliocytes of all the structures. An early reaction of the morpho-functional states of endotheliocytes to ischemic-reperfusion is absent in animal with diabetes mellitus, exept the vessels of the ventromedial hypothalamus while a late one is restricted by a growth content in RNA cells.

The perforating branches of the P1 segment of the posterior cerebral artery.

The perforating branches of the P1 segment of the posterior cerebral artery are vulnerable to injury. Because of their close proximity to the basilar artery, the vulnerability occurs especially during surgical interventions for vascular pathologies such as basilar apex aneurysms. Therefore, extensive knowledge of the microsurgical anatomy of this area is mandatory to prevent poor post-operative outcomes. We microscopically examined 28 P1 segments obtained from 14 adult fresh cadaver brains (6 silicone injected, 8 freshly examined). The P1 segments ranged between 2.8mm and 12.2mm (mean 6.8mm) in length with a mean outer diameter of 1.85 mm (range 0.8-4.5mm). All 94 thalamoperforating branches identified in 27 P1 segments (mean 3.35 branches per segment) arose from the postero-superior aspect of P1 and were the most proximally originating branch in nearly all specimens (96.4%). In addition in 28 P1s, 12 short circumflex arteries (42.8%; mean 0.42 branches per segment), 16 long circumflex arteries (57.1%; mean 0.57 branches per segment) and 10 medial posterior choroidal arteries (35.7%; mean 0.35 branches per segment) were identified and all originated from the posterior or postero-inferior surface of the P1 segment. When the P1 segment had more than one type of branch, it was the short circumflex arteries that were always more proximal in origin than the others. The medial posterior choroidal arteries were always more distal in origin. All three branches were not observed together in any of the P1 segments. The findings in this, and future, anatomical studies may help to reduce the post-surgical morbidity and mortality rates after surgery for posterior circulation aneurysms.

Neuropathology of central nervous system arterial syndromes. Part I: the supratentorial circulation.

The objective of this review is to illustrate the principal cerebrovascular arterial pathoanatomical syndromes using the unique collection of whole brain sections in the Raymond Escourolle Neuropathology Laboratory at Salpêtrière in Paris. The arterial supratentorial syndromes are presented in Part I; the infratentorial and spinal cord syndromes will be presented subsequently in Part II. No attempt is made to be all-inclusive in the review of the literature; rather, we cite only those bibliographic references that are historically noteworthy and with some exceptions that particularly emphasize the neuropathologic rather than radiographic/imaging aspects of the vascular syndromes. From these studies and our own archival material, we have synthesized the salient clinicopathologic aspects of the individual syndromes.

The middle perforated substance of the diencephalon.

The diencephalon, upper brain stem and other basal brain structures are supplied chiefly by penetrating branches of the cerebral arteries. We examined the retrochiasmatic space between the superior border of the pons and posterior edge of the optic chiasm in six randomly selected adult fresh brain specimens. Lateral or anterolateral to the mamillary bodies, two small quadrangular spaces (2.5 x 3.5 mm) were found that were limited laterally by the junction of the optic tract and crus cerebri. These spaces were pierced on each side by 1 to 5 small penetrating branches (premamillary arterial complex) of the posterior communicating artery. A single, large and obliquely oriented penetrating branch of the posterior communicating artery (the so-called premamillary, thalamotuberal or mamillothalamic artery) was found to pierce this area in all specimens. Based on our findings, the above-mentioned vessels of this perforating substance supply the floor of third ventricle, hypothalamus and ventral thalamic nuclei. Hence, special attentions should be made during surgery in this area such as third ventriculostomy for hydrocephalus.

Episodic diencephalic hypoperfusion in Kleine-Levin syndrome.

A 22 year-old woman suffered from recurrent episodes of hypersomnia, apathy, and hyperphagia. The symptoms occurred 3 to 4 times per year, and each attack lasted 2 to 3 weeks. 99mTc-ethylcysteinate dimer brain single photon emission computed tomography (SPECT) was performed during symptomatic and asymptomatic periods. To localize brain regions with perfusion changes during symptomatic period, asymptomatic SPECT was subtracted from symptomatic SPECT. The subtracted SPECT showed significant hypoperfusion in the left hypothalamus, bilateral thalami, basal ganglia, bilateral medial and dorsolateral frontal regions, and left temporal lobe during the symptomatic period. These cerebral hypoperfusion areas support the diencephalic hypothesis and clinical symptoms of Kleine-Levin syndrome.

[Convergence nystagmus and vertical gaze palsy of vascular origin]. / Nystagmus de convergence et paralysie de la verticalité du regard d'origine vasculaire.

A case of convergence-retraction nystagmus with upward vertical gaze paralysis and skew deviation (right hypotropia), without any other neurological signs, is reported. The probably vascular lesion was located at the mesodiencephalic junction, lying between the right border of the posterior commissure, the right interstitial nucleus of Cajal and the periaqueductal grey matter, accounting for the three ocular motor signs. The particular interest of this case is due to the relative smallness of the lesion.

Microsurgical anatomy of the venous drainage of the mesencephalodiencephalic junction.

OBJECTIVE: The veins draining the posterior wall of the third ventricle and its adjacent structures and the posterior part of the midbrain have been the most neglected of the intracranial vascular structures in both the anatomic and neurosurgical literature. During our dissections of the pineal region and the quadrigeminal cistern, we did not always encounter topographic anatomy as described in previous articles. The purpose of this study is to describe the topographic anatomy and normal variations of the specific veins that drain the collicular plate and the pineal body and their adjacent structures with a view to better defining neurosurgical approaches to the pineal region. METHODS: The deep cerebral veins draining the pineal body, the collicular plate, and their surrounding neural structures were examined on both sides of 25 adult cadaveric brains. In all specimens, the carotid and vertebral arteries and the jugular veins were perfused with red or blue silicone, respectively, to facilitate dissection under x3 to x40 magnification. RESULTS: The venous plexus on the dorsal aspect of the collicular plate drains via collicular veins according to three different patterns. These types of drainage are closely related to the existence or absence of the basal vein on one or both sides. CONCLUSION: The veins draining the superior and inferior aspects of the pineal body form a superior and an inferior pineal vein that usually drain into the internal or great cerebral vein.

Ultrastructural evidence of brain mast cell activation without degranulation in monkey experimental allergic encephalomyelitis.

Experimental allergic encephalomyelitis (EAE) is an animal model for the human demyelinating disease multiple sclerosis (MS). Increased permeability of the blood-brain barrier (BBB) precedes the development of clinical or pathologic findings in MS and may be induced by perivascular brain mast cells secreting vasoactive and proinflammatory molecules. Brain mast cells were investigated ultrastructurally in acute EAE of the non-human primate common marmoset Callithrix jacchus, which develops a mild neurologic relapsing-remitting course. Control diencephalic samples contained perivascular mast cells with mostly intact electron dense granules. In contrast, EAE samples had marked demyelination and mast cells with numerous altered secretory granules; their electron dense content varied in amount and texture with a "honeycomb" or "target" appearance, but without degranulation. These changes were evident even before the development of any clinical symptoms and suggest that brain mast cells may be involved in EAE, and possibly MS, through a unique process that may involve selective secretion of molecules able to disrupt the BBB.

Acute stress increases permeability of the blood-brain-barrier through activation of brain mast cells.

Disruption of the blood-brain-barrier (BBB) is important in the pathophysiology of various inflammatory conditions of the central nervous system (CNS), such as multiple sclerosis (MS), in which breakdown of the BBB precedes any clinical or pathological findings. There is some evidence that relapsing-remitting MS attacks may be correlated with certain types of acute stressful episodes. Stress typically activates the hypothalamic-pituitary-adrenal (HPA) axis through the release of corticotropin releasing hormone (CRH), leading to production of glucocorticoids that down regulate immune responses. However, acute stress also has pro-inflammatory effects that appear to be mediated through activation of mast cells. Here we show that acute stress by immobilization increased permeability of rat BBB to intravenous 99Technetium gluceptate (99Tc). This effect was statistically significant in the diencephalon and the cerebellum, while it was absent in the cerebral cortex where there are not mast cells. Immobilization stress also induced activation of mast cells in diencephalon, the site where most mast cells are found in the rat brain. Both BBB permeability and mast cell activation were inhibited by the 'mast cell stabilizer' disodium cromoglycate (cromolyn). These results expand the pathophysiology of mast cells and implicate them in CNS disorders, that may possibly be induced or exacerbated by stress.

Chronic akinetic mutism after mesencephalic-diencephalic infarction: remediated with dopaminergic medications.

OBJECTIVE: Akinetic mutism (AKM) is an uncommon disorder with a complex neuropathology. There is no generally accepted treatment, and it is not known if late treatments are effective. The relationship between AKM and abulia is uncertain. METHODS: The effects of dopaminergic treatment of a patient with chronic AKM after discrete bilateral infarctions of the mesencephalic ventral tegmental area and the lateral hypothalamus were studied with motor measures, the Functional Independence Measure (FIM), and neuropsychological tests. RESULTS: Treatment with a combination of carbidopa/levodopa and pergolide produced prompt amelioration of AKM with dramatic and rapid improvement in FIM. An apathetic, amotivational state persisted despite resolution of akinesia and normal frontal executive functions. CONCLUSIONS: AKM may respond to dopaminergic treatment even after months of severe akinesia. The mechanism of abulia is more complex than simply a partial dopaminergic deficiency state and may persist even when AKM is treated and frontal cognitive functions are normal.

The distribution of FOS-immunoreactive neurons in the brainstem, midbrain and diencephalon of fetal sheep in response to acute hypoxia in mid and late gestation.

FOS immunohistochemistry was used to map the distribution of neuronal pathways activated by hypoxia in fetal sheep. Conscious pregnant sheep were exposed to hypoxia (7-9% O2, 1-2% CO2, balance N2) for 2 h at either 100-105 days (n=5) or 130-133 days gestation (n=5); term is approximately 147 days. The hypoxia caused cessation of breathing movements at both fetal ages, and increased FOS staining in the medulla (area postrema, dorsal motor nucleus of vagus, nucleus solitary tract, ventrolateral medulla); pons (locus coeruleus and subcoeruleus, lateral and medial parabrachial nuclei); midbrain (habenula, periaqueductal grey, substantia nigra, areas ventrolateral to Red Nucleus); and hypothalamus (anterior and lateral hypothalamic areas, paraventricular and supraoptic nuclei). The results were essentially the same at both gestational ages, except that hypoxia increased FOS-staining in the habenula only in the older fetuses. The presence of FOS protein in pontomedullary cardiorespiratory nuclei at 100-105 days gestation indicates that the peripheral chemoreceptors respond to hypoxia at this early age, and in the subcoeruleus and medial parabrachial regions of the pons is consistent with lesion studies suggesting these areas mediate the inhibition of fetal breathing in response to hypoxia. FOS staining in the ventrolateral periaqueductal grey and habenula was unexpected, and suggests that pathways normally involved in response to noxious stimuli, or which are part of the hypothalamic 'defense' response are activated by hypoxia in the fetus. Some FOS-labelling could arise secondarily as a consequence of the cardiovascular and endocrine responses to hypoxia.

Aetiology of transient global amnesia.

The pathophysiology of transient global amnesia (TGA) has been obscure since the definition of this syndrome more than 30 years ago. Current hypotheses include migraine, seizure, or transient cerebral arterial ischaemia. However, none of these potential mechanisms explain both the absence of other neurological signs or symptoms during TGA, and its frequent precipitating activities: many of which would be expected to result in marked increases in venous return from the arms to the superior vena cava. Patients with TGA also commonly have a Valsalva manoeuvre at the onset of attacks. I suggest that a Valsalva manoeuvre, blocking venous return through the superior vena cava, may allow brief retrograde transmission of high venous pressure from the arms to the cerebral venous system, resulting in venous ischaemia to the diencephalon or mesial temporal lobes and to TGA.

Progressive neurologic impairment from an arteriovenous malformation vascular steal.

Approximately 15% of all cerebral arteriovenous malformations (AVMs) present with progressive neurologic deficits, the pathogenic mechanism of which has not been established. One suggestion is that AVMs by expanding over time compress normal surrounding cerebral parenchyma and thereby cause progressive neurologic impairment. Alternatively, a vascular steal results in progressive ischemia of normal cerebral tissue. Because the area occupied by the AVM and the area of observed blood flow reductions in all reported patients have overlapped, delineating the relative contribution of local compression from that of vascular steal has not been possible. We present a 7-month-old girl and a 7-year-old boy with AVMs restricted to the diencephalon who had progressive cognitive impairment and dystrophic cerebral hemispheral calcification (in the 7-month-old girl) indicating diffuse cerebral cortical involvement remote from the AVM. These patients provide evidence for vascular steal, and not local compression, as the primary mechanism underlying a progressive neurologic course associated with some AVMs.

Narcolepsy associated with arteriovenous malformation of the diencephalon.

Narcolepsy associated with localized brain lesions is rare, and few reports of well-documented cases have been published. We describe the case of a 20-year-old male (HLA DQw1 negative) who fulfilled clinical and polygraphic criteria of symptomatic narcolepsy. Narcolepsy in this patient was associated with an arteriovenous malformation involving the structures around the third ventricle. Clinical symptoms improved after embolization and radiosurgery. These findings support the hypothesis that lesions in the vicinity of the third ventricle can cause symptomatic narcolepsy.

Mesencephalo-diencephalic angioanatomy in arteriovenous malformations. Endovascular management of transmesencephalic vs subependymal supply in 954 cases between 1982 and 1994.

This report presents the arteries of the mesencephalo-diencephalic region and their different role in the supply to the cerebral structures. Among them, the authors distinguish the subependymal and transmesencephalic arteries to which they pay a special attention since these vessels present a specific angiographic aspect. The importance of their differentiation is emphasized. The authors discuss the management of subependymal and (trans)mesencephalic arteries during endovascular neuro-intervention illustrative cases.

Thalamic infarctions: differential effects on vestibular function in the roll plane (35 patients).

We determined the subjective visual vertical (SVV), ocular torsion (OT), skew deviation, and lateral head tilt in 35 patients with acute thalamic infarctions (14 paramedian, 17 posterolateral, and four anterior polar) and in five patients with mesodiencephalic hemorrhages to obtain the tonic effects on vestibular function in the roll plane. Eight of 14 paramedian infarctions had complete ocular tilt reaction (OTR) with contraversive head tilt, skew deviation, OT, and SVV tilt. The OTR was due to ischemia of the rostral midbrain tegmentum, including the interstitial nucleus of Cajal (INC), and not to thalamic ischemia. Thus, the INC (and the rostral interstitial nucleus of the medial longitudinal fascicle) is the most rostral brainstem structure mediating eye-head coordination in roll. Eleven of 17 posterolateral infarctions exhibited moderate SVV tilts that were either ipsiversive or contraversive. In these 11 cases, vestibular thalamic nuclei (nucleus ventro-oralis intermedius, nucleus ventrocaudalis externus, and nucleus dorsocaudalis) were involved; infarctions in the remaining six were more ventromedial. Anterior polar infarctions did not affect vestibular function in roll.

The effects of prostaglandin E1 and nicardipine on cerebral blood flow, blood volume and oxygenation in young rabbits.

The effects of the vasodilators, prostaglandin E1 and nicardipine, on cerebral blood flow (CBF), cerebral blood volume and oxygenation were studied in young rabbits of 2 weeks of age using the hydrogen clearance method and near infrared spectrophotometry. Prostaglandin E1 decreased CBF in the cerebral cortex. However, cerebral oxygenation through oxyhemoglobin and cytochrome a, a3 was not affected by the drug. On the other hand, nicardipine increased CBF in the cerebral white matter and diencephalon in spite of the fall in blood pressure and the decreased cerebral blood volume due to deoxyhemoglobin. Oxidized cytochrome a, a3 variably increased. These results suggest that nicardipine, a calcium channel antagonist, may cause dilation of cerebral arterioles, increase CBF and cellular oxidation, and cause constriction of cerebral veins, in contrast to the little effect of prostaglandin E1 on cerebral vessels.

Secondary hypotensive insults in a rat forebrain ischemia model.

Previous studies have shown that the recently injured brain has an increased sensitivity to subsequent brief episodes of severe ischemia. This investigation was designed to assess whether less severe secondary insults, which alone would be incapable of producing injury, exacerbate brain damage resulting from a primary episode of global ischemia. Rats were subjected to either 10 min of 2-vessel forebrain ischemia (primary insult alone), 20 min of hypotension (mean arterial pressure, MAP = either 40 or 25 mmHg) without vessel occlusion (secondary insult alone), or 10 min ischemia followed 1 h later by the hypotensive challenge (primary + secondary insult). Seven days later, the animals were neurologically evaluated and the brains then prepared for histologic analysis. Neither magnitude of secondary insult alone was found to produce injury. In contrast, the primary insult alone caused moderate damage in the hippocampus, caudoputamen and neocortex. With the exception of increased neuronal necrosis in the hippocampal CA1 sector in rats receiving the primary + secondary insult (MAP = 25 mmHg), no worsening of outcome could be attributed to the secondary insults. These results indicate that the recovering brain may not be as sensitive to hypoperfusion as has previously been suggested.

Effects of a new calcium channel blocker, KB-2796, on protein synthesis of the CA1 pyramidal cell and delayed neuronal death following transient forebrain ischemia.

The effects of a new calcium channel blocker, 1-[bis(4-fluorophenyl)methyl]-4-(2,3,4-trimethoxybenzyl)-piperazine dihydrochloride (KB-2796), on delayed neuronal death (DND) in the hippocampus were examined in gerbils in comparison with those of pentobarbital and flunarizine. The neuronal density in the hippocampal CA1 subfield was counted on the seventh day of recirculation following 5 min of bilateral carotid occlusion, and protein biosynthesis in the brain was also determined at 1, 2, 4, 24, and 72 h following occlusion. The drugs were intraperitoneally administered after recirculation. KB-2796 (10 mg/kg) significantly prevented DND in the CA1 subfield. Pentobarbital (40 mg/kg), but not flunarizine (3 and 10 mg/kg), inhibited DND. Protein synthetic activity in the CA1 subfield was reduced by ischemia and the reduction was not restored even at 72 h after recirculation. KB-2796 did not ameliorate the reduction of protein synthesis in the CA1 subfield by 24 h after recirculation, but in one of three animals restoration of protein synthesis was observed at 72 h of recirculation. Pentobarbital also restored the reduced protein synthesis in two of three animals at 72 h. These results suggest that calcium influx into neurons participates in the pathogenesis of DND, and also that KB-2796 might prevent both morphological and functional cell damage in CA1 neurons induced by transient ischemia.