Long survival of primary diffuse leptomeningeal gliomatosis following radiotherapy and temozolomide: case report and literature review.

OBJECTIVE: Primary diffuse leptomeningeal gliomatosis (PDLG) is a rare neoplasm with a short survival time of a few months. There is currently no standardized therapeutic approach for PDLG. - MATERIAL AND METHODS: We report on a 53-year-old male patient who presented with epileptic seizures, gait disturbance, paraparesis and sensory deficits in the dermatomes T8-10. - RESULTS: Magnetic resonance imaging (MRI) revealing numerous spinal and cranial gadolinium-enhancing nodules in the meninges and histopathology led us to diagnose primary diffuse leptomeningeal gliomatosis with WHO grade III astrocytic cells. Consecutively, the patient underwent craniospinal radiotherapy (30Gy) and 11 sequential cycles of temozolomide. This regimen led to partial tumor regression. Thirteen months later, spinal MRI revealed tumor progression. Second-line chemotherapy with 5 cycles of irinotecan and bevacizumab did not prevent further clinical deterioration. The patient died twenty-two months after diagnosis, being the longest survival time described thus far with respect to PDLG consisting of astrocytic tumor cells. - CONCLUSIONS: Radiochemotherapy including temozolomide, as established standard therapy for brain malignant astrocytomas, might be valid as a basic therapeutic strategy for this PDLG subtype.

Non-tau based neuronal degeneration in Alzheimer's disease -- an immunocytochemical and quantitative study in the supragranular layers of the middle temporal neocortex.

In Alzheimer's disease (AD), cortical neurons develop neurofibrillary tangles (NFTs) consisting of hyperphosphorylated tau. The neurons eventually die. There are some hints that cortical neurons may also degenerate without the development of cytoskeletal changes. We investigated this possibility by comparing changes in APP staining and neuronal size with respect to the presence or absence of hyperphosphorylated tau. Adjacent sections of the medial temporal neocortex (Brodmann's area 22) of 5 male AD patients aged 60-88 years (Braak V-VI) and 5 age-matched male non-demented control subjects were i) stained with a modified Bielschowsky silver method in order to reveal NFTs and 'ghost' tangles, ii) single-stained with anti-APP, and iii) double-labeled with anti-APP and AT8. Anti-APP is directed against the beta-amyloid precursor protein and stains virtually all perikarya and proximal neurites of the cortical neurons. AT8 stains pre-tangles, NFTs and extracellular 'ghost' tangles due to the recognition of hyperphosphorylated tau. The study was focused on the supragranular cortical layers II-III, since these layers can be clearly delineated from the adjacent molecular and granular cell layers. The results showed that i) APP staining intensity in neurons was variable in the AD cortex, being clearly different from the invariably intense neuronal staining in all controls. Reduced cytoplasmic APP staining was observed, particular in small neurons, while lack of anti-APP staining in proximal neurites, too, was associated with AD. In addition, ii) cross-sectional area measurement on anti-APP-stained neurons revealed that in AD, as compared to controls, a clear decrease in the number of mainly large-sized neurons (>150 microm2) was accompanied by a significant increase in the percentage of neurons in the smaller size classes, indicating that many large-sized neurons became smaller in AD. iii) Reduced APP staining and decreased neuronal size were not necessarily associated with the presence or absence of hyperphosphorylated tau in these cells. iv) Twenty-six percent of the neurons contained hyperphosphorylated tau, while the level of NFT-related neuronal loss was low in AD. The present study suggests that non-tau based neuronal degeneration is a major phenomenon in the AD neocortex.

Fibromuscular dysplasia of the basilar artery: an unusual case with medico-legal implications.

A 28-year-old male car driver was reported to suddenly loose the control over his vehicle, to hit the right and middle crash barrier, and to be unconscious as the car came to a halt in a position at right angles to the road. The car was hit in its left side by an automobile with high velocity, and the 28-year-old driver died. Examination of the brain revealed a massive isolated basal subarachnoid hemorrhage and a complete tearing of the basilar artery. A macroscopically detectable aneurysm was not found. However, histological examination of the large arteries at the base of the brain showed (i) fibromuscular dysplasia (FMD) mostly involving the basilar artery (ii) with a ruptured micro-aneurysm in its upper third part. The observations of the eye witnesses that the driver initially lost control over his car were judged in favour of the accused to be due to that rupture of the micro-aneurysm, while complete transverse tearing of the basilar artery occurred during the car crash due to hyperextension and rotation of his neck. Intracranial FMD is a rare cause in the differential diagnosis of isolated basal subarachnoid hemorrhage. The medico-legal implications of this entity are described in the presented case.

Multifocal epithelioid hemangioendothelioma: case report of a clinical chamaeleon.

Epithelioid hemangioendothelioma is an extremely rare vascular bone tumor with a slow growth and poor prognosis. The term was designed to describe neoplasms that had an appearance in between hemangiomas and sarcomas. Various synonyms for epithelioid hemangioendothelioma are used clinically: low grade anaplastic angiosarcoma, cellular hemangioma, histiocytoid hemangioma and angioendothelioma. However, it represents 1% of all vascular neoplasms and is locally aggressive. We report the course of disease of a 47-year-old man who presented to our clinic with unspecific abdominal and back pain. Radiological findings revealed multiple lesions in the spine as well as liver and spleen involvement. Tumor histology of the bone and liver biopsies confirmed the diagnosis of epithelioid hemangioendothelioma. Although treatment was initiated with thalidomide, the patient developed multiple organ dysfunction syndrome (MODS) and succumbed to his disease. This case report may contribute to the data on clinical findings and natural history of this rare tumor.

Immunohistochemical profile and chromosomal imbalances in papillary tumours of the pineal region.

The histopathology of papillary tumours of the pineal region (PTPR) closely resembles that of ependymomas and choroid plexus tumours. Therefore, immunohistochemical staining profiles were investigated in a series of 15 PTPR. In addition to cytokeratin, synaptophysin and glial fibrillary acidic protein expression, PTPR were examined for the presence of dot- or ring-like epithelial membrane antigen (EMA) immunoreactivity typically encountered in ependymoma, staining for inwardly rectifying potassium channel Kir7.1 and stanniocalcin-1 (specifically expressed in choroid plexus tumours) as well as microtubule-associated protein-2 (MAP-2). Furthermore, comparative genomic hybridization was performed in five PTPR. Cytokeratin was expressed in all PTPR examined, whereas glial fibrillary acidic protein and synaptophysin staining were absent. Dot- or ring-like EMA immunoreactivity was only observed in 1 out of 15 PTPR. Membranous Kir7.1 and cytoplasmic stanniocalcin-1 staining were present in the minority of PTPR (3/15 and 4/15, respectively). In contrast, MAP-2 immunoreactivity was encountered in 13 out of 15 PTPR, but was significantly less frequently observed in a series of choroid plexus tumours (7/37). PTPR mainly presented with chromosomal losses affecting chromosomes 10 (4/5 cases) and 22q (3/5 cases) as well as gains on chromosomes 4 (4/5 cases), 8 (3/5 cases), 9 (3/5 cases) and 12 (3/5 cases). To conclude, the majority of PTPR can be distinguished from ependymomas and choroid plexus tumours by absent staining for epithelial membrane antigen, Kir7.1 and staniocalcin-1 as well as the presence of distinct MAP-2 immunoreactivity. Antibodies directed against these antigens are thus expected to be valuable markers in the diagnosis of papillary tumours located in the vicinity of the third ventricle.

Cerebral metastasis from an undifferentiated sarcoma of the left atrium.

A rare case of a cerebral metastasis 13 months after open heart surgery because of an undifferentiated sarcoma of the left atrium is presented.

Beta-protein/A4 deposits are not associated with hyperphosphorylated tau in somatostatin neurons in the hypothalamus of Alzheimer's disease patients.

With respect to the pathogenesis of Alzheimer's disease (AD), it has been hypothesized that amorphous plaques containing beta-protein/A4 (Abeta) would locally induce cytoskeletal changes, and that neurons affected by neurofibrillary tangles (NFTs) lose their neuropeptide concentration and eventually die. To test this presumed cascade of events, the hypothalami of 14 non-demented subjects (Braak 0-III) and 28 AD patients (Braak IV-VI) aged 40-98 years were selected. The subject of our study was the nucleus tuberalis lateralis (NTL), which harbors a subpopulation of somatostatinergic neurons with extensive intrinsic interconnectivity. We used Gallyas silver staining, Congo staining, single- and double-staining with monoclonal antibody AT8 and polyclonal antibody anti-Abeta, and double-immunolabeling with AT8 and anti-somatostatin(1-12) with the following results: (1) Significant amounts of silver-staining NFTs were present in only three AD patients. (2) High densities of AT8-stained cytoskeletal changes were mainly found in aged, demented patients. (3) In contrast, large amounts of Abeta deposits were mainly observed in young and middle-aged (40-59 years) AD patients, and were very low or absent mainly in the older non-demented subjects and in AD patients. (4) Reduced anti-somatostatin staining was observed in the NTL of most AD patients, but anti-somatostatin/AT8 double-stained neurons were found virtually exclusively in aged AD patients. Thus, the occurrence of Abeta deposits and hyperphosphorylated tau formation in somatostatin cells are basically independent events, while decreased somatostatin staining only partly goes together with cytoskeletal changes in somatostatin cells in the NTL of AD patients. These observations cannot be explained by the amyloid cascade hypothesis.

Surgical treatment of intramedullary spinal cord metastases of systemic cancer: functional outcome and prognosis.

OBJECTIVE: Intramedullary spinal cord metastases (ISCM) of systemic cancer are rare. To date, patients with ISCM tend to benefit only to a limited extend from surgery and adjuvant therapy. Subject of this investigation is to assess predictive factors for surgical outcome and survival and to evaluate the value of surgical radicality in the treatment of ISCM. PATIENTS AND METHODS: Between 1990 and 2004, a series of 146 patients with intramedullary tumors underwent surgical treatment in our institution. Among these, 13 patients with intramedullary cancer metastases (7 adenocarcinomas, 3 poorly differentiated carcinomas, 3 sarcomas) were identified. Standard microsurgical removal of the ISCM was performed. Functional outcome was graded according to a standardized scale and factors influencing outcome and survival were statistically analyzed. RESULTS: Median progression-free survival was 13 weeks and median overall survival was 31 weeks. In 5 patients (38) the intramedullary lesion was the initial manifestation of the malignant disease. All poorly differentiated carcinomas and all sarcomas were resected incompletely. Surgical radicality presented a negative predictive factor for functional outcome, increasing radicality leading to functional deterioration. Age, sex, tumor localization, surgical radicality and the presence of neoplastic meningeosis did not affect survival. CONCLUSION: Surgery of ISCM can be performed with an acceptable operative morbidity. Radicality depended on tumor histology. However, radical tumor removal did not affect survival and was correlated with a poor functional outcome. Therefore, complete surgical removal of ISCM should only be intended in patients in whom an unproblematic excision is feasible.

Mini-infarct encephalopathy associated with uncommon microvessel convolute formation presenting with presenile dementia.

A female patient started to suffer from transient ischemic attacks when she was 47 years of age, followed by increasing predominantly left-side spastic tetraparesis, generalized seizures and progressive dementia over a period of 11 years. She died when she was 58 years of age. On gross examination the brain showed enlarged ventricles and arteriosclerotic changes of large extracerebral vessels of the circulus arteriosus. Microscopic examination of the atrophic brain showed innumerable incomplete microinfarcts in the white and gray matter throughout all parts of the brain. In the white matter these lesions were characterized by small foci of demyelination and loss of oligodendrocytes while occasionally some scavenger cells were seen. Axons seemed to be unaffected or displayed irregular axonal regeneratory growth. Any inflammatory reaction failed. In the cerebral cortex and subcortical nuclei the lesions showed loss of neurons and decrease in synaptophysin expression. Intracerebral arteries showed fibrosis or fibrohyalinosis of the entire intracerebral small-vessel network. In addition, numerous uncommon clusters of angioma-like telangiectatic vessels were observed. Medium-sized ischemic infarcts were found in the right putamen and adjacent internal capsule region, left-side dorsolateral brain stem and cerebellar hemisphere as well as a left-side pyramidal tract degeneration. Contralateral pseudohypertrophy of the inferior olivary nucleus was seen. The clinical and the neuropathologic observations made in this patient are compatible with small vessel disease characterized by a multicentric special and not yet described type of incomplete mini-infarcts in cerebral cortex and white matter accompanied by some larger ischemic infarcts of the common type in brain stem and cerebellum.

Interstitial cells subjacent to the entorhinal region expressing somatostatin-28 immunoreactivity are susceptible to development of Alzheimer's disease-related cytoskeletal changes.

Interstitial cells are isolated neurons located in the infracortical white matter that are known to express neuropeptides. Twenty-four cases selected for the absence, slight (Braak stages I-II), moderate (Braak stages III-IV), or serious degree (Braak stages V-VI) of cortical neurofibrillary pathology were studied for the presence of Alzheimer's disease-related abnormal tau in interstitial cells of the entorhinal region. AT8-immunoreactive white matter neurons were observed in all Braak stages of cortical neurofibrillary pathology. Both normal-appearing neurons and neurons with degenerative changes in the cellular processes were observed. Normal-appearing cells were predominantly found in stages I and II, whereas degenerative interstitial cells numerically increased from stage I onwards. The normal-appearing cells were medium-sized (10-25 micro m), with ovoid, fusiform, triangular or multipolar cell bodies, and showed an extensive dendritic field, which was oriented perpendicular to the direction of the perforant pathway. Since the morphology of the AT8-immunopositive normal-appearing cells was similar to that reported on somatostatinergic interstitial cells subjacent to the entorhinal region, double-labeling with AT8 and anti-somatostatin-28 (S309) was performed. All AT8-immunoreactive normal-appearing interstitial cells revealed co-staining with somatostatin-28 antiserum, whereas some of the AT8-immunopositive cells with degenerative processes reacted positively and others negatively with S309. In summary, a distinctive interstitial cell type characterized by extensive arborization oriented perpendicular to the course of the perforant pathway and showing somatostatin expression is susceptible to developing the Alzheimer's disease-related cytoskeletal changes. Progression in cytoskeleton change is accompanied by loss of somatostatin.

A solitary manifestation of mastocytosis in the head and neck.

Solitary mastocytosis in adulthood is a rare finding. Only two such lesions have been reported in the head and neck. We describe a 27-year-old woman who had a 10-year history of a forehead swelling that had fluctuated in size. Light trauma or pressure on the lesion resulted in an increase in its size. A mass was found to be situated just below the galea and was successfully removed surgically using a high forehead lift. Histologically, the specimen contained predominantly mast cells. A systemic mastocytosis was excluded by a multidisciplinary diagnostic approach and measurement of the 24-h urinary excretion of histamine metabolites. After 36 months of follow-up there has been no recurrence.

Comparison of beta-protein/A4 deposits and Alz-50-stained cytoskeletal changes in the hypothalamus and adjoining areas of Alzheimer's disease patients: amorphic plaques and cytoskeletal changes occur independently.

Alzheimer's disease is characterized neuropathologically by senile plaques and cytoskeletal changes. It has been proposed that amorphic plaques would locally induce anterograde propagation of cytoskeletal changes in consecutive neurons followed by amorphic plaque deposition at their axonal terminals. The Alzheimer changes would spread in this way along neural pathways. To test the 'primary amyloid anatomical cascade hypothesis', Congo red staining, beta-protein/A4 (Abeta) antiserum and Alz-50, which recognizes cytoskeletal changes, were applied to the hypothalamus and adjoining brain areas of five Alzheimer's disease patients of 40-90 years of age and five age- and sex-matched controls. The results showed that (1) virtually all Abeta plaques in the hypothalamus were of the Congo red-negative amorphic type; (2) amorphic plaques and Alz-50-stained cytokeletal changes were observed not only in all Alzheimer's disease patients but also in a non-demented, 90-year-old control subject; (3) the density of amorphic plaques in the hypothalamus was unrelated to the duration of the dementia; (4) the density of amorphic plaques was unrelated to that of Alz-50-stained cytoskeletal changes; (5) double-labeling with anti-Abeta and Alz-50 did not show an evident topical relationship between amorphic plaque deposition and the occurrence of cytoskeletal changes; and (6) the distribution of Abeta and Alz-50 staining in five brain areas, for which essential anatomical information is available, did not support the primary amyloid anatomical cascade hypothesis. Amorphic plaques and cytoskeletal changes rather occur independently.

Somatostatin 1-12 immunoreactivity is decreased in the hypothalamic lateral tuberal nucleus of Huntington's disease patients.

The hypothalamic lateral tuberal nucleus (NTL) can be recognized in man and higher primates, only. The function of this nucleus is unknown, but the NTL is affected in a variety of human neurodegenerative diseases, including Huntington's disease (HD) and Alzheimer's disease. In the present study we demonstrate an abundant presence of somatostatin 1-12 (SST1-12) immunoreactivity in both neurites and perikarya of the NTL. This immunoreactivity could be visualized best after microwave pretreatment. In HD brains, NTL SST1-12 immunoreactivity was greatly reduced, providing further evidence of the presence of SST1-12 as an intrinsic neuropeptide in the NTL. Although striatal SST neurons escape destruction in HD, our study demonstrates that not all SST neurons are resistant to the degenerative process in this disease.

Early cytoskeletal changes as shown by Alz-50 are not accompanied by decreased neuronal activity.

The nucleus tuberalis lateralis (NTL) is located in the basolateral part of the hypothalamus and is only present as a well-delineated nucleus in human and higher primates. In Alzheimer's disease (AD), NTL neurons show strong early cytoskeletal alterations, as revealed by the antibody Alz-50, but practically no senile plaques or neurofibrillary tangles. To study whether the activity of NTL neurons decreases when cytoskeletal changes appear, i.e., during aging and in AD, we applied a polyclonal antibody raised against the medial cisternae of the Golgi apparatus (GA). The size of the GA and the cell profile of NTL neurons, two established parameters for neuronal activity, were measured by an image analysis system. No significant change in the size of the profiles of the GA or of the neurons was observed in this nucleus during aging or AD. Earlier studies have shown that there is no decrease in cell number in the NTL in AD. We conclude that in the NTL an early hallmark of AD, i.e., cytoskeletal changes as stained by Alz-50, does not correlate with decreased neuronal activity, as reflected by the size of the GA, nor with a decrease in cell number. In addition, we found that the very early occurring and abundant presence of lipofuscin in NTL neurons does not go together with decreased neuronal activity.

The monoclonal antibody Alz-50, used to reveal cytoskeletal changes in Alzheimer's disease, also reacts with a large subpopulation of somatostatin neurons in the normal human hypothalamus and adjoining areas.

The monoclonal antibody Alz-50 is directed against Alzheimer's disease-related modified tau proteins and reveals cytoskeletal changes, i.e. neurofibrillary tangles and dystrophic neurites. The present study shows that, in the hypothalamus of non-demented control subjects, this same antibody gives a distinctive staining pattern of a subpopulation of somatostatin neurons and beaded fibres. Furthermore, Alz-50 occasionally recognizes somatostatin-containing cell bodies and dystrophic neurite-like fibers in the (neuritic) senile plaques of AD patients. These observations have direct consequences for the interpretation of Alz-50 staining in diagnostic usage and for the assessment of Alzheimer's disease-like changes induced by beta-amyloid in experimental animal brains. On dot spotting, Alz-50 was found to bind to a number of fragments from the somatostatin precursor, of which somatostatin 15-28 stained best. Preadsorption of Alz-50 by somatostatin 15-28, as well as other specificity tests, failed, however, to provide any clue to the nature of the unknown compound(s) stained in the control hypothalamus.

Functional neuroanatomy and neuropathology of the human hypothalamus.

The human hypothalamus is involved in a wide range of functions in the developing, adult and aging subject and is responsible for a large number of symptoms of neuroendocrine, neurological and psychiatric diseases. In the present review some prominent hypothalamic nuclei are discussed in relation to normal development, sexual differentiation, aging and a number of neuropathological conditions. The suprachiasmatic nucleus, the clock of the brain, shows seasonal and circadian variations in its vasopressin neurons. During normal aging, but even more so in Alzheimer's disease, the number of these neurons decreases. In homosexual men this nucleus is larger than in heterosexual men. The difference between the sexually dimorphic nuclei of men and women arises between the ages of 2-4 to puberty. In adult men this nucleus is twice as large as in adult women. In the process of aging, a sex-dependent decrease in cell number occurs. The vasopressin and oxytocin cells of the supraoptic and paraventricular nucleus are present in adult numbers as early as mid-gestation. Lower oxytocin neuron numbers are found in Prader-Willi syndrome, AIDS and Parkinson's disease. Familial hypothalamic diabetes insipidus is based upon a point mutation in the vasopressin-neurophysin-glycopeptide gene. Parvicellular corticotropin-releasing hormone-containing neurons in the paraventricular nucleus increase in number and are activated during the course of aging. In post-menopausal women, the infundibular or arcuate nucleus contains hypertrophic neurons containing oestrogen receptors. These neurons may be involved in the initiation of menopausal flushes. The nucleus tuberalis lateralis may be involved in feeding behaviour and metabolism. In Huntington's disease the majority of its neurons is lost; in Alzheimer's disease it shows very strong cytoskeletal alterations. Tuberomammillary nucleus neurons contain, e.g., histamine or galanine, and project to the cortex. Strong cytoskeletal changes, as well as plaques and tangles are found in this nucleus in Alzheimer's disease. The various hypothalamic nuclei are probably involved in many functions and symptoms of which only a minority has been revealed.

The distribution of Alz-50 immunoreactivity in the hypothalamus and adjoining areas of Alzheimer's disease patients.

The monoclonal antibody Alz-50 is directed against modified forms of tau proteins. Various hypotheses have been put forward concerning the meaning of Alz-50 staining in Alzheimer's disease brains. Cytoskeletal alterations are reported to occur exclusively in the cortex and the subcortical nuclei directly connected with the cortex. In addition, Alz-50 staining is presumed to be indicative of impending neuronal death. In order to test these hypotheses Alz-50 was applied to the hypothalamus and adjoining areas of five Alzheimer's disease patients of 40-90 years of age and five sex- and age-matched, non-demented controls. The results showed the following: (i) Alz-50 immunoreactivity is not restricted to Alzheimer's disease patients. Alz-50 immunoreactive beaded nerve fibres and patchy, granular cell bodies were observed in some hypothalamic nuclei of all controls with the exception of the youngest one. Dystrophic neurites were not only observed in all Alzheimer's disease hypothalami but also in that of the oldest control. (ii) In the hypothalamic area various nuclei had different Alz-50 staining patterns. Alz-50 staining could not, however, be related to neuronal death in the different nuclei. (iii) Histopathological changes in Alzheimer's disease patients are not restricted to the cortex or subcortical areas connected directly with the cortex. The present report indicates that the hypothalamus is considerably more affected in Alzheimer's disease than has often been assumed. However, these changes can also be found in non-demented old people.

Tau and ubiquitin in the human hypothalamus in aging and Alzheimer's disease.

Immunocytochemical staining of hypothalamic cell groups with four antibodies to Alzheimer paired helical filaments (PHF) (i.e., anti-PHF serum 60e and monoclonal antibody (mAb) Alz-50, both directed against normal and abnormally phosphorylated tau; mAb tau-1, which recognizes tau; and mAb 3-39 to PHF, which recognizes the carboxy terminal domain of ubiquitin) revealed a clear distinction between 12 Alzheimer's disease (AD) patients and seven controls in the hypothalamus. Dystrophic neurites, which appeared to be the most specific components in AD, were most conspicuous after Alz-50 staining. However, Alz-50 also stained neuronal cytoplasm and normal, thin, beaded neurites in the paraventricular nucleus (PVN) of controls, even of young cases. This staining was clearly distinct from the staining of cytoplasm and dystrophic neurites in the PVN of Alzheimer patients. The abundant staining of dystrophic neurites and cell bodies in the nucleus tuberalis lateralis (NTL) in AD, in which no neuronal loss is observed, suggests that alterations in cytoskeletal markers do not necessarily indicate impending cell death. Moreover, the cytoskeletal changes in the NTL, sexually dimorphic and suprachiasmatic nuclei in AD indicate that this condition is not restricted to cortical areas or nuclei projecting to the cortex. Consequently, the pathophysiological implications of cytoskeletal staining in AD are at present far from clear. The human hypothalamus may not only provide a better insight into the pathogenesis of Alzheimer's disease, but could also be of help in the neuropathological diagnosis of this condition.