Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH3 causing CADASIL.

Several hereditary small vessel diseases (SVDs) of the brain have been reported in recent years. In 1977, Sourander and Wålinder described hereditary multi-infarct dementia (MID) in a Swedish family. In the same year, Stevens and colleagues reported chronic familial vascular encephalopathy in an English family bearing a similar phenotype. These disorders have invariably been suggested to be cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) but their genetic identities remain unknown. We used molecular, radiological and neuropathological methods to characterize these disorders. Direct DNA sequencing unexpectedly confirmed that affected members of the English family carried the R141C mutation in the NOTCH3 gene diagnostic of CADASIL. However, we did not detect any pathogenic mutations in the entire 8091 bp reading frame of NOTCH3 or find clear evidence for NOTCH3 gene linkage in the Swedish DNA. This was consistent with the lack of hyperintense signals in the anterior temporal pole and external capsule in Swedish subjects upon magnetic resonance imaging. We further found no evidence for granular osmiophilic material in skin biopsy or post-mortem brain samples of affected members in the Swedish family. In addition, there was distinct lack of NOTCH3 N-terminal fragments in the cerebral microvasculature of the Swedish hereditary MID subjects compared to the intense accumulation in the English family afflicted with CADASIL. Several differences in arteriosclerotic changes in both the grey and white matter were also noted between the disorders. The sclerotic index values, density of collagen IV immunoreactivity in the microvasculature and number of perivascular macrophages were greater in the English CADASIL samples compared to those from the Swedish brains. Multiple approaches suggest that the Swedish family with hereditary MID suspected to be CADASIL has a different novel disorder with dissimilar pathological features and belongs to the growing number of genetically uncharacterized familial SVDs.

Cryptic cerebellopontine angle neuroglial cyst presenting with hemifacial spasm.

Hemifacial spasm (HFS) is commonly caused by a vascular loop compressing the Root Exit Zone (REZ) of the facial nerve. We report a case of HFS caused by a vascular loop that was abnormally displaced by a neuroglial cyst not seen in Magnetic Resonance Imaging (MRI). Microvascular decompression (MVD) was planned and the patient underwent a key-hole retromastoid posterior fossa exposure. A cystic lesion was found in the cerebellopontine angle (CPA), located around the seventh and eighth cranial nerves extending from the porous acousticus to the brainstem REZ of the facial nerve. The cyst wall was partially excised revealing the region of the neurovascular conflict. MVD of the facial nerve was performed with immediate postoperative complete resolution of the patient's symptoms.

Treatment of CNS malignant rhabdoid tumors.

BACKGROUND: Central Nervous System (CNS) rhabdoid tumours are a highly malignant group of neoplasms usually occurring in children under 2 years of age with characteristic histopathologic findings but unclear histiogenesis and almost uniformly fatal outcome. There is still no proven curative therapy available. PROCEDURE: The clinical course and the successful outcome of therapy in two children with primary CNS rhabdoid tumour are described in this context. Both children had subtotal excision of the primary tumour and received chemotherapy based on the SIOP Malignant Mesenchymal Tumour (MMT-95) protocol with addition of triple intrathecal chemotherapy. Following this, one of the patients received high dose therapy (busulphan and thiotepa), whereas the other had craniospinal radiotherapy with a boost to the primary site. RESULTS: The treatment was reasonably well tolerated and both patients are alive with no evidence of disease 52 months and 65 months after the primary diagnosis. Their favourable outcomes are compared with those of 49 others reported in the literature. CONCLUSIONS: Intensified therapy (with autologous bone marrow transplantation and intrathecal chemotherapy) may improve the prognosis of patients with malignant rhabdoid tumour.

A medical research council randomized trial in patients with primary cerebral non-Hodgkin lymphoma: cerebral radiotherapy with and without cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy.

BACKGROUND: The role of chemotherapy in the treatment of patients with primary central nervous system lymphoma (PCL) remains unclear, with no randomized trials available to aid in the interpretation of the current data. The Medical Research Council therefore conducted the current randomized trial to assess the impact on survival of postradiotherapy chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in nonimmunocompromised adult patients with pathologically proven PCL. METHODS: After surgery, patients were randomized at a ratio of 1:2 to radiotherapy alone (RT: 40 grays [Gy] in 20 fractions to the whole brain followed by a 14-Gy boost to the tumor plus a 2-cm tumor margin) or to the same radiotherapy followed by six cycles of CHOP chemotherapy given at 3-week intervals (RT-CHOP). The target sample size was 90 patients, which allowed 90% power to detect a doubling of the median survival time. RESULTS: Between 1988 and 1995, 53 patients were randomized: Fifteen patients were randomized to RT, and 38 patients were randomized to RT-CHOP. The trial closed earlier than planned through poor accrual. The median patient age was 57 years, 57% of the patients were male, and 75% of the patients had unifocal disease. The median number of chemotherapy cycles received was 6 (mean, 4 cycles). Forty-three patients have died, and the median follow-up of survivors is 5 years (range, 1-9 years). There was no evidence of a benefit from RT-CHOP with respect to overall survival (hazard ratio [HR], 1.19; 95% confidence interval, 0.51-2.76) after adjustment for prognostic factors (patient age and neurologic performance status) in an analysis in which HR > 1 favored the control (RT) group. CONCLUSIONS: CHOP has no clear role in the postradiotherapy treatment of patients with PCL. Chemotherapy is poorly tolerated and largely palliative in older, less fit patients. In younger patients, initial chemotherapy designed to penetrate the blood-brain barrier warrants further investigation.

Quantitative electroencephalographic evaluation of non-fatal and fatal traumatic coma.

Diffuse axonal injury (DAI) is an important cause of morbidity and mortality after traumatic brain injury (TBI), and its severity is therefore a major determinant of outcome. There have been suggestions that the extent of DAI may be reflected in quantitative measures of cerebral function, including the electroencephalogram (EEG) and brain-stem auditory evoked potentials (BAEPs). It has therefore been proposed that these quantitative methods of analysis may provide objective predictors of outcome following TBI. We prospectively investigated the relationship between quantitative EEG and BAEP measures and outcome, in 60 comatose patients (47 male and 13 female; age range 1-80 years, mean 36.4) after severe, closed head injury (post-resuscitation Glasgow Coma Scale (GCS) of 8). The Spearman correlation coefficients (rs) have been calculated for quantitative EEG measures (mean regional power and interhemispheric coherence) and BAEPs with patient outcome on the Glasgow Outcome and Disability Rating Scales at 6 months and 1 year. The measures most significantly correlated with outcome (P < 0.001) are over the left hemisphere, beta activity power (amplitude squared) in the fronto-central and centro-temporal regions, and alpha activity power in the centro-temporal region. We found no correlation between interhemispheric coherence (a statistical measure of cross-correlation in the frequency domain) and outcome at either 6 months or 1 year post-injury. In 10 fatalities, we examined the relationship between interhemispheric EEG coherence prior to deaths and the histopathological severity of DAI, in concordant regions. The only significant correlation between DAI and interhemispheric coherence is seen in the alpha band at the temporo-occipital site (rs = -0.79, P = 0.007). Our data indicate that there is regional information in EEG power spectra over the left hemisphere, which could be used in prognostic predictions for patients in coma after severe TBI. We were unable to demonstrate a correlation between interhemispheric coherence and outcome, or any clear and consistent evidence of a relationship between interhemispheric coherence and the severity of DAI.

Progressive myoclonus epilepsy with focal brainstem degeneration and paternal inheritance. An autopsy report of 4 cases from 2 pedigrees.

Four autopsied cases of myoclonus, ataxia, and epilepsy from 2 separate pedigrees are described. An identical pattern of focal brainstem lesions was found in all the cases with selective and symmetrical degeneration of the dentate and second order somatosensory nuclei. The combined clinical and pathological features did not appear to match any familial disorder previously described as causing progressive myoclonus epilepsy. Myoclonus epilepsy with ragged red fibres was excluded on the grounds of paternal inheritance and negative muscle biopsy findings, but the more acute lesions seen in 1 case are reminiscent of those found in Leigh's syndrome, and suggest that some other form of inherited defect of oxidative metabolism may be involved.

Tophaceous gout of the spine causing spinal cord compression.

Tophaceous gout of the spine rarely causes spinal cord compression. Only eight cases have been reported previously. We report a further case presenting with progressive quadriparesis caused by gouty tophi at C1, treated successfully by decompressive laminectomy and internal fixation. This case and the previously reported cases are reviewed.

Clinical and autopsy findings in two cases of MELAS presenting with stroke-like episodes but without clinical myopathy.

We report the clinical and autopsy findings of two patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). The cases were unusual in that both patients presented with stroke-like episodes and neither patient had clinically evident myopathy, consequently in neither case was the correct diagnosis made during life. Despite the absence of myopathy clinically, at autopsy skeletal muscle showed the characteristic features of mitochondrial cytopathy. One of the patients, in addition to the features of MELAS, also had gastrointestinal involvement at presentation which was sufficiently severe to warrant surgery and a peripheral neuropathy.

Characterization of the mononuclear cell infiltrate and HLA-Dr expression in 19 oligodendrogliomas.

We have studied frozen tissue from 19 oligodendrogliomas with a panel of antibodies to lymphocytes and their subsets, macrophages, natural killer cells, and HLA-Dr antigens. Macrophages were detected in moderate numbers in 60%-100% of tumors depending on the antibody used. T lymphocytes were fewer in number than macrophages and were present in 62% of cases. Most of the T lymphocytes were of the CD8 phenotype. CD4 lymphocytes were very few in number and present in only 18%. B cells and natural killer cells were absent from all cases. HLA-Dr antigens were expressed by macrophages in all cases but never on tumor cells. The implications of these findings are that macrophages and, to a lesser extent, CD8 lymphocytes are the predominant cells infiltrating oligodendrogliomas and that they may exert cellular immune functions.

Gadolinium-labeled liposomes containing various amphiphilic Gd-DTPA derivatives: targeted MRI contrast enhancement agents for the liver.

Unique paramagnetic liposomal contrast agents were synthesized and utilized for selective augmentation of T1 MR imaging of the livers of normal Balb/c mice. A series of amphipathic gadolinium complexes, which mimic phospholipids, was incorporated into the lamella of small unilamellar liposomes such that they become an integral part of its surface. The amphipathic complexing agents consisted of DTPA reagents in which two stearyl chains are attached via amide, ester, and thioester linkages. The in vitro stability and the in vivo lifetimes of the new amphipathic agents were dependent on the method used to attach the long-chain alkyl groups.

Differentiation in embryonal neuroepithelial tumors of the central nervous system.

Ninety-six embryonal neuroectodermal tumors were studied histologically and immunohistologically with a panel of antibodies including glial, neuronal, epithelial, mesodermal, and myelin markers. In 71 tumors there was glial and neuronal differentiation and expression both of an S (photoreceptor) antigen and vimentin. In five tumors there was only glial differentiation and in 20 tumors only neuronal differentiation. No reactivity for myelin and epithelial markers was found. Histologic and immunohistologic findings identified various degrees of differentiation in different tumors, which was bipolar (glial and neuronal) in most tumors and unipolar in the remainder. The authors suggest that their findings may be the result of normal or aberrant oncogenic differentiation, agreeing with the nomenclature of the World Health Organization classification for these tumors with and the inclusion of a category for ependymoblastoma.

Distribution of beta-nerve growth factor receptors in the human basal forebrain.

The distribution of neurons expressing the receptor for beta-nerve growth factor has been examined immunohistochemically in serial coronal sections of basal forebrain from aged normal human subjects. Neurons expressing the receptor were observed in the nucleus of the diagonal band of Broca and in the anterior, the intermediate, and the posterior portions of the nucleus basalis of Meynert. Neurons could also be seen in the medial septal nucleus and embedded in myelinated fibre tracts such as those of the external capsule, cingulum, medullary laminae of the globus pallidus, ansa penduncularis, ansa lenticularis, and anterior commissure. In situ hybridization with a 35S cDNA probe to the human beta-nerve growth factor receptor confirms a neuronal location as the site of synthesis of beta-nerve growth factor receptors in the nucleus basalis of Meynert in a fifth brain. A high percentage of Nissl-stained hyperchromic magnocellular neurons expressed the receptor for beta-nerve growth factor, suggesting that most neurons in the human cholinergic magnocellular basal forebrain system express these receptors. Recent data suggest that beta-nerve growth factor functions as a neurotrophic factor in basal forebrain cholinergic neurons. In Alzheimer's disease there is known to be a reduction in cholinergic function and an apparent loss of neurons in the cholinergic nucleus basalis of Meynert. For this reason we have examined the distribution of receptors for beta-nerve growth factor in the normal human basal forebrain in order to form a basis for comparison to those with Alzheimer's disease.

The mononuclear cell infiltrate compared with survival in high-grade astrocytomas.

Frozen samples from 92 malignant astrocytomas were stained with a panel of monoclonal antibodies directed against macrophages and lymphocytes. A follow-up to death was available on 68 cases which form the basis of this study. Large numbers of macrophages were found in all cases; T lymphocytes, mostly of the CD8 phenotype were also seen in moderate numbers in 70% of cases. CD4-positive cells were present in small numbers in 32% and B cells were seen in only 8% of cases. Analysis of the survival showed no demonstrable correlation between the numbers of macrophages or CD4 lymphocytes and survival. The survival curves for parenchymal CD8 infiltration diverged after 9 months suggesting increased survival for those patients without such an infiltration but the difference failed to reach statistical significance (P = 0.37). No correlation between lymphocytic cuffing and survival was seen after studying all paraffin-embedded material. We conclude that there is no significant statistical correlation between survival and the various types of mononuclear cell infiltrating malignant astrocytomas.

Mononuclear cell infiltrate and HLA-DR expression in low grade astrocytomas. An immunohistological study of 23 cases.

Frozen samples from 23 low grade (grade I and II) astrocytomas were studied by means of a panel of monoclonal antibodies to macrophages, lymphocytes (and their subsets) and HLA-DR antigens. Macrophages were present in low to moderate numbers in 38%-86% of cases, the variance in figures depending on the antibody used. T lymphocytes, the majority of CD8 phenotype, were detected in low numbers in 78% of tumours. B lymphocytes were scanty in 22% (5/22) and totally absent in the remaining cases. HLA-DR antigen was expressed by tumour cells in 35% (6/17) of cases. These findings indicate that in some low grade astrocytomas there is a mononuclear cell infiltrate with macrophages and secondarily CD8+ lymphocytes playing the major role. The significance of these findings remains speculative at present.

Immunohistochemical characteristics of haemangiopericytic meningiomas: comparison with typical meningiomas, haemangioblastomas and haemangiopericytomas from extracranial sites.

The relationship between malignant vascular meningeal tumours and typical meningiomas remains controversial, despite the need for accurate diagnostic distinction between the two, and some forms of vascular meningioma may be more closely allied to haemangioblastomas or extracranial haemangiopericytomas than to true meningiomas. In order to try to clarify the diagnostic characteristics and origins of the entity known as haemangiopericytic meningioma, 10 histologically typical cases were stained by the immunoperoxidase technique with a panel of seven antibodies. The results were compared with those obtained from typical and angiomatous meningiomas, haemangioblastomas and haemangiopericytomas from extracranial sites. Both the haemangiopericytic meningiomas and the extracranial haemangiopericytomas showed a similar staining pattern, which differed from that of the typical and angiomatous meningiomas in the strikingly focal nature of the vimentin staining and the lack of reactivity with antibodies to epithelial elements. The haemangioblastomas were less consistent in their individual staining characteristics, but had a quite different overall pattern from all the other tumour types. It is, therefore, suggested that so-called haemangiopericytic meningiomas are in fact primary haemangiopericytomas of the meninges, antigenically distinct from true meningiomas and displaying a malignant potential appropriate to haemangiopericytomas arising in any other sites.

Atypical motor neuron disease with features of a multisystem degeneration: a non-familial case with prominent sensory involvement.

A 66-year-old male with no family history of neurological disease developed symmetrical paraesthesia, numbness and flaccid weakness of the hands and feet. Both the weakness and sensory loss became progressively more severe, and spread to involve the forearms and lower legs. Limb muscle wasting and tongue fasciculation only became apparent late in the disease course, and death eventually occurred from respiratory failure eight years after the onset of symptoms. Postmortem examination revealed most of the typical histological features of motor neuron disease, but in addition there was degeneration of the spinocerebellar tracts and spinal cord posterior columns, with degeneration and loss of their associated neuronal perikarya in Clarke's nuclei and dorsal root ganglia. The clinical and pathological features of this case suggest that it is a non-familial but atypical form of motor neuron disease, and support the concept that this disease represents part of a spectrum of neuronal degenerative processes rather than a circumscribed disorder limited to motor neurons.