[Fatal cardiomyopathy in adult in polyglucosan body disease]. / Letale Kardiomyopathie bei adulter Polyglukosankörperkrankheit.

Adult polyglucosan body disease (APBD) is a rare genetic disorder, inherited in an autosomal recessive mode. The disease is caused by mutations of the gene coding for the glycogen-branching enzyme, which is essential for branching of polyglucose chains in the normal glycogen molecule. The age of clinical manifestation of the disease mostly is between 40 and 60 years and its course is slowly progressive. Characteristic globular deposits (polyglucosan bodies, PGB) can be detected in biopsies of skin and skeletal muscle as well as in the peripheral and central nervous system. Biochemically, PGBs consist of poorly branched glycogen molecules with abnormally long polysaccharide chains. We report the case of a 50-year-old female patient with APBD who suffered from neurological symptoms such as spastic tetraparesis, urinary incontinence, hypesthesia and dementia. She died unexpectedly of cardiac failure. At autopsy a severe cardiomyopathy with abundant PGBs in the heart muscle fibres could be proven as the cause of death. This observation shows that in addition to the known deposition of PGBs in nervous system and skeletal muscle, an involvement of the heart has to be considered in APBD as well.

Connective tissue growth factor is expressed by a subset of reactive astrocytes in human cerebral infarction.

Connective tissue growth factor (CTGF), a transforming growth factor (TGF)-beta1 downstream mediator, is a secreted cell matrix-inducing peptide involved in both tissue regeneration mechanisms, such as wound repair, and also in aberrant deposition of extracellular matrix. The present study reports CTGF expression by cells associated with matrix deposition and glial scar formation in human cerebral infarction. CTGF was localized by immunohistochemistry in 17 brains of patients after focal infarction and in three neuropathologically normal control brains. CTGF expression was selectively localized to the cytoplasm of stellate reactive astrocytes. Compared to peripheral areas and brain controls without neuropathological findings, the total number CTGF+ astrocytes was significantly higher (P < 0.0001) in border zones adjacent to the core, corresponding to the penumbra. These numbers were significantly increased at day 1 and day 3 and remained persistently elevated up to several months post-infarction (P < 0.0001). The restricted expression and accumulation of CTGF+ reactive astrocytes adds convincing evidence for CTGF participation in the gliotic astrocyte CNS injury response involved in glial scar formation. CTGF can be considered a sensitive marker of early human astrocyte activation and a possible target for pharmacological intervention of aberrant matrix deposition.

"Allograft-inflammatory-factor-1 is upregulated in microglial cells in human cerebral infarctions".

Allograft inflammatory factor-1 (AIF-1) is a 17-kDa-peptide identified in rat cardiac allografts undergoing chronic rejection and in activated microglial cells in inflammatory autoimune disease of the CNS. We have investigated the expression of AIF-1 in 18 autopsy cases of human focal cerebral infarction. AIF-1-positive cells show the morphology of microglia and are CD68- but not GFAP-positive. The peptide is expressed at a low level in normal brain. In infarctions, activated microglial cells in the area of glial reaction show strongly enhanced cytoplasmic immunoreactivity. The density of AIF-1-expressing cells increases during the first three days post infarction and remains elevated until chronic cystic stages. The upregulation of AIF-1-immunoreactivity precedes the rise in expression of the S-100-protein MRP-8. We conclude that AIF-1 is a sensitive marker of human microglial activation not only in inflammation but also in non-inflammatory lesions of the CNS.

Selective accumulation of cyclooxygenase-1-expressing microglial cells/macrophages in lesions of human focal cerebral ischemia.

Cyclooxygenases (COX; prostaglandin endoperoxide H synthases) are key enzymes in the conversion of arachidonic acid into prostanoids which mediate inflammation, immunomodulation, mitogenesis, ovulation, fewer, apoptosis and blood flow. Here, we report COX-1 expression following focal cerebral infarctions (FCI). In healthy control brains, COX-1 was localized by immunohistochemistry to a few endothelial cells, single neurons and rare, evenly distributed brain microglia/macrophages. In infarctioned brains, COX-1+ cells accumulated highly significantly (P < 0.0001) in peri-infarctional areas and in the developing necrotic core early after infarction. Here, cell numbers remained persistently elevated up to several months post infarction. Further, clusters of COX-1+ cells were located in perivascular regions related to the Virchow-Robin space. Double-labeling experiments confirmed co-expression of COX-1 by CD68+ microglia/macrophages. Co-expression of the activation antigens HLA-DR, -DP, -DQ (MHC class II) or the macrophage inhibitor factor-related protein MRP-8 (S100A8) by most COX-1+ microglia/macrophages was only seen early after infarction. Thus, COX-1 appeared to be expressed in microglial cells regardless of their activation state. However, the prolonged accumulation of COX-1+ microglia/macrophages restricted to peri-infarctional areas enduring the acute post-ischemic inflammatory response points to a role of COX-1 in tissue remodeling or in the pathophysiology of secondary injury. We have identified localized, accumulated COX-1 expression as a potential pharmacological target following FCI. Therefore we suggest that therapeutic approaches based on selective COX-2 blocking might not be sufficient for suppressing the local synthesis of prostanoids.

Allograft-inflammatory-factor-1 is upregulated in microglial cells in human cerebral infarctions.

Allograft inflammatory factor-1 (AIF-1) is a 17-kDa-peptide identified in rat cardiac allografts undergoing chronic rejection and in activated microglial cells in inflammatory autoimune disease of the CNS. We have investigated the expression of AIF-1 in 18 autopsy cases of human focal cerebral infarction. AIF-1-positive cells show the morphology of microglia and are CD68- but not GFAP-positive. The peptide is expressed at a low level in normal brain. In infarctions, activated microglial cells in the area of glial reaction show strongly enhanced cytoplasmic immunoreactivity. The density of AIF-1-expressing cells increases during the first three days post infarction and remains elevated until chronic cystic stages. The upregulation of AIF-1-immunoreactivity precedes the rise in expression of the S-100-protein MRP-8. We conclude that AIF-1 is a sensitive marker of human microglial activation not only in inflammation but also in non-inflammatory lesions of the CNS.

[Morphology of neurological complications of intravascular lymphomatosis]. / Morphologie neurologischer Komplikationen bei der intravaskulären Lymphomatose.

Intravascular lymphomatosis (IVL) is a rare lymphoproliferative disease characterized by intravascular growth of lymphoma cells in small vessels. Most frequently, its first manifestations occur in the central nervous system or skin. Based on autoptical findings in a 68-year-old-man with IVL, the pathological morphology in the central nervous system is compared to the course of neurological symptoms. The disease could not be diagnosed during his lifetime. The spectrum of neurological deficits can be explained histopathologically by occlusive intravascular aggregations of lymphomatous cells in small vessels of the spinal leptomeninges and nerve roots causing perfusion deficits and areas of ischemic necrosis of up to 4 mm in diameter in the medulla. Aggregations of lymphoma cells in the vessels of other organs are also found, but did not result in clinical symptoms. In reference to the present case, a survey of other literature reports on IVL with neurological and psychiatric manifestations is given. In patients with this condition, even an invasive biopsy has to be considered in order to make the correct diagnosis at an early clinical stage.

Intracranial inflammatory tumors: a survey of their various etiologies by presentation of 5 cases.

Due to similar clinical and neuroradiological features, intracranial inflammatory tumors (IITs) are frequently misdiagnosed as brain neoplasms, from which they notably differ in respect to therapy and prognosis. In this article, five cases of such tumors are presented. Three of the patients with brain tumors (cases 3, 4 and 5) presented a history of 'pararheumatic' syndromes but no diagnosis of defined immunopathies. On the basis of radiological findings, all processes were classified as genuine brain neoplasms, but histology showed reactive inflammatory features. The possible etiologies of these 'tumors' are discussed on the basis of all clinical and histological data of the patients. The spectrum of diseases potentially leading to the manifestation of an IIT is reviewed. Additionally, the presentation of case 5, who developed a highly malignant B-cell-lymphoma 6 months after the removal of an IIT without any histological signs of atypia, shows that this differential diagnosis always has to be kept in mind.

Brain metastasis in renal cell carcinoma: clinical data and neuropathological differential diagnoses.

Beside lung and skeleton, renal cell carcinoma (RCC) can also metastasize to the brain. In order to collect clinical and histopathological data on these tumors, we studied the local distribution of 50 metastases of RCC in different brain regions (frontal, parietal, temporal occipital lobe and brain stem/cerebellum) and found frequencies ranging from 18.4% to 22.4% in each region. This indicates that there is no preferable site of renal cell carcinoma metastases in the brain. In 46 (92%) of the cases the primary tumor or metastases in other organs had already been diagnosed before operation of a brain metastasis. This shows that the latter mostly is a late manifestation at an advanced stage of disease. 44 (88%) of the metastases showed the typical clear cell pattern. In case of unknown primary tumor, these have to be distinguished from other potentially intracranial neoplasms with similar histologic features. These are chordoma, germinoma, paraganglioma, alveolar sarcoma of soft tissue and the epitheloid variant of malignant peripheral nerve sheath tumor.

Mosaicism for Charcot-Marie-Tooth disease type 1A: onset in childhood suggests somatic reversion in early developmental stages.

A 1.5 Mb duplication on chromosome 17p11.2 is typical for the great majority of patients suffering from Charcot-Marie-Tooth type 1A (CMT1A) disease. A female child of 4 years with clinical signs and symptoms of a demyelinating neuropathy was examined for the presence of this duplication. Analysis of MspI polymorphisms in DNA extracted from peripheral blood failed due to homozygosity for probes pVAW409R3a and pEW401HE. Also, no EcoRI/SacI 3.2 kb junction fragment or dosage difference with probe pLR7.8, characteristic of the CMT1A duplication, was found. However, fluorescence in situ hybridization (FISH) analysis with the PMP22 specific probe c132G8 revealed in peripheral blood lymphocytes 60% of interphase nuclei with CMT1A duplication indicating the probability of mosaicism. In interphase nuclei extracted from nerve tissue the duplication was detectable in 88%, in muscle tissue in 72% of the analyzed nuclei. This suggests the presence of a somatic CMT1A duplication mosaicism that can only be reliably detected by FISH. The early onset and severity of the phenotype indicates that the hypothesized somatic reversion is probably fixed to early developmental stages.

Expression of the S-100 proteins MRP-8 and -14 in ischemic brain lesions.

So far, microglial activation in cerebral ischemia has only been studied in different animal models. We have investigated the activation of microglial cells in human cerebral ischemia. As a marker for the activation of these "brain macrophages," we have used the macrophage inhibitor factor-related-proteins MRP-8 and MRP-14, which belong to the calcium binding S-100 protein family. The proteins can be detected on microglial cells in bacterial encephalitis and Alzheimer's disease but have so far not been studied in non-inflammatory diseases, in which microglial activation also occurs. Antibodies against MRP-8 and -14 detected ramified microglial cells within the first 3 days after cerebral infarction. Labeled cells were found selectively in the periinfarctional area. To support the notion that these cells belong to the locally activated resident microglial population, we studied their proliferation rate by staining the Ki-67 antigen with the antibody MIB-1. Double-labeling clearly showed that in the early phase of cerebral infarction microglial cells in the periinfarctional area express MRP-8 and -14 and also proliferate. Surprisingly, MRPs are expressed no longer than 3 days post infarction. This indicates that the activation of the resident microglia is an early step of tissue reaction after cerebral infarction. Additionally, we found evidence that microglial cells contribute to the population of phagocytes only during the first 3 days post infarction. The majority of lipid phagocytes found in the later stages are obviously recruited from the blood-borne macrophage pool.

Twenty-four-hour analysis of lymphocyte subpopulations and cytokines in healthy subjects.

Fourteen healthy male subjects were studied under resting conditions for 24 or 48 h. The 24-h variations of ACTH and cortisol with peaks in the morning were confirmed. Interleukin-2 release was profoundly reduced at 8: 00. A cosine function could be fitted to lymphocyte subpopulations including populations such as T helper-memory cells (CD4+/CDw29) and HLA-DR-bearing cells displaying peak values during the night and minimal values at 9:00. Numbers of natural killer cells (CD57) were not correlated to other cell populations and no rhythm could be detected. Interleukin- 1 beta was detectable in some plasma samples only with an interleukin- 1 ELISA kit (Quantakine HS(R)), but neither a 24-h rhythm nor reproducible results could be obtained for day 1 and 2 of the study. We conclude that there might be a temporal relation between the parameters analyzed: Higher levels of endogenous cortisol in the morning hours probably inhibit the cellular interleukin-2 synthesis and are responsible for an enhanced migration of lymphocytes from the blood into the tissues of the reticuloendothelial system. These results might be indicative of a circadian organization of the immune system which may play a role in both physiological and pathological functioning.