A case of late-onset, thymoma-associated myasthenia gravis with ryanodine receptor and titin antibodies and concomitant granulomatous myositis.

BACKGROUND: Myasthenia gravis is an autoimmune neuromuscular disorder, which has only rarely been reported to co-manifest with myositis. The diagnosis of concomitant myositis in patients with myasthenia gravis is clinically challenging, and requires targeted investigations for the differential diagnosis, including EMG, autoantibody assays, muscle biopsy and, importantly, imaging of the mediastinum for thymoma screening. CASE PRESENTATION: This report presents a case-vignette of a 72-year-old woman with progressive proximal muscle weakness and myalgias, diagnosed with thymoma-associated myasthenia and bioptically verified granulomatous myositis, with positive autoantibody status for ryanodine receptor and titin antibodies. CONCLUSIONS: The diagnosis of concurrent myositis and myasthenia gravis, especially in the presence of ryanodine receptor and titin antibodies, should lead neurologists to adopt different treatment strategies compared to those applied in myasthenia or myositis alone. Moreover, further evidence is warranted that titin and, particularly, ryanodine receptor antibodies may co-occur or be pathophysiologically involved in myasthenia-myositis cases.

[Lysosomal storage diseases: A brief summary]. / Lysosomale Speicherkrankheiten : Ein kurzer Abriss.

BACKGROUND: A considerable number of lysosomal storage diseases (LSD), which can occur at any age in life, should be included in the differential diagnosis of histiocytic diseases. OBJECTIVE: To what extent can pathologists contribute to the diagnostics of LSD? MATERIAL AND METHODS: In material collected from LSD, morphological storage phenomena in some disease forms, particularly in histiocytic cells from bone marrow smears and some tissues are highlighted, presented and described. Due to the multitude and heterogeneity of LSDs this list is by no means exhaustive. RESULTS: In Gaucher disease, the forms of Niemann-Pick disease, cholesteryl ester storage disease (CESD), GM1 gangliosidosis and other LSDs, the histiocytic storage cells seen, for example, in bone marrow smears can be finely and ultrastructurally differentiated. Thereby, not only the presence of an LSD in general but also some individual types of LSD can be identified, even though preliminarily. To confirm the diagnosis the genetic and sometimes biochemical analysis of blood samples or fibroblast cultures from patients is usually required. CONCLUSION: The pathologist may be the first to suspect LSD and this applies to LSDs that show storage histiocytes or one of a number of other LSDs in which only minor or absent storage is seen in histiocytes but marked storage phenomena are found in other cell systems. Some of the numerous, extremely heterogeneous LSDs may, however, be overlooked as detailed knowledge of the generally rare LSDs is the domain of LSD specialists. Clinicians, pathologists, geneticists and biochemists should cooperate in solving the diagnostic problems.

Absence of integrin alpha 7 causes a novel form of muscular dystrophy.

Integrin alpha 7 beta 1 is a specific cellular receptor for the basement membrane protein laminin-1 (refs 1,2), as well as for the laminin isoforms -2 and -4 (ref. 3). The alpha 7 subunit is expressed mainly in skeletal and cardiac muscle and has been suggested to be involved in differentiation and migration processes during myogenesis. Three cytoplasmic and two extracellular splice variants that have been described are developmentally regulated and expressed in different sites in the muscle. In adult muscle, the alpha 7A and alpha 7B subunits are concentrated in myotendinous junctions but can also be detected in neuromuscular junctions and along the sarcolemmal membrane. To study the potential involvement of alpha 7 integrin, during myogenesis and its role in muscle integrity and function, we generated a null allele of the alpha 7 gene (Itga7) in the germline of mice by homologous recombination in embryonic stem (ES) cells. Surprisingly, mice homozygous for the mutation are viable and fertile, indicating that the alpha 7 beta 1 integrin is not essential for myogenesis. However, histological analysis of skeletal muscle revealed typical symptoms of a progressive muscular dystrophy starting soon after birth, but with a distinct variability in different muscle types. The observed histopathological changes strongly indicate an impairment of function of the myotendinous junctions. These findings demonstrate that alpha 7 beta 1 integrin represents an indispensable linkage between the muscle fibre and the extracellular matrix that is independent of the dystrophin-dystroglycan complex-mediated interaction of the cytoskeleton with the muscle basement membrane.

Spinocerebellar ataxia type 1 (SCA1): new pathoanatomical and clinico-pathological insights.

AIMS: Spinocerebellar ataxia type 1 (SCA1) represents the first molecular genetically characterized autosomal dominantly inherited cerebellar ataxia and is assigned to the CAG-repeat or polyglutamine diseases. Owing to limited knowledge about SCA1 neuropathology, appropriate pathoanatomical correlates of a large variety of SCA1 disease symptoms are missing and the neuropathological basis for further morphological and experimental SCA1 studies is still fragmentary. METHODS: In the present study, we investigated for the first time serial tissue sections through the complete brains of clinically diagnosed and genetically confirmed SCA1 patients. RESULTS: Brain damage in the three SCA1 patients studied went beyond the well-known brain predilection sites of the underlying pathological process. Along with neuronal loss in the primary motor cortex, it included widespread degeneration of gray components of the basal forebrain, thalamus, brainstem and cerebellum, as well as of white matter components in the cerebellum and brainstem. It involved the motor cerebellothalamocortical and basal ganglia-thalamocortical circuits, the visual, auditory, somatosensory, oculomotor, vestibular, ingestion-related, precerebellar, basal forebrain cholinergic and midbrain dopaminergic systems. CONCLUSIONS: These findings show for the first time that the extent and severity of brain damage in SCA1 is very similar to that of clinically closely related spinocerebellar ataxias (that is, SCA2, SCA3 and SCA7). They offer suitable explanations for poorly understood SCA1 disease symptoms and will facilitate the interpretation of further morphological and experimental SCA1 studies.

Cerebral low-grade lymphoma and light chain deposition disease: exceedingly high IgG levels in the cerebrospinal fluid as a diagnostic clue.

Herein, we report the case of a 72-year-old male with an exceedingly rare manifestation of a low-grade lymphoma in the brain associated with light chain deposition disease (LCDD). The patient presented with epileptic seizures. Magnetic resonance imaging (MRI) of the brain revealed multiple hyperintense lesions in the right parietal lobe that were suspicious of vasculitis, low-grade glioma, or neurosarcoidosis. In the cerebrospinal fluid (CSF), but not in the serum, highly elevated IgG was found. A stereotactic biopsy of one cerebral lesion was performed. Histopathology revealed a low grade lymphoplasmacytic B-cell lymphoma with light chain deposition disease (LCDD). Bone marrow biopsy and laboratory workup did not show any systemic involvement. LCDD exclusively affecting the brain is an exceedingly rare finding. It can be associated with low-grade B-cell lymphoma. This is the first report of LCDD exclusively affecting the brain in an elderly patient. Compared with the two younger patients previously reported, the course of the disease was of a slow-evolving nature. In constellations of highly elevated IgG in CSF and multiple white matter lesions, LCDD should be considered as underlying pathology.

The microglial/macrophagic response at the tumour-brain border of invasive meningiomas.

AIMS: Little is known about the immune response of the brain to invasive meningiomas. The present study was based upon the hypothesis that the microglial/macrophagic response towards brain-invasive meningiomas is dependent on the intactness of the pial-glial basement membrane. METHODS: We immunostained sections from 40 brain-invasive meningiomas that were graded according to World Health Organization (WHO) 2007 criteria. Thirty-three tumours were histologically WHO grade II (18, 'otherwise benign', and 15, 'otherwise atypical'), and seven, grade III. Microglial/macrophagic cells were labelled with antibodies directed against major histocompatibility complex class II, CD68, CD14 and CD163. Anti-collagen IV was used to visualize basement membranes. RESULTS: Twenty-five per cent (10/40) meningiomas (1/18 WHO grade II 'otherwise benign', 3/15 grade II 'otherwise atypical' and 6/7 WHO grade III) contained microglial/macrophagic cells at the tumour-brain border. The presence of these cells correlated with the absence of the pial-glial basement membrane (BM) and with WHO grade III. The monocytic response was of two kinds: one consisted of a dense layer of mononuclear cells at the tumour-brain border in nine cases, the other of an elevated number of microglial cells expressing CD14 or CD163 (two cases). CONCLUSIONS: The immune response at the tumour-brain interface correlates with the absence of the pial-glial BM and with malignancy grade. It remains to be established whether the mononuclear cells at the tumour-brain border are native microglia or blood-derived macrophages.

Andermann syndrome can be a phenocopy of hereditary motor and sensory neuropathy--report of a discordant sibship with a compound heterozygous mutation of the KCC3 gene.

Andermann syndrome is a rare autosomal recessive disorder characterized by agenesis of the corpus callosum (ACC), progressive motor-sensory neuropathy, mental retardation and facial features. We report on two siblings with the clinical picture of a demyelinating hereditary motor and sensory neuropathy (HMSN), where only the presence of ACC in the younger brother pointed to the diagnosis of Andermann syndrome. Mutation analysis of the KCC3 (SLC12A6) gene showed a compound heterozygous mutation; a maternal missense mutation c.1616G>A (p.G539D) and a paternal splice mutation c.1118+1G>A in both siblings. We hypothesize that mutations of the KCC3 gene may result in non-syndromic childhood onset HMSN.

[Myositides]. / Myositiden.

Idiopathic inflammatory myopathies (IIM) are diseases that are potentially amenable to immunomodulatory therapy. The challenge for the neuropathologist consists in distinguishing these myopathies from secondary inflammatory myopathies, especially in the context of some muscular dystrophies and metabolic diseases that may also show inflammatory infiltrates. There are generalized IIMs (dermatomyositis, polymyositis, sporadic inclusion body myositis) and focal ones (e.g., proliferative myositis, macrophagic myofasciitis). This review provides diagnostic criteria for each of these and includes pathogenetic mechanisms where available.

[Sporadic adult form of nemaline myopathy--a difficult differential diagnosis]. / Sporadische adulte Form der Nemalinmyopathie--eine schwierige Differenzialdiagnose.

We report on a 79 years old female patient with slowly progressive painful weakness of the proximal upper and lower limbs. CK was slightly elevated (242 U 7 l). MRI guided biopsy of the proximal lower limbs revealed the rare findings of nemaline myopathy.

Spinal cord compression through extraosseous extension of a vertebral low-grade hemangioendothelioma with histiocytoid differentiation.

Herein, we report the case of a 47-year-old man clinically presenting a slow progressive loss of lower extremity functions within 8 weeks followed by an acute neurogenic bladder dysfunction. The patient exhibited high-grade paralysis of both legs with reduced sensation from dermatome Th11 downwards as well as marked spasticity of the lower extremity. Neuroradiological examinations revealed a protruding spinal tumor with extraosseous-intraspinal extension. The resected tumor mass exhibited a highly vascularized tumor with architectural complexity and high cellularity finally leading to the diagnosis of a hemangioendothelioma. Interesting was the fact that the tumor vasculature exhibited many CD68-positive cells protruding into the lumen and, therefore, being part of a partially histiocytoid differentiation which is all the more uncommon in hemangioendothelioma. The time frame of 3 hours between embolization and tumor resection is too short to explain a monocytic intravascular reaction. Usually, hemangioendotheliomas arise from the soft tissue, lungs or liver, but intraspinal manifestations are only rarely observed. Furthermore, the clinical course with a progressive development of a paraparesis due to a hemangioendothelioma is very uncommon.

Tuberculum sellae meningioma symptomatic during pregnancy: pathophysiological considerations.

A 31 year old woman in her second pregnancy presented in the 31st (+4) week of gestation with progressive visual impairment of the right eye. Magnetic resonance imaging (MRI) demonstrated a tuberculum sellae meningioma that was displaced upward by a markedly enlarged pituitary gland. Neuro-ophthalmological follow-up examinations showed a progressive decrease of visual acuity and right temporal field loss. Therefore, a caesarean section was performed in the 34th (+8) week. The meningioma was removed three days after childbirth via a right-sided pterional approach. Post-operatively, visual function was completely restored. Immunohistochemical examination showed positive staining for progesterone receptors (PR) in approximately 50% of tumour cells. Enlargement of the pituitary gland during late pregnancy in conjunction with a preexisting tuberculum sellae meningioma is the most likely pathophysiological factor responsible for visual loss. Enlargement of the PR-positive meningioma in the hormonal milieu of pregnancy might have contributed additionally to visual loss.

Hypericin uptake: a prognostic marker for survival in high-grade glioma.

Currently adjuvant chemotherapy for glioblastoma patients can prolong survival time relative to patients who receive only surgery and radiotherapy. Despite these improvements and experimental and clinical efforts the prognosis for glioblastoma patients remains poor. At present, interest is focused on individual prognostic factors influencing patient responses to therapy. Photodynamic therapy may be a promising therapeutic option in the treatment of glioblastoma. In this investigation we examined whether uptake of hypericin (HY), a fluorescent photosensitization agent, by ex vivo glioblastoma cell lines correlates with prognosis of the individual from which the cell lines were derived. Twelve primary human glioma cell cultures were incubated with 20 micromol HY. Fluorescence intensity was measured using fluorescence microscopy. Three patients suffered from an anaplastic astrocytoma, WHO grade III, nine had a glioblastoma, WHO grade IV. In 6/12 patients complete tumour resection was possible. The mean survival time of the six patients in whom complete tumour resection was performed was 26 months, compared with 5 months for those who underwent incomplete resection. Eleven patients received radiation therapy. The five patients who received chemotherapy survived for a mean duration of 26 months, compared with the seven patients who survived for a mean duration of 5 months without chemotherapy. Statistical analysis using a parametric survival model based on the Weibull distribution showed that fluorescence intensity was the variable with the lowest p-value associated with survival (p=0.0225). An increase of 553 arbitrary units of fluorescence intensity is predicted to double survival time. Uptake of HY, a lipophilic molecule, is assumed to be related to low-density lipoprotein (LDL) uptake and metabolism. Cell proliferation is associated with a high turnover of cholesterol and membrane growth, which is related to cholesterol uptake by LDL. In summary, HY uptake by ex vivo glioblastoma cell cultures seems to be positively associated with survival of patients with malignant glioma.

Major intensification of Atlantic overturning circulation at the onset of Paleogene greenhouse warmth.

During the Late Cretaceous and early Cenozoic the Earth experienced prolonged climatic cooling most likely caused by decreasing volcanic activity and atmospheric CO2 levels. However, the causes and mechanisms of subsequent major global warming culminating in the late Paleocene to Eocene greenhouse climate remain enigmatic. We present deep and intermediate water Nd-isotope records from the North and South Atlantic to decipher the control of the opening Atlantic Ocean on ocean circulation and its linkages to the evolution of global climate. The marked convergence of Nd-isotope signatures 59 million years ago indicates a major intensification of deep-water exchange between the North and South Atlantic, which coincided with the turning point of deep-water temperatures towards early Paleogene warming. We propose that this intensification of Atlantic overturning circulation in concert with increased atmospheric CO2 from continental rifting marked a climatic tipping point contributing to a more efficient distribution of heat over the planet.

Pegvisomant treatment in gigantism caused by a growth hormone-secreting giant pituitary adenoma.

BACKGROUND: Gigantism is rare with the majority of cases caused by a growth hormone (GH)-secreting pituitary adenoma. Treatment options for GH-secreting pituitary adenomas have been widened with the availability of long-acting dopamine agonists, depot preparations of somatostatin analogues, and recently the GH receptor antagonist pegvisomant. CASE REPORT: A 23-year-old male patient presented with continuous increase in height during the past 6 years due to a GH-secreting giant pituitary adenoma. Because of major intracranial extension and failure of octreotide treatment to shrink the tumour, the tumour was partially resected by a trans-frontal surgical approach. At immunohistochemistry, the tumour showed a marked expression of GH and a sparsely focal expression of prolactin. Somatostatin receptors (sst) 1-5 were not detected. Tumour tissue weakly expressed dopamine receptor type 2. The Gs alpha subunit was intact. Conversion from somatostatin analogue to pegvisomant normalized insulin-like-growth-factor-I (IGF-I) levels and markedly improved glucose tolerance. CONCLUSION: Pegvisomant is a potent treatment option in patients with pituitary gigantism. In patients who do not respond to somatostatin analogues, knowledge of the SST receptor status may shorten the time to initiation of pegvisomant treatment.

Subcellular localization of GLUT4 in nonstimulated and insulin-stimulated soleus muscle of rat.

Soleus muscles of fed rats were fixed by vascular perfusion with paraformaldehyde; individual fibers were teased and immunostained with a polyclonal antibody against the COOH-terminal of GLUT4. The binding sites were visualized by a horseradish peroxidase-coupled secondary antibody and diaminobenzidine. The fibers were embedded in epoxy resin and studied by electron microscopy. Strong immunoreactivity was found in subsarcolemmal clusters of vesicles and cisternae, Golgilike structures, and triadic junctions. Clusters of vesicles between myofibrils were occasionally stained. The plasma membrane was unlabeled. However, the plasma membrane was labeled when the rats had been injected with insulin (40 U/kg body wt) 15 min before perfusion fixation. In non-insulin-injected rats, the plasma membrane might show spotty staining close to clusters of intensely labeled subsarcolemmal vesicles. This may have been due to diffusion but may also indicate that there are domains of GLUT4 in the plasma membrane of nonstimulated fibers or that the endogenous insulin activity to some extent had translocated GLUT4 from the intracellular pool into the plasma membrane. Coated vesicles that were also labeled were found adjacent to subsarcolemmal vesicles and cisternae; it is possible that coated vesicles play a role during insulin- or contraction-induced translocation of GLUT4 between subsarcolemmal pool and plasma membrane. It has been proposed that glucose uptake into skeletal muscle fibers takes place across the t-tubule membrane rather than across the plasma membrane. This would explain the presence of GLUT4 at triadic junctions. Alternatively, we suggest that GLUT4 in t-tubules represents a second intracellular pool.

Long-term MRI and clinical follow-up of symptomatic and presymptomatic carriers of dysferlin gene mutations.

We report the results of a longitudinal study involving MRI and clinical follow-up in nine siblings from four families with Miyoshi myopathy (MM). All individuals carried pathogenic dysferlin gene (DYSF) mutations with six of them suffering from symptomatic disease and three being presymptomatic. In presymptomatic subjects, MRI was sensitive to detect alterations in muscle tissue years before disease onset. The first MRI alteration to disclose was evidence for myoedema in dorsal compartment muscles of the legs followed by fatty degeneration. Moreover, MRI changes anticipated the topography of subsequent clinical muscle involvement and progressed from distal to proximal dorsal leg muscles. In symptomatic subjects, MRI changes reflected the pattern and severity of clinical muscle involvement. MRI evidence, however, suggests that muscle involvement is much more prominent in early disease stages than clinically seen. Clinical follow-up up to 8 years made evident that MM onset occurs at a mean age of 18.4 years. The most prominent initial deficit was impaired tiptoe gait due to muscle plantarflexor dysfunction followed by impaired dorsiflexor function. Dorsal compartments were predominantly affected not only in distal but also in proximal leg muscles, and a more rapid progression was noticed during the early phase of the disease. Our data suggest that MRI is a helpful diagnostic tool for an early diagnosis of MM and other distal myopathies since it provides sensitive and topographic information about initial and even preclinical muscle involvement. This is of particular relevance in Miyoshi myopathy because distinct CK elevation is present long before its clinical onset and often misdiagnosed as "idiopathic".

Recurrence and increased proliferation rate of a solitary fibrous tumor in the central nervous system--case report and review of the literature.

Meningeal solitary fibrous tumors (SFTs) were at first estimated as rare benign tumors which can be cured by total resection. To date, only 37 patients with intracranial SFTs have been reported. Therefore, the natural history of this tumor entity needs more enlightenment. The authors report a case of a 77-year-old female in whom a SFT with infiltration of the transversal sinus was subtotally resected. After a short time, interval tumor recurrence was seen, 2 years and 6 months later second surgery was performed. Immunohistologically, in both specimens typical features for SFT with positivity for CD34, vimentin and BCL-2 and negative for epithelial membrane antigen was seen. No signs for malignancy occurred in the second resection. Notably the MIB-1 index increased from 1 to 5%. In conclusion, consequent long-time follow-up for SFTs are necessary, especially after incomplete tumor resection.

Extraventricular neurocytoma presenting with intratumoral hemorrhage.

A case of extraventricular neurocytoma with spontaneous intratumoral hemorrhage is reported. A 47-year-old man presented with sudden left-sided hemiparesis. Magnetic resonance imaging revealed a right parietal subcortical mass with intratumoral hemorrhagic transformation and without contact to the ventricular system. After complete microsurgical removal, the tumor was histologically diagnosed as neurocytoma. Usually, the term "central neurocytoma" is restricted to neurocytic neoplasms arising within the cerebral ventricles. In the majority of the cases, these slow-growing, generally circumscribed lesions become symptomatic by obstructive hydrocephalus. Hemorrhagic onset is sporadically reported in the literature. In contrast to central neurocytomas, neurocytic lesions located within the brain parenchyma, so-called "extraventricular neurocytomas" are very uncommon. To the knowledge of the authors, this is the first case of an extraventricular neurocytoma with histological classic features presenting with intratumoral hemorrhage in adults.

Allograft inflammatory factor-1 is expressed by macrophages in injured skeletal muscle and abrogates proliferation and differentiation of satellite cells.

Secretion of regulatory peptides by macrophages in injured skeletal muscle constitutes a pivotal determinator of tissue homeostasis. We analyzed expression of a novel Ca2+- binding peptide expressed by activated macrophages, the allograft inflammatory factor-1 (AIF-1), in rat devascularized skeletal muscle. AIF-1 expression was observed in 94% of all macrophages at the site of the injury 48 hours postdevascularization. The physiological function of AIF-1 in injured skeletal muscle was analyzed using a rat in-vitro model of satellite cell proliferation and differentiation. Addition of AIF-1 to the culture medium resulted in a concentration-dependent and reversible reduction of the total number of cells expressing M-cadherin (p < or = 0.0001), a mediator of the differentiation process of skeletal muscle cells, the proliferation associated PCNA (p < or = 0.0001), and the initiator of muscle differentiation myogenin (p < or = 0.0001). These results provide convincing evidence that activated AIF-1 expressing macrophages constitute the predominant cell type in skeletal muscle 48 hours postinjury, and that AIF-1 regulates reduced proliferation, differentiation, and activation of satellite cells.

Diagnostic protein expression in human muscle biopsies.

Using immunohistochemistry in diagnosing neuromuscular diseases is meant to enhance the diagnostic yield in two ways. The first application aims at visualizing molecules which are developmentally, neurally, and/or immunologically regulated and not expressed by normal muscle. They are upregulated in pathological conditions and may help assign a given muscular biopsy to one of the main diagnostic entities (muscular dystrophies, inflammatory myopathy, neurogenic atrophy). In the past, muscle-specific molecules with a defined expression pattern during fetal myogenesis served as antigens, with the rationale that the developmental program was switched on in new fibers. Recently, myofibers in diseased muscle are thought of as targets of stimuli which are released by macrophages in muscular dystrophy, by lymphocytes in inflammatory myopathies, or by a lesioned peripheral nerve in neurogenic atrophies. This has somewhat blurred the borders between the diagnostic groups, for certain molecules, e.g. cytokines, may be upregulated after experimental necrotization, denervation, and also in inflammatory myopathies. In the second part of this review we summarise the experiences of a Centre in the North of England that specialises in the diagnosis and clinical support of patients with muscular dystrophy. Emphasis is placed on the use of protein expression to guide mutation analysis, particularly in the limb-girdle muscular dystrophies (a group of diseases that are very difficult to differentiate on clinical grounds alone). We confirm that genetic analysis is essential to corroborate the results of protein analysis in certain conditions (particularly in calpainopathy). However, we conclude that analysing biopsies for abnormal protein expression is very useful in aiding the decision between alternative diagnoses.