Hypertrophic pachymeningitis (HP) is an uncommon disorder that causes a localized or diffuse inflammatory fibrosis and thickening of the dura mater. It has been associated with various causes including infections, autoimmune diseases, vasculitic disorders, and malignancy, but the majority of cases are regarded as idiopathic. Most cases of idiopathic HP are now thought to belong to the spectrum of immunoglobulin G4 (IgG4)-related disease. Symptoms result from mass effect, nerve compression, or vascular compromise. HP can be suspected on magnetic resonance imaging (MRI) and diagnosed pathologically on dural biopsy. Major histopathologic features include a dense lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis. Although not pathognomonic, a cutoff value of 10 IgG4+ plasma cells per high power field and an IgG4+/IgG+ plasma cell ratio >40%, are suggestive of IgG4-related HP. High-dose steroids are a first-line treatment, and methotrexate may be beneficial in steroid-refractory cases. Rituximab may also be beneficial for IgG4-related HP.

Three genera of spirochetes cause infections of the CNS in humans: Treponema, Borrelia, and Leptospira. Syphilis is a chronic sexually transmitted infection (STI) caused by Treponema pallidum. The CNS can be involved at any of the disease's four stages. The leptomeninges are commonly invaded during secondary syphilis, but symptomatic neurosyphilis occurs predominantly in the tertiary stage. Neurosyphilis includes meningovascular neurosyphilis (chronic meningitis, multifocal arteritis, and gummas) and parenchymatous neurosyphilis (general paralysis [or paresis] of the insane and tabes dorsalis). Patients with human immunodeficiency virus (HIV) are at increased risk for neurosyphilis, which can progress rapidly to symptomatic neurosyphilis with an accelerated disease course. Borreliosis includes Lyme disease, a tick-borne multisystem infection caused by the spirochete Borrelia burgdorferi sensu lato and relapsing fever; the latter's causative organism and associated vector vary in different geographic regions. Borrelia recurrentis, transmitted by the human body louse, causes epidemic relapsing fever, mainly in Africa. Tick-borne relapsing fever is more frequent in the United States. Neurological complications include meningitis, encephalomyelitis, and cranial or peripheral neuropathies. Leptospirosis is caused by spirochetes of the genus Leptospira. Rodents are the reservoirs, and are the usual source of human infection. Most neurological complications (i.e. meningitis, encephalitis, or myelitis) occur during the immune phase of the disease. In severe icteric leptospirosis (Weil disease), subarachnoid hemorrhage and intracerebral bleeding may occur.

Of 100 known herpesviruses, only 8 are pathogenic to humans and 5 cause CNS infections. In this chapter those resulting from herpes simplex virus 1 and 2 (HSV-1 and HSV-2) are described. HSV-1 and HSV-2 produce two major disease patterns: Primary or recurrent infection in adults and children and neonatal infection. Sporadic HSV encephalitis is the most common form of encephalitis and is usually fatal without treatment. It is characterized by inflammatory necrotic and hemorrhagic lesions containing viral inclusions, predominantly involving the medial and inferior temporal lobes and often asymmetric.

The clinical response to pathogens infecting the CNS is a result of the combined effects of environmental factors, including microbial variations and host-specific factors, mainly immunological or genetic. Although their number and definition are rapidly increasing with the development of molecular technologies, primary and congenital immunodeficiencies, particularly those underlying CNS infections, remain relatively rare and mainly relate to specific infections. Most immunodeficiencies underlying CNS infection are acquired. The number of affected patients is increasing because of the aging population, the growing numbers and longer survival of patients with debilitating diseases, and of those receiving immunosuppressive drugs for inflammatory and neoplastic diseases and for organ transplantation. The acquired immunodeficiency syndrome (AIDS) epidemic also accounts for a major cause of acquired immunodeficiency. This chapter describes the different types of immunodeficiency and related opportunistic infections (OIs) of the CNS and their variation according to patient age, particularly intrauterine infections and infections in neonates and children.

This chapter describes and illustrates the different neuropathological changes observed in a wide range of systemic acquired metabolic diseases that affect the central or peripheral nervous systems: hypoxia, hypoglycemia, hyperthermia, disorders of serum electrolytes, vitamin deficiencies, and exogenous intoxications, particularly alcoholism and intoxications by drugs, methanol, and heavy metals. In the central nervous system, lesions may find expression via selective involvement of some brain regions, with simultaneous complete preservation of others. The pathogenesis of the predisposition to injury for a particular anatomic region or for some specific set of cell types (neurons mostly) varies considerably form one disease to another and is undoubtedly multifactorial. The chapter also considers central nervous system abnormalities secondary to systemic diseases, including respiratory encephalopathies, hepatic encephalopathy, multifocal necrotizing leukoencephalopathy, and paraneoplastic encephalomyelopathies.

Brain homeostasis deteriorates in sepsis, giving rise to a mostly reversible sepsis-associated encephalopathy (SAE). Some survivors experience chronic cognitive dysfunction thought to be caused by permanent brain injury. In this study, we investigated neuroaxonal pathology in sepsis.

Objective: To explore potential spreading to peripheral nerves of the mitochondrial dysfunction in chronic progressive external ophthalmoplegia (CPEO) by assessing axonal excitability.Methods: CPEO patients (n = 13) with large size deletion of mitochondrial DNA and matching healthy controls (n = 22) were included in a case-control study. Muscle strength was quantified using MRC sum-score and used to define two groups of patients: CPEO-weak and CPEO-normal (normal strength). Nerve excitability properties of median motor axons were assessed with the TROND protocol and changes interpreted with the aid of a model.Results: Alterations of nerve excitability strongly correlated with scores of muscle strength. CPEO-weak displayed abnormal nerve excitability compared to CPEO-normal and healthy controls, with increased superexcitability and responses to hyperpolarizing current. Modeling indicated that the CPEO-weak recordings were best explained by an increase in the 'Barrett-Barrett' conductance across the myelin sheath.Conclusion: CPEO patients with skeletal weakness presented sub-clinical nerve excitability changes, which were not consistent with axonal membrane depolarization, but suggested Schwann cell involvement.Significance: This study provides new insights into the spreading of large size deletion of mitochondrial DNA to Schwann cells in CPEO patients. (C) 2017 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Amyloid β peptide (Aβ) immunization of Alzheimer's disease (AD) patients has been reported to induce amyloid plaque removal, but with little impact on cognitive decline. We have explored the consequences of Aβ immunotherapy on neurons in post mortem brain tissue. Eleven immunized (AN1792, Elan Pharmaceuticals) AD patients were compared to 28 non-immunized AD cases. Immunohistochemistry on sections of neocortex was performed for neuron-specific nuclear antigen (NeuN), neurofilament protein (NFP) and phosphorylated-(p)PKR (pro-apoptotic kinase detected in degenerating neurons). Quantification was performed for pPKR and status spongiosis (neuropil degeneration), NeuN-positive neurons/field, curvature of the neuronal processes and interneuronal distance. Data were corrected for age, gender, duration of dementia and APOE genotype and also assessed in relation to Aβ42 and tau pathology and key features of AD. In non-immunized patients, the degree of neuritic curvature correlated with spongiosis and pPKR, and overall the neurodegenerative markers correlated better with tau pathology than Aβ42 load. Following immunization, spongiosis increased, interneuronal distance increased, while the number of NeuN-positive neurons decreased, consistent with enhanced neuronal loss. However, neuritic curvature was reduced and pPKR was associated with Aβ removal in immunized patients. In AD, associations of spongiosis status, curvature ratio and pPKR load with microglial markers Iba1, CD68 and CD32 suggest a role for microglia in neurodegeneration. After immunization, correlations were detected between the number of NeuN-positive neurons and pPKR with Iba1, CD68 and CD64, suggesting that microglia are involved in the neuronal loss. Our findings suggest that in established AD this form of active Aβ immunization may predominantly accelerate loss of damaged degenerating neurons. This interpretation is consistent with in vivo imaging indicating an increased rate of cerebral atrophy in immunized AD patients.

Human signal transducer and activator of transcription 3 (STAT3) deficiency (Online Mendelian Inheritance in Man [OMIM] no. 147060) is a rare primary immunodeficiency caused by heterozygous mutations of STAT3, conferring susceptibility to infections and skeletal and connective tissues features. Recent morphologic data revealed that STAT3 deficiency is responsible for a diffuse vasculopathy,1Ling J.C. Freeman A.F. Gharib A.M. Arai A.E. Lederman R.J. Rosing D.R. et al.Coronary artery aneurysms in patients with hyper IgE recurrent infection syndrome.Clin Immunol. 2007; 122: 255-258Crossref PubMed Scopus (57) Google Scholar, 2Gharib A.M. Pettigrew R.I. Elagha A. Hsu A. Welch P. Holland S.M. et al.Coronary abnormalities in hyper-IgE recurrent infection syndrome: depiction at coronary MDCT angiography.AJR Am J Roentgenol. 2009; 193: W478-W481Crossref PubMed Scopus (18) Google Scholar, 3Freeman A.F. Avila E.M. Shaw P.A. Davis J. Hsu A.P. Welch P. et al.Coronary artery abnormalities in hyper-IgE syndrome.J Clin Immunol. 2011; 31: 338-345Crossref PubMed Scopus (52) Google Scholar, 4Chandesris M.O. Azarine A. Ong K.T. Taleb S. Boutouyrie P. Mousseaux E. et al.Frequent and widespread vascular abnormalities in human signal transducer and activator of transcription 3 deficiency.Circ Cardiovasc Genet. 2012; 5: 25-34Crossref PubMed Scopus (40) Google Scholar which is characterized by alteration in mechanotransduction in the arterial wall causing hypotrophic remodeling despite increased forces exerting on the wall (circumferential wall stress), leading to enhanced susceptibility to aneurysm.The high vascular risk of such lesions was confirmed by the sudden death of a 35-year-old patient (carrying a missense F384L STAT3 mutation) after rupture of a giant basilar artery aneurysm (see Fig E1 in this article's Online Repository at www.jacionline.org). After consent of his family, an autopsy was performed 24 hours after death.We report on the neuropathological study of the brain. The materials and methods used in this study are detailed in the Methods section in this article's Online Repository at www.jacionline.org. Macroscopic analysis confirmed that aneurysmal rupture led to abundant bleeding, intracranial hypertension, and fatal tonsillar herniation. The white matter appeared grayish in areas where white matter hyperintensities had been observed in magnetic resonance imaging. Microscopy revealed damage of both blood vessels and white matter.The aneurysmal wall (Fig 1) presented marked thickness variations of the intima with focal intimal hyperplasia and of the media with loss of vascular smooth muscle cells (VSMCs) in atrophic areas. The internal elastic lamina exhibited major irregularities with either focal thickening or disruption in areas with marked VSMC loss. Medial calcifications were observed as either thin deposits along the internal elastic lamina or massive aggregates. The absence of lipids and inflammation in the aneurysmal wall or the other cerebral vessels ruled out atherosclerosis and vasculitis as causes.The large vessels (basilar, vertebral, and carotid arteries; see Fig E2 in this article's Online Repository at www.jacionline.org) appeared flattened, with thinned walls, marked fibrosis of the media, focal endothelial hyperplasia, and an abnormal thick, irregular, disrupted internal elastic membrane containing alcianophilic (mucopolysaccharide) deposits. There were also focal calcium deposits affecting all 3 layers of the vessel wall. Apart from the calcifications, the abnormalities observed in the small and medium arteries (Willis circle and middle and anterior cerebral arteries) were similar to those of large vessels.In agreement with magnetic resonance imaging data, white matter changes (Fig 2) were mild and limited in extent, affecting the deep white matter in the parieto-occipital and fronto-orbital regions. They included spongiosis, oligodendroglial tumefaction, dilation of the perivascular spaces with plasma exudate, pigment-laden macrophages, signs of microglial activation, and astrocytic gliosis. These features, which were consistent with chronic edema and involvement of the blood-brain barrier, were associated with an abnormal convoluted and frizzy aspect of the vascular wall. In immunohistochemistry CD3 lymphocytes and CD68 macrophages were scarce, confirming the absence of inflammation.Fig 2White matter and intracerebral small-vessel disease. A, Coronal section of the right cerebral hemisphere (Klüver and Barrera stain) revealing mild and ill-delimited myelin pallor in the deep white matter. B, Spongiosis and oligodendroglial tumefaction (Klüver and Barrera stain). C, Microglial activation (anti-CD68 staining). D, Astrocytic gliosis (glial fibrillary acidic protein). E, Dilation of the perivascular spaces with plasma exudate and accumulation of macrophages containing brownish pigment (hematoxylin and eosin). F and G, Convoluted and frizzy-like aspect of the small-vessel wall (Fig 2, F, hematoxylin and eosin; Fig 2, G, periodic acid–Schiff).View Large Image Figure ViewerDownload Hi-res image Download (PPT)The medial VSMCs of the basilar aneurysm expressed higher levels of TGF-β than in healthy control arteries, but no difference was detected in phospho-SMAD2 expression (see Fig E3 in this article's Online Repository at www.jacionline.org). Although all vascular cells showed STAT3 expression, phospho-STAT3 staining was negative in medial VSMCs of the basilar aneurysm and was reduced in the patient's nonaneurysmal cerebral and peripheral arteries compared with strong positive staining in healthy control arteries.This neuropathological analysis provides insights into the nature of the vascular lesions observed in patients with STAT3 deficiency. It decisively rules out atherosclerosis, inflammatory mechanisms, and/or infectious disease and reveals lesions that had never been described before. The association of vascular lesions with white matter changes similar to those seen in patients with chronic vascular leukoencephalopathy prompted us to suggest an exclusively vascular noninflammatory mechanism combining ischemia and chronic edema. However, it is noteworthy that conditional Stat3 deficiency in murine astrocytes is associated with exacerbated white matter injuries,5Nobuta H. Ghiani C.A. Paez P.M. Spreuer V. Dong H. Korsak R.A. et al.STAT3-mediated astrogliosis protects myelin development in neonatal brain injury.Ann Neurol. 2012; 72: 750-765Crossref PubMed Scopus (69) Google Scholar suggesting that alterations in STAT3 signaling in nonvascular cells might also contribute to white matter abnormalities. The present morphologic and histologic characteristics are somewhat reminiscent of other genetic connective tissue diseases associated with an increased risk of cardiovascular complications, including aneurysm formation (see Table E1 in this article's Online Repository at www.jacionline.org). However, their pathophysiological link remains hypothetical.Pseudoxanthoma elasticum (OMIM no. 264800), which is caused by autosomal recessive mutations in ABCC6 coding for an ATP-binding protein, is characterized by elastocalcinosis (resulting in elastic fiber fragmentation) and proteoglycan accumulation in soft conjunctive tissues and the arterial media.6Leftheriotis G. Omarjee L. Le Saux O. Henrion D. Abraham P. Prunier F. et al.The vascular phenotype in Pseudoxanthoma elasticum and related disorders: contribution of a genetic disease to the understanding of vascular calcification.Front Genet. 2013; 4: 4Crossref PubMed Scopus (65) Google Scholar The arterial lesions consist of mineralization of the elastic fibers within the media of small- and medium-caliber musculoelastic arteries associated with abnormal extracellular matrix remodeling (proteoglycan replacement and activation of matrix metalloproteinases). However, the VSMCs appear to be normal, and the arterial elasticity is either unchanged or increased. The link between these 2 conditions remains hypothetical because the ABCC6 gene product's putative biological functions and substrates are unknown and a relationship with STAT3 has not been demonstrated.Williams-Beuren syndrome (OMIM no. 194050) is a genetic multisystem disease related to deletion of genes on chromosome 7q11.23, including ELN, which encodes for elastin.7Pober B.R. Williams-Beuren syndrome.N Engl J Med. 2010; 362: 239-252Crossref PubMed Scopus (562) Google Scholar The main pathological feature consists of VSMC overgrowth toward the lumen with wall expansion responsible for a systemic obstructive arteriopathy. Apart from the common alteration in elastic fibers, the other pathological features are not observed in the STAT3-deficient patient. Moreover, interaction between STAT3 and elastin has never been reported.Marfan syndrome (OMIM no. 154700) is caused by mutations in FBN1, encoding fibrillin 1, the main component of the extracellular matrix microfibril present in all tissues.8Judge D.P. Dietz H.C. Marfan's syndrome.Lancet. 2005; 366: 1965-1976Abstract Full Text Full Text PDF PubMed Scopus (842) Google Scholar The main pathological features include low elastin content, calcifications and fragmentation of elastic fibers, vascular wall inflammation, intimal hyperplasia (caused by VSMC overgrowth), and structural collapse of the vessel wall resulting in aortic root aneurysm with high risk of dissection and valve disease. In this respect it is noteworthy that conditional deletion of Stat3 in murine astrocytes is associated with enhanced production of TGF-β,5Nobuta H. Ghiani C.A. Paez P.M. Spreuer V. Dong H. Korsak R.A. et al.STAT3-mediated astrogliosis protects myelin development in neonatal brain injury.Ann Neurol. 2012; 72: 750-765Crossref PubMed Scopus (69) Google Scholar as is the case in syndromic and nonsyndromic aneurysms.9Gomez D. Al Haj Zen A. Borges L.F. Philippe M. Gutierrez P.S. Jondeau G. et al.Syndromic and non-syndromic aneurysms of the human ascending aorta share activation of the Smad2 pathway.J Pathol. 2009; 218: 131-142Crossref PubMed Scopus (146) Google Scholar This putative link between STAT3- and TGF-β–related aneurysms is worth further investigation.In conclusion, this is the first detailed report on a unique and previously uncharacterized vasculopathy associated with STAT3 deficiency. The fact that this vascular phenotype has some features in common with other multisystem genetic connective tissue diseases reinforces the hypothesis of a common underlying mechanism. Further investigation of this hypothesis might provide important insights into new potential treatments for connective tissue diseases. In the meanwhile, strict control of vascular risk factors (smoking, overweight, and hypertension) that might accelerate disease progression is necessary. Human signal transducer and activator of transcription 3 (STAT3) deficiency (Online Mendelian Inheritance in Man [OMIM] no. 147060) is a rare primary immunodeficiency caused by heterozygous mutations of STAT3, conferring susceptibility to infections and skeletal and connective tissues features. Recent morphologic data revealed that STAT3 deficiency is responsible for a diffuse vasculopathy,1Ling J.C. Freeman A.F. Gharib A.M. Arai A.E. Lederman R.J. Rosing D.R. et al.Coronary artery aneurysms in patients with hyper IgE recurrent infection syndrome.Clin Immunol. 2007; 122: 255-258Crossref PubMed Scopus (57) Google Scholar, 2Gharib A.M. Pettigrew R.I. Elagha A. Hsu A. Welch P. Holland S.M. et al.Coronary abnormalities in hyper-IgE recurrent infection syndrome: depiction at coronary MDCT angiography.AJR Am J Roentgenol. 2009; 193: W478-W481Crossref PubMed Scopus (18) Google Scholar, 3Freeman A.F. Avila E.M. Shaw P.A. Davis J. Hsu A.P. Welch P. et al.Coronary artery abnormalities in hyper-IgE syndrome.J Clin Immunol. 2011; 31: 338-345Crossref PubMed Scopus (52) Google Scholar, 4Chandesris M.O. Azarine A. Ong K.T. Taleb S. Boutouyrie P. Mousseaux E. et al.Frequent and widespread vascular abnormalities in human signal transducer and activator of transcription 3 deficiency.Circ Cardiovasc Genet. 2012; 5: 25-34Crossref PubMed Scopus (40) Google Scholar which is characterized by alteration in mechanotransduction in the arterial wall causing hypotrophic remodeling despite increased forces exerting on the wall (circumferential wall stress), leading to enhanced susceptibility to aneurysm. The high vascular risk of such lesions was confirmed by the sudden death of a 35-year-old patient (carrying a missense F384L STAT3 mutation) after rupture of a giant basilar artery aneurysm (see Fig E1 in this article's Online Repository at www.jacionline.org). After consent of his family, an autopsy was performed 24 hours after death. We report on the neuropathological study of the brain. The materials and methods used in this study are detailed in the Methods section in this article's Online Repository at www.jacionline.org. Macroscopic analysis confirmed that aneurysmal rupture led to abundant bleeding, intracranial hypertension, and fatal tonsillar herniation. The white matter appeared grayish in areas where white matter hyperintensities had been observed in magnetic resonance imaging. Microscopy revealed damage of both blood vessels and white matter. The aneurysmal wall (Fig 1) presented marked thickness variations of the intima with focal intimal hyperplasia and of the media with loss of vascular smooth muscle cells (VSMCs) in atrophic areas. The internal elastic lamina exhibited major irregularities with either focal thickening or disruption in areas with marked VSMC loss. Medial calcifications were observed as either thin deposits along the internal elastic lamina or massive aggregates. The absence of lipids and inflammation in the aneurysmal wall or the other cerebral vessels ruled out atherosclerosis and vasculitis as causes. The large vessels (basilar, vertebral, and carotid arteries; see Fig E2 in this article's Online Repository at www.jacionline.org) appeared flattened, with thinned walls, marked fibrosis of the media, focal endothelial hyperplasia, and an abnormal thick, irregular, disrupted internal elastic membrane containing alcianophilic (mucopolysaccharide) deposits. There were also focal calcium deposits affecting all 3 layers of the vessel wall. Apart from the calcifications, the abnormalities observed in the small and medium arteries (Willis circle and middle and anterior cerebral arteries) were similar to those of large vessels. In agreement with magnetic resonance imaging data, white matter changes (Fig 2) were mild and limited in extent, affecting the deep white matter in the parieto-occipital and fronto-orbital regions. They included spongiosis, oligodendroglial tumefaction, dilation of the perivascular spaces with plasma exudate, pigment-laden macrophages, signs of microglial activation, and astrocytic gliosis. These features, which were consistent with chronic edema and involvement of the blood-brain barrier, were associated with an abnormal convoluted and frizzy aspect of the vascular wall. In immunohistochemistry CD3 lymphocytes and CD68 macrophages were scarce, confirming the absence of inflammation. The medial VSMCs of the basilar aneurysm expressed higher levels of TGF-β than in healthy control arteries, but no difference was detected in phospho-SMAD2 expression (see Fig E3 in this article's Online Repository at www.jacionline.org). Although all vascular cells showed STAT3 expression, phospho-STAT3 staining was negative in medial VSMCs of the basilar aneurysm and was reduced in the patient's nonaneurysmal cerebral and peripheral arteries compared with strong positive staining in healthy control arteries. This neuropathological analysis provides insights into the nature of the vascular lesions observed in patients with STAT3 deficiency. It decisively rules out atherosclerosis, inflammatory mechanisms, and/or infectious disease and reveals lesions that had never been described before. The association of vascular lesions with white matter changes similar to those seen in patients with chronic vascular leukoencephalopathy prompted us to suggest an exclusively vascular noninflammatory mechanism combining ischemia and chronic edema. However, it is noteworthy that conditional Stat3 deficiency in murine astrocytes is associated with exacerbated white matter injuries,5Nobuta H. Ghiani C.A. Paez P.M. Spreuer V. Dong H. Korsak R.A. et al.STAT3-mediated astrogliosis protects myelin development in neonatal brain injury.Ann Neurol. 2012; 72: 750-765Crossref PubMed Scopus (69) Google Scholar suggesting that alterations in STAT3 signaling in nonvascular cells might also contribute to white matter abnormalities. The present morphologic and histologic characteristics are somewhat reminiscent of other genetic connective tissue diseases associated with an increased risk of cardiovascular complications, including aneurysm formation (see Table E1 in this article's Online Repository at www.jacionline.org). However, their pathophysiological link remains hypothetical. Pseudoxanthoma elasticum (OMIM no. 264800), which is caused by autosomal recessive mutations in ABCC6 coding for an ATP-binding protein, is characterized by elastocalcinosis (resulting in elastic fiber fragmentation) and proteoglycan accumulation in soft conjunctive tissues and the arterial media.6Leftheriotis G. Omarjee L. Le Saux O. Henrion D. Abraham P. Prunier F. et al.The vascular phenotype in Pseudoxanthoma elasticum and related disorders: contribution of a genetic disease to the understanding of vascular calcification.Front Genet. 2013; 4: 4Crossref PubMed Scopus (65) Google Scholar The arterial lesions consist of mineralization of the elastic fibers within the media of small- and medium-caliber musculoelastic arteries associated with abnormal extracellular matrix remodeling (proteoglycan replacement and activation of matrix metalloproteinases). However, the VSMCs appear to be normal, and the arterial elasticity is either unchanged or increased. The link between these 2 conditions remains hypothetical because the ABCC6 gene product's putative biological functions and substrates are unknown and a relationship with STAT3 has not been demonstrated. Williams-Beuren syndrome (OMIM no. 194050) is a genetic multisystem disease related to deletion of genes on chromosome 7q11.23, including ELN, which encodes for elastin.7Pober B.R. Williams-Beuren syndrome.N Engl J Med. 2010; 362: 239-252Crossref PubMed Scopus (562) Google Scholar The main pathological feature consists of VSMC overgrowth toward the lumen with wall expansion responsible for a systemic obstructive arteriopathy. Apart from the common alteration in elastic fibers, the other pathological features are not observed in the STAT3-deficient patient. Moreover, interaction between STAT3 and elastin has never been reported. Marfan syndrome (OMIM no. 154700) is caused by mutations in FBN1, encoding fibrillin 1, the main component of the extracellular matrix microfibril present in all tissues.8Judge D.P. Dietz H.C. Marfan's syndrome.Lancet. 2005; 366: 1965-1976Abstract Full Text Full Text PDF PubMed Scopus (842) Google Scholar The main pathological features include low elastin content, calcifications and fragmentation of elastic fibers, vascular wall inflammation, intimal hyperplasia (caused by VSMC overgrowth), and structural collapse of the vessel wall resulting in aortic root aneurysm with high risk of dissection and valve disease. In this respect it is noteworthy that conditional deletion of Stat3 in murine astrocytes is associated with enhanced production of TGF-β,5Nobuta H. Ghiani C.A. Paez P.M. Spreuer V. Dong H. Korsak R.A. et al.STAT3-mediated astrogliosis protects myelin development in neonatal brain injury.Ann Neurol. 2012; 72: 750-765Crossref PubMed Scopus (69) Google Scholar as is the case in syndromic and nonsyndromic aneurysms.9Gomez D. Al Haj Zen A. Borges L.F. Philippe M. Gutierrez P.S. Jondeau G. et al.Syndromic and non-syndromic aneurysms of the human ascending aorta share activation of the Smad2 pathway.J Pathol. 2009; 218: 131-142Crossref PubMed Scopus (146) Google Scholar This putative link between STAT3- and TGF-β–related aneurysms is worth further investigation. In conclusion, this is the first detailed report on a unique and previously uncharacterized vasculopathy associated with STAT3 deficiency. The fact that this vascular phenotype has some features in common with other multisystem genetic connective tissue diseases reinforces the hypothesis of a common underlying mechanism. Further investigation of this hypothesis might provide important insights into new potential treatments for connective tissue diseases. In the meanwhile, strict control of vascular risk factors (smoking, overweight, and hypertension) that might accelerate disease progression is necessary. MethodsAutopsy was performed 24 hours after death. Gross examination of the formalin-fixed brain was performed on coronal sections of the cerebral hemispheres and sections of the brain stem and cerebellum perpendicular to their axis. Large coronal slices of the cerebral hemispheres were embedded in paraffin, and 15-μm-thick sections were stained with hematoxylin and eosin and a combination of cresyl violet and Luxol fast blue (Klüver and Barrera stain). Smaller blocks were taken from the cerebral vessels, aneurysm, cerebral cortex with underlying white matter, deep white matter, deep gray nuclei, midbrain, cerebellum, and brainstem and then embedded in paraffin. Five-micrometer-thick sections were stained with hematoxylin and eosin, cresyl violet, Masson trichrome, periodic acid–Schiff, Bodian silver impregnation combined with Luxol fast blue, alcian blue, orcein elastin stain (to highlight elastic fibers), and von Kossa stain (to highlight calcium deposits).An immunohistochemical analysis was performed on selected samples from frontal and occipital white matter, cerebral vessels, and the aneurysm by using either a Roche Diagnostic (Mannheim, Germany) automat for routine antibodies (CD3, CD68, and glial fibrillary acidic protein) or a manual technique for the other specific antibodies (with an avidin-biotin complex and peroxidase [Vector Laboratories, Burlingame, Calif]). Specific primary antibodies against the following antigens were used: CD3 (for T lymphocytes), CD68 (for macrophages), glial fibrillary acidic protein (for astrocytes; all from Dako Cytomation, Glostrup, Denmark), STAT3, phospho-STAT3, phospho-SMAD2 (all from Cell Signaling, Danvers, Mass), and TGF-β (AbD Serotec, Raleigh, NC). In negative controls specific primary antibodies were replaced by nonrelevant mouse or rabbit antibodies. The immunohistochemical data for the basilar trunk were compared with those for a normal popliteal artery section (obtained during femoral-popliteal bypass surgery).Fig E2Microscopic appearance of the arteries in the circle of Willis. A, Full section of the basilar artery (hematoxylin and eosin stain). The vessel appears somewhat flattened, with a thin wall. B, Full section of the right vertebral artery (hematoxylin and eosin stain). Again, the vessel appears somewhat flattened, with a thin wall. Note the basophilic calcium deposits in the media and (focally) intima. C, Left middle cerebral artery (hematoxylin and eosin stain) showing focal endothelial hyperplasia. Note the eosinophilic deposits under the intima (arrow). D, Full section of the left vertebral artery section (von Kossa stain). The vessel appears somewhat flattened, with a thin wall. Note the calcium deposits (stained black with the von Kossa technique) in the adventitia (arrows). E-H, Right vertebral artery (Fig E2, E, orcein stain for elastin; Fig E2, F, hematoxylin and eosin stain; Fig E2, G, alcian blue stain; and Fig E2, H, von Kossa stain). The internal elastic membrane shows abnormal thickening, irregularities and disruptions (Fig E2, E) associated with alcianophilic (mucopolysaccharide) deposits (Fig E2, G) and basophilic (Fig E2, F) von Kossa–positive (Fig E2, H) calcium deposits.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig E3Expression levels of TGF-β, phospho-SMAD2, STAT3, and phospho-STAT3 in VSMCs from a normal (control) artery and from the basilar artery aneurysm. TGF-β expression was higher in the aneurysm than in the normal artery. No difference was observed for phospho-SMAD2. Although both the control artery and basilar aneurysm artery expressed similar levels of STAT3, phospho-STAT3 was differentially expressed. The VSMCs in the basilar artery aneurysm did not express phospho-STAT3, whereas the protein was strongly expressed in the normal (control) artery. Immunohistochemistry was performed with specific primary antibodies (original magnification ×10).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table E1Comparative analysis of STAT3 deficiency-related vasculopathy with the vasculopathy of 3 relevant genetic connective tissue diseasesAD-HIESPseudoxanthoma elasticumWilliams-Beuren syndromeMarfan syndromeGeneSTAT3ABCC6ELNFBN1Size of involved vesselsLarge/medium/smallMedium/smallLarge/mediumLarge/mediumAneurysmYesYesNoYesStenosisYesYesYes (severe)NoCerebral parenchyma (MRI)Leukoencephalopathy, strokes, atrophyStrokesAtrophy, strokesStrokesIMTDecreased (despite endothelial hyperplasia)Increased because of PG accumulationIncreased because of VSMC overgrowthIncreased because of VSMC overgrowthElastic fiber involvementYesYesYesYesWall thicknessThinnedIncreasedIncreasedIncreasedInvolved layersIntima/media/adventitiaMedia > intimaMediaIntimaCalcium depositsYesYesNoYesInflammationNoNoNoYesAD-HIES, Autosomal dominant hyper-IgE syndrome; ELN, elastin gene; FBN1, fibrillin gene; IMT, intima media thickness; MRI, magnetic resonance imaging; PG, proteoglycan. Open table in a new tab Autopsy was performed 24 hours after death. Gross examination of the formalin-fixed brain was performed on coronal sections of the cerebral hemispheres and sections of the brain stem and cerebellum perpendicular to their axis. Large coronal slices of the cerebral hemispheres were embedded in paraffin, and 15-μm-thick sections were stained with hematoxylin and eosin and a combination of cresyl violet and Luxol fast blue (Klüver and Barrera stain). Smaller blocks were taken from the cerebral vessels, aneurysm, cerebral cortex with underlying white matter, deep white matter, deep gray nuclei, midbrain, cerebellum, and brainstem and then embedded in paraffin. Five-micrometer-thick sections were stained with hematoxylin and eosin, cresyl violet, Masson trichrome, periodic acid–Schiff, Bodian silver impregnation combined with Luxol fast blue, alcian blue, orcein elastin stain (to highlight elastic fibers), and von Kossa stain (to highlight calcium deposits). An immunohistochemical analysis was performed on selected samples from frontal and occipital white matter, cerebral vessels, and the aneurysm by using either a Roche Diagnostic (Mannheim, Germany) automat for routine antibodies (CD3, CD68, and glial fibrillary acidic protein) or a manual technique for the other specific antibodies (with an avidin-biotin complex and peroxidase [Vector Laboratories, Burlingame, Calif]). Specific primary antibodies against the following antigens were used: CD3 (for T lymphocytes), CD68 (for macrophages), glial fibrillary acidic protein (for astrocytes; all from Dako Cytomation, Glostrup, Denmark), STAT3, phospho-STAT3, phospho-SMAD2 (all from Cell Signaling, Danvers, Mass), and TGF-β (AbD Serotec, Raleigh, NC). In negative controls specific primary antibodies were replaced by nonrelevant mouse or rabbit antibodies. The immunohistochemical data for the basilar trunk were compared with those for a normal popliteal artery section (obtained during femoral-popliteal bypass surgery). AD-HIES, Autosomal dominant hyper-IgE syndrome; ELN, elastin gene; FBN1, fibrillin gene; IMT, intima media thickness; MRI, magnetic resonance imaging; PG, proteoglycan.

Objective To describe characteristics and outcomes of a multicenter cohort of patients diagnosed as having primary angiitis of the central nervous system (PACNS). Methods In 2010, we initiated a cohort study of adults diagnosed as having PACNS ≤15 years ago and with followup of >6 months (unless they died earlier of biopsy‐proven PACNS). Its first analysis was planned at 2 years. Multidisciplinary investigators verified that appropriate investigations were done and excluded patients with possible alternative diagnoses. We analyzed patient demographics and symptoms, laboratory, radiographic, and histologic findings, and treatments. Studied outcomes included treatment response(s), relapse, death, and disability. Results We included 52 patients (30 males; median age at diagnosis 43.5 years [range 18–79 years]) in whom PACNS was diagnosed between 1996 and 2012. Nineteen (61%) of 31 patients who had undergone brain biopsy had histologic vasculitis (biopsy‐proven PACNS), while the other 12 patients had normal or noncontributive biopsy samples. An additional 21 patients had signs suggestive of PACNS on conventional cerebral angiography. All but 1 patient received corticosteroids, and 44 patients received cyclophosphamide (CYC). After a median followup of 35 months (range 2–148 months) postdiagnosis (1 patient with biopsy‐proven PACNS died 2 months after diagnosis), 32 patients responded to treatment with improved modified Rankin scale scores, 4 patients (8%) did not respond, 14 patients (27%) had relapse of their disease at least once, and 3 patients (6%) died (1 patient after a relapse). Relapse was more common in patients with than in those without meningeal gadolinium enhancements on magnetic resonance imaging (MRI) (8 of 10 [80%] versus 6 of 32 [19%]; P = 0.001) and more common in patients with than in those without seizures at diagnosis (8 of 17 [47%] versus 6 of 35 [17%]; P = 0.04). Conclusion In this cohort of patients with PACNS, most patients received corticosteroids and CYC, and mortality was low. Patients with seizures at diagnosis or meningeal enhancements on MRI may be prone to relapse and require a different treatment strategy.

Aims: Sarco/Endoplasmic Reticulum Calcium ATPase-type calcium pumps (SERCA enzymes) control cell activation by sequestering calcium ions from the cytosol into the endoplasmic reticulum. Although endoplasmic reticulum calcium signalling plays an important role in the regulation of choroid plexus epithelial function, SERCA expression in the choroid plexus has not been investigated so far. Methods: In this work we investigated the expression of the SERCA3-type calcium pump in choroid plexus epithelial cells grown in vitro, and in normal and hyperplastic choroid plexus tissue, in choroid plexus papillomas displaying various degrees of atypia, and in choroid plexus carcinoma by immunohistochemistry in situ. Results: Whereas normal choroid plexus epithelial cells express SERCA3 abundantly, SERCA3 expression is strongly decreased in papillomas, and is absent in choroid plexus carcinoma, while expression in hyperplastic epithelium is high, similarly to normal epithelium. SERCA3 expression was detected also in normal primary choroid plexus epithelial cells grown in vitro, and expression was markedly enhanced by short-chain fatty acid-type cell differentiation inducing agents, including valproate. Conclusion: These observations show that SERCA3 is a new phenotypic marker of normal choroid plexus epithelial differentiation, and that SERCA3 constitutes an early tumour marker 'by loss of expression' in the choroid plexus that may be useful to distinguish hyperplastic processes from papillomas. Endoplasmic reticulum calcium homeostasis becomes anomalous, due to loss of SERCA3 expression, already in benign neoplastic lesions of the choroid plexus epithelium.

BACKGROUND Despite its overall efficacy, combined antiretroviral therapy (cART) has failed to control human immunodeficiency virus (HIV) infection of the central nervous system (CNS). New acute and chronic neurological complications continue to be reported. METHODS We conducted a retrospective study of 14 HIV-infected patients with documented encephalitis, which was initially attributed to an undetermined origin. Brain magnetic resonance imaging (MRI) uniformly revealed unusual, multiple linear gadolinium-enhanced perivascular lesions. RESULTS All patients had manifested acute or subacute neurological symptoms; the brain MRIs indicating diffuse brain damage. The mean duration of HIV infection was approximately 10 years, and 8 patients were immunovirologically stable. Cerebrospinal fluid abnormalities with mildly elevated protein and pleocytosis with >90% lymphocytes, predominantly CD8, were found in all but 1 patient. The mean cerebral spinal fluid HIV load was 5949 copies/mL. Six patients reported a minor infection a few days prior to neurological symptoms, 2 patients presented criteria for the immune reconstitution inflammatory syndrome of the CNS, 2 were in virological escape, and 1 developed encephalitis after interruption of cART. Brain biopsies revealed inflammatory encephalitis associated with astrocytic and microglial activation as well as massive perivascular infiltration by polyclonal CD8(+) lymphocytes. All patients had been treated with glucocorticosteroids. The long-term therapeutic response varied from excellent, with no sequalae (n = 5), to moderate, with cognitive disorders (n = 4). The mean survival time was 8 years; however, 5 patients died within 13 months of initiation of treatment. CONCLUSIONS CD8 encephalitis in HIV-infected patients receiving cART is a clinical entity that should be added to the list of HIV complications.

We report the neuropathological findings in 10 HIV-infected patients treated by combination antiretroviral therapy who developed subacute encephalopathy of rapidly progressive onset. Brain biopsy showed encephalitic lesions variably associated with myelin loss and slight axonal damage. There was inconstant, weak expression of HIV protein p24; tests for other pathogens were negative. The most striking feature was diffuse, perivascular and intraparenchymal infiltration by CD8+ T-lymphocytes. Six patients improved after the treatment. Four had an unfavorable outcome and died within a year. Post-mortem in one case confirmed HIV leukoencephalitis with p24-positive multinucleated giant cells, associated with acute demyelinating encephalomyelitis (ADEM) in the cerebellum. There was diffuse infiltration by CD8+ lymphocytes; CD4+ cells were virtually absent. These cases may represent a specific clinicopathological entity, of which a few comparable cases have been already described. They can be included in the wide framework of immune reconstitution disease. Such syndromes have been described with opportunistic infections, but only seldom with HIV infection of the central nervous system (CNS). Our findings support the hypothesis that CD8+ cytotoxic lymphocytes can be harmful in immune reconstitution disease, particularly in the absence of CD4+ lymphocytes. CD8 cytotoxicity produces an acutization of a smoldering infection and/or an immunopathological reaction similar to ADEM.

Alzheimer's disease (AD) patients in Aβ immunotherapy trials have demonstrated amyloid plaque removal but with little evidence of slowed cognitive decline. We have explored the consequences of immunotherapy on neuronal density and the morphology of neuronal processes. 11 immunised AD patients (iAD) (Elan Pharmaceuticals, AN1792) were compared to 28 non-immunised AD patients (cAD) as controls. Immunohistochemistry on sections of cortex from frontal, temporal and parietal lobes was performed for: neuron-specific nuclear antigen (NeuN), neurofilament (NFP) and pPKR (phosphorylated pro-apoptotic kinase detected in degenerating neurons). Status spongiosus (neuropil degeneration) was assessed in haematoxylin-and eosin-stained sections. We quantified NFP and pPKR labelling as load (%), the percentage area of cortex showing status spongiosus, NeuN-positive neurons/field, curvature of the neuronal processes and interneuronal distance (m m). Data were corrected for age, gender, duration of dementia and APOE genotype. Our data show in the iAD compared to the cAD cases: a significantly higher degree of spongiosus (53.3 vs 48.6, P = 0.013), fewer NeuN-positive neurons/field (66.8 vs 73.7, P = 0.036), lower curvature of neuronal processes (1.13 vs 1.23, P < .001), a trends towards a lower pPKR load (0.08 vs 0.16, P = 0.070) and no-significant change in mean interneuronal distance (713.6 vs 705.2, P = 0.370). After immunisation, there is evidence of enhanced neuronal damage in the form of exacerbated status spongiosus and a lower density of neurons. Remaining neurons seem “healthier” (less curvature of neuronal processes, less pPKR). The data raise the possibility that A β immunisation may accelerate the removal of neurons damaged by AD and are consistent with the report of increased cerebral atrophy detected with MRI.