Pathological integrations in the central nervous system

Damage to the nervous system is a causal and conditioning event leading to the development of pathological processes mediated via such endogenous mechanisms as the formation of integrative complexes from damaged and secondary changed nervous structures that are pathological by their nature, mechanisms, and effects. At the level of neural relationships such pathological integrative complex (PIC) is formed by an aggregate of hyperactive neurons (generator of pathologically enhanced excitation, GPEE) producing uncontrollable ongoing flow of nerve impulses. At the systemic level, PIC is a new pathodynamic system composed of various subdivisions of the CNS, which acts as a pathological system. The subdivision of the CNS containing GPEE assumes the role of a pathological determinant due to its enhanced activity. This pathological determinant induces the formation of a pathological system and controls its activity at the early period of its genesis. Every neuropathological syndrome is a clinical or behavioral manifestation of pathological system activity. Pathological determinant and pathological system are general biological categories that fall outside the scope of nervous disorders. They can arise in various systems at the micro- and macroscopic levels and induce systemic pathology. Translated fromByulleten's Eksperimental'noi Biologii i Meditsiny, Vol. 127, No. 3, pp. 244–247, March, 1999 Original article submitted October 5, 1998     

Systemic mechanisms of nervous disorders]

Apart from the lesion and destruction of nervous structures and nervous links there is a different, so far little known, aspect of pathogenesis of nervous disorders, i.e. appearance of new pathological integrations in the nervous system. Formation and activity of these integrations is realized by endogenous, intrinsic to the damaged nervous system itself mechanisms. Pathologic integration occurring at the level of systemic relations is a pathologic system. The main biological sign of a pathologic system, due to which it differs from a physiologic system, is a dysadaptive or directly pathogenic significance of its activity for the organism. The pathologic system may be originate as a result of hyperactivation and loss of control over the physiologic system or due to the formation of a new, pathodynamic organization in the central nervous system. The neuropathological syndrome is clinical expression of the corresponding pathologic system activity. Every syndrome has its pathologic system and the specificity of the syndrome depends on what structures of the central nervous system are part of the pathologic system. Simple, linear pathologic systems underlie the monomorphic syndromes and symptoms, and complex ones underlie the polymorphic syndromes. Due to plasticity the positive connections between the parts of the pathologic system are consolidated therefore with course of time the resistance of the pathologic system to the endogenous sanogenetic mechanisms and to therapy increases. Stabilization of pathologic system underlies the chronization of nervous disorders. The concept of the pathologic system as a basic pathophysiological mechanism of nervous disorders is a new approach to understanding pathogenesis, elaboration of models and development of new principles and method of treatment of nervous disorders.     

Neuroimmunopathology]

The paper deals with a part of neuroimmunopathology which is concerned with the role of the pathologically altered nervous system in the pathology of the immune system and vice versa and considers disturbances in the interconnection of nervous and immune systems. Antibodies against neuromediators and nervous tissue can produce both pathogenetic and sanogenic effects depending on the neurotransmitter function or the nervous structure which they are specifically directed towards. The effects of systematically administered antibodies against nervous tissue and neuromediators demonstrate that antibodies can penetrate into the central nervous system (CNS). The adoptive transfer of the signs of a pathological condition by immunocytes from CNS abnormalities illustrates the role of the immune system in nervous diseases.     

The definition of HIV-specific neuropathology

Evaluation of a neuropathological series of 160 HIV-infected patients, almost all in the terminal AIDS stage of the infection, allowed recognition of novel syndromes which can be regarded as HIV-specific neuropathology because: 1) they are not observed in non-HIV tissues; 2) HIV is, in our hands consistently by immunocytochemistry, demonstrable in large amounts within these lesions; 3) other pathogens are not detectable within these lesions; and 4) these lesions may occur in isolated fashion within CNS tissues (40% of HIV-specific neuropathology in this series), without any other CNS pathology. HIV-specific neuropathology was found in 34% in this series and comprised two prototypes within a spectrum of frequently overlapping changes: multifocal microgranulomatous lesions of HIV encephalitis, and diffuse white matter damage of HIV leukoencephalopathy. In almost all cases, multinucleated giant cells signal the local presence of HIV in routine stains. In contrast to HIV-specific neuropathology, various unspecific nervous tissue syndromes do not consistently exhibit the local presence of HIV and thus are designated HIV-associated or possibly HIV-induced lesions: lymphocytic meningitis, vacuolar myelopathy, multifocal vacuolar leukoencephalopathy, and diffuse poliodystrophy. Although these unspecific syndromes may also contribute to clinical manifestations, their pathogenetic relation with HIV remains to be established.     

Mental deficiency,alterations in performance,and CNS abnormalities in overgrowth syndromes

Mental deficiency, alterations in performance, and central nervous system (CNS) abnormalities are discussed in the following overgrowth syndromes: Sotos syndrome, Weaver syndrome, Proteus syndrome, neurofibromatosis type 1, fragile X syndrome, syndromes with neonatal hypoglycemia, Simpson-Golabi-Behmel syndrome, hemihyperplasia, Sturge-Weber syndrome, Bannayan-Riley-Ruvalcaba/Cowden syndrome, macrocephaly-autism syndrome, PEHO syndrome, chromosomal syndromes, and other miscellaneous syndromes.     

The Definition of HIV-specific Neuropathology

Evaluation of a neuropathological series of 160 HIV infected patients, almost all in the terminal AIDS stage of the infection, allowed recognition of novel syndromes which can be regarded as HIV specific neuropathology because: 1) they are not observed in non HIV tissues; 2) HIV is, in our hands consistently by immunocytochemistry, demonstrable in large amounts within these lesions; 3) other pathogens are not detectable within these lesions; and 4) these lesions may occur in isolated fashion within CNS tissues (40% of HIV-specific neuropathology in this series), without any other CNS pathology. HIV specific neuropathology was found in 34% in this series and comprised two prototypes within a spectrum of frequently overlapping changes: multifocal microgranulomatous lesions of HIV encephalitis, and diffuse white matter damage of HIV leukoencephalopathy. In almost all cases, multinucleated giant cells signal the local presence of HIV in routine stains. In contrast to HIV-specific neuropathology, various unspecific nervous tissue syndromes do not consistently exhibit the local presence of HIV and thus are designated HIV associated or possibly HIV induced lesions: lymphocytic meningitis, vacuolar myelopathy, multifocal vacuolar leukoencephalopathy, and diffuse poliodystrophy. Although these unspecific syndromes may also contribute to clinical manifestations, their pathogenetic relation with HIV remains to be established.     

Functional assays for neurotoxicity testing

Neurobehavioral and pathological evaluations of the nervous system are complementary components of basic research and toxicity testing of pharmaceutical and environmental chemicals. While neuropathological assessments provide insight as to cellular changes in neurons, behavioral and physiological methods evaluate the functional consequences of disruption of neuronal communications. The underlying causes of certain behavioral alterations may be understood, but many do not have known direct associations with specific brain pathologies. In some cases, however, rapidly expanding mouse models (transgenic, knock-out) are providing considerable information on behavioral phenotypes of altered pathology. Behavior represents the integrated sum of activities mediated by the nervous system, and functional tests used for neurotoxicity testing tap different behavioral repertoires. These tests have an advantage over pathologic measures in that they permit repeated evaluation of a single animal over time to determine the onset, progression, duration, and reversibility of a neurotoxic injury. Functional assays range from a screening-level battery of tests to refined procedures to tap specific forms of learning and/or memory. This article reviews common procedures for behavioral toxicity testing and provides examples of chemical-specific neurobehavioral-pathological correlations in order to inform interpretation and integration of neuropathological and behavioral outcomes.     

Genetic localization of an autosomal dominant leukodystrophy mimicking chronic progressive multiple sclerosis to chromosome 5q31

The hereditary leukodystrophies represent a group of neurological disorders, in which complete or partial dysmyelination occurs in either the central nervous system (CNS) and/or the peripheral nervous system. Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive, neurological disorder characterized by symmetrical widespread myelin loss in the CNS, and the phenotype is similar to that of chronic progressive multiple sclerosis. We report clinical, neuroradiological and neuropathological data from the originally reported ADLD family. Furthermore, we have localized the gene that causes ADLD to a 4 cM region on chromosome 5q31. Linkage analysis of this family yielded a LOD score of 5.72 at theta = 0.0 with the microsatellite marker D5S804. Genetic localization will lead to cloning and characterization of the ADLD gene and may yield new insights into myelin biology and demyelinating diseases.     

Immunologic aspects of pathologic pain

The scientific review is devoted to an analysis of neuro-immune aspects of the pathological pain and to the role of disregulation between the central nervous system (CNS) and the immune system in triggering the mechanisms of such pain. The importance of anti-inflammatory cytokines (interleukins, and tumor necrosis factor) as well as of autoantibodies to neuro-mediators in the pathogenesis of different forms of hyperalgetic conditions is evaluated. New data are discussed, which are related with the possibility of modulating the antibodies to neuro-transmitters (serotonin and catecholamines) of experimental neuropathic pain syndromes.     

Central nervous system involvement in arthrogryposis multiplex congenita: Overview of causes,diagnosis, and care

Arthrogryposis or AMC, arthrogryposis multiplex congenita, is defined as multiple congenital joint contractures in more than two joints and in different body areas. The common cause of all AMC is lack of movement in utero, which in turn can have different causes, one of which is CNS involvement. Intellectual disability/CNS involvement is found in approximately 25% of all AMC. AMC with CNS involvement includes a large number of genetic syndromes. So far, more than 400 genes have been identified as linked to AMC, with and without CNS involvement. A number of neonatally lethal syndromes and syndromes resulting in severe disability due to CNS malfunction belong to this group of syndromes. There are several X‐linked disorders with AMC, which are primarily related to intellectual disability. A number of neuromuscular disorders may include AMC and CNS/brain involvement. Careful clinical evaluation by a geneticist and a pediatrician/pediatric neurologist is the first step in making a specific diagnosis. Further investigations may include MRI of the brain and spinal cord, electroencephalogram, blood chemistry for muscle enzymes, other organ investigations (ophtalmology, cardiology, gastrointestinal, and genitourinary systems). Nerve conduction studies, electromyogram, and muscle pathology may be of help when there is associated peripheral nervous system involvement. But most importantly, genetic investigations with targeted or rather whole exome or genome sequencing should be performed. A correct diagnosis is important in planning adequate treatment, in genetic counselling and also for future understanding of pathogenic mechanisms and possible new treatments. A multidiciplinary team is needed both in investigation and treatment.     

Clinical and Neuropathological Variability in Clinically Isolated Central Nervous System Whipple's Disease

Central nervous system Whipple's disease (CNS‐WD) with clinically isolated neurological involvement is a rare condition fatal without an early diagnosis. We aimed to present clinical and neuropathological features of three cases of pre‐ or post‐mortem polymerase chain reaction confirmed CNS‐WD with distinct clinical presentation, outcome and pathological findings. One patient had an acute onset with spinal and brainstem involvement and died without CNS‐WD diagnosis after 14 weeks. Neuropathology showed extensive inflammatory and necrotizing lesions with abundant foamy periodic‐acid‐Schiff (PAS)+ macrophages. The second patient had a subacute evolution with late CNS‐WD diagnosis and death occurring 18 months after onset despite antibiotic treatment. Brain examination showed inflammatory lesions in the brainstem, thalamus and cerebellum, and abundant foamy PAS+ macrophages. The third case was diagnosed within 4 weeks of onset and treated with an excellent response. He died after a disease‐free period of 24 months of unrelated causes. Neuropathology showed cystic residual lesions devoid of microorganisms without inflammatory reaction. CNS‐WD may have an acute or subacute course with variable response to treatment. Accordingly, subjacent lesions may be those of a severe acute necrotizing encephalitic process or subacute inflammatory lesions involving diencephalic, brainstem, cerebellar and spinal regions. Chronic, cavitary brain lesions may be sequelae of a successful treatment. Early diagnosis should allow appropriate treatment and improve prognosis.     

Invasion of the central nervous system by intracellular bacteria

Infection of the central nervous system (CNS) is a severe and frequently fatal event during the course of many diseases caused by microbes with predominantly intracellular life cycles. Examples of these include the facultative intracellular bacteria Listeria monocytogenes, Mycobacterium tuberculosis, and Brucella and Salmonella spp. and obligate intracellular microbes of the Rickettsiaceae family and Tropheryma whipplei. Unfortunately, the mechanisms used by intracellular bacterial pathogens to enter the CNS are less well known than those used by bacterial pathogens with an extracellular life cycle. The goal of this review is to elaborate on the means by which intracellular bacterial pathogens establish infection within the CNS. This review encompasses the clinical and pathological findings that pertain to the CNS infection in humans and includes experimental data from animal models that illuminate how these microbes enter the CNS. Recent experimental data showing that L. monocytogenes can invade the CNS by more than one mechanism make it a useful model for discussing the various routes for neuroinvasion used by intracellular bacterial pathogens.     

Boosting T-cell immunity as a therapeutic approach for neurodegenerative conditions: The role of innate immunity

Our research group has been working for more than a decade on the cross-talk between the immune and the nervous systems. Due to the unique nature of the central nervous system (CNS) as an immune privileged site, it was commonly believed that the nervous system functions optimally without any immune intervention, and that any immune cell infiltration to the CNS is a sign of pathology. However, since the immune system constitutes the body's major defense and repair mechanism, it seemed unreasonable that the CNS would have completely lost the need for assistance from this system. This insight prompted us to revisit the entire question of whether immune cells are required for recovery from CNS injuries. We subsequently made numerous fundamental observations that led us to formulate a unified theory linking all neurodegenerative conditions; thus, we suggested that “T-cell immunity to self maintains the self,” at least in the CNS. According to this view, immunity to self (“protective autoimmunity”) provides a pivotal role in maintenance, protection, and repair of the healthy and diseased CNS. We further showed that the T cells mediate their effect, at least under pathological conditions, by controlling the recruitment of blood-borne monocytes, which play a crucial local role that cannot be replaced by the resident microglia. Boosting of such a T cell response specific for brain proteins, while carefully choosing the antigen, the carrier, timing, dosing, and regimen should be considered as a way of augmenting a physiological repair mechanism needed to ameliorate disease conditions while restoring equilibrium needed for protection, repair and renewal; such therapy is not intended to modify a single mediator of a single disease, but rather, would serve as an approach for adjusting the levels of the immune response needed to restore a lost balance.     

Microglia dysfunction in schizophrenia: an integrative theory

Schizophrenia is a devastating illness of unknown etiology. It is characterized by increased brain ventricular volume, suggesting a progressive neurodevelopmental condition. There is evidence suggesting a correlation between in utero viral exposure and subsequent occurrence of schizophrenia. Many neurotransmitter systems have been implicated as being dysfunctional in schizophrenia. There are also data suggesting immune system dysfunction in schizophrenia, and a negative correlation between schizophrenia and rheumatoid arthritis. Microglia are phagocytic immune cells in the central nervous system (CNS) derived from peripheral blood monocytes. They are involved in brain development, neuroproliferative and neurodegenerative activities, several CNS illnesses, and CNS viral immunity. They may also be involved in neurotransmitter regulation. The current theory postulates microglial dysfunction initiated by early CNS viral exposure results in the abnormal neural development and neurotransmitter dysfunction seen in schizophrenia.     

Lethal familial fetal akinesia sequence (FAS) with distinct neuropathological pattern: Type III lissencephaly syndrome

We report on a distinct pattern of primary central nervous system (CNS) degeneration affecting neuronal survival in the brain and spinal cord in 5 fetuses with fetal akinesia sequence (FAS). This neuropathological pattern is characteristic of a lethal entity that we propose calling type III lissencephaly syndrome. Parental consanguinity and the recurrence in sibs support a genetic cause. The mechanism of neuronal death is not yet understood; abnormal apoptosis and/or deficiency in neurotropic factors may be considered possible causes. © 1996 Wiley-Liss, Inc.     

Parasitic diseases of the central nervous system

Parasitic infections, though endemic to certain regions, have over time appeared in places far removed from their original sites of occurrence facilitated probably by the increase in world travel and the increasing migration of people from their native lands to other, often distant, countries. The frequency of occurrence of some of these diseases has also changed based on a variety of factors, including the presence of intermediate hosts, geographic locations, and climate. One factor that has significantly altered the epidemiology of parasitic diseases within the central nervous system (CNS) is the HIV pandemic. In this review of the pathology of parasitic infections that affect the CNS, each parasite is discussed in the sequence of epidemiology, life cycle, pathogenesis, and pathology.     

Systemic vasculitis positive for circulating anti-neutrophil cytoplasmic antibodies and with predominantly neurological presentation

Summary A 57-year-old male patient suffering from dramatically deteriorating diffuse and focal central nervous system symptoms was admitted to hospital after a short prodromal period in a somnolent state. He was diagnosed as having systemic vasculitis positive for circulating anti-neutrophil cytoplasmic antibodies, primarily involving the brain, but also most other organ systems. Circulating anti-neutrophil cytoplasmic antibodies are highly specific for Wegener granulomatosis, though they have been detected in rare cases of other vasculitic syndromes. Central nervous system lesions as presenting signs in Wegener granulomatosis have to be regarded as rare. This case nonetheless suggests that Wegener granulomatosis has to be considered in patients with a predominantly cerebral manifestation of a vasculitic syndrome.Abbreviations C-ANCA circulating anti-neutrophil cytoplasmic antibodies - CNS central nervous system - CRP C-reactive protein - CSF cerebrospinal fluid - EGG electrocardiogram - Hb hemoglobin - IgA immunoglobulin A - PAN polyarteritis nodosa - WBC White blood count - WG Wegener granulomatosis     

Pathogenesis of HIV in the Central Nervous System

HIV can infect the brain and impair central nervous system (CNS) function. Combination antiretroviral therapy (cART) has not eradicated CNS complications. HIV-associated neurocognitive disorders (HAND) remain common despite cART, although attenuated in severity. This may result from a combination of factors including inadequate treatment of HIV reservoirs such as circulating monocytes and glia, decreased effectiveness of cART in CNS, concurrent illnesses, stimulant use, and factors associated with prescribed drugs, including antiretrovirals. This review highlights recent investigations of HIV-related CNS injury with emphasis on cART-era neuropathological mechanisms in the context of both US and international settings.     

CNS pathology in hereditary syndromes of congenital developmental defects

Analysis of the incidence and diagnostic importance of the congenital central nervous system (CNS) defects in 334 children with multiple congenital developmental defects (MCDD) dying under 1 year allowed the author to distinguish 4 groups of defects according to their informative value for establishing the nosological diagnosis: defects of a high, moderate, small informative value and noninformative ones. Special microscopic study of the CNS performed in 116 stillborns and children of the first year of life with various MCDD showed the disturbance of main morphogenetic processes (mitotic cell activity, cell migration, differentiation and maturation) as a basis of the observed pathological conditions. General rules of the CNS developmental defects in chromosomal and non-chromosomal syndromes may point to the common routes of the genetic material realization.     

Prolongation of sleep as the result of the creation of a generator of pathologically enhanced excitation in the orbital cortex

In acute experiments on cats injection of tetanus toxin, which disturbs various types of inhibition, into the orbital cortex caused the formation of a local generator of pathologically enhanced excitation in that region. In chronic experiments on cats with such a generator in the orbital cortex pathological changes of sleep appeared: a decrease in the duration of wakefulness and the development of a prolonged sleep state, while the normal ratio between slow-wave and paradoxical stages in the sleep continuum was preserved. The results confirm the view that the orbitofrontal cortex participates in the induction of sleep and they develop the general concept of the role of determinant structures in the activity of the nervous system and the theory of generator mechanisms of neuropathological syndromes characterized by hyperactivity of its systems.Laboratory of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Department of Pathological Physiology, N. I. Pirogov Odessa Medical Institute. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 84, No. 11, pp. 531–534, November, 1977.