Potassium channel antibody associated encephalopathy presenting with a frontotemporal dementia like syndrome.

OBJECTIVE: To describe a patient who presented with features suggestive of frontotemporal dementia (FTD) but with some atypical findings and antibodies to neuronal voltage-gated potassium channels (VGKC-Abs). DESIGN: Case report. SETTING: Mater Misericordiae University Hospital, Dublin, Ireland. RESULTS: An 82-year-old man presented with progressive changes in personality, social conduct, and executive function with preservation of memory, deteriorating from baseline to requiring acute hospitalization within 6 months. Transient deterioration (episodic speech arrest) with spontaneous recovery, atypical for frontotemporal dementia, was observed. The patient had an elevated VGKC-Ab titer (2624 pM [normal range, < 100 pM]), elevated protein levels in cerebrospinal fluid, and a negative evaluation for malignancy. Magnetic resonance imaging of brain was normal but [(18)F]-fluorodeoxyglucose positron emission tomographic imaging revealed bifrontal hypometabolism. A marked and sustained improvement with steroid therapy was observed. CONCLUSION: Workup for a potentially reversible autoimmune-mediated encephalopathy, including a VGKC-Ab titer, should be considered in patients presenting with rapidly progressive behavioral and cognitive decline.

Purinergic receptors modulate MAP kinases and transcription factors that control microglial inflammatory gene expression.

Following many types of brain injury, microglial cell hyperactivation, and the subsequent release of neurotoxic mediators into the CNS contributes to inflammation and neuronal death. Among the proteins important for modulating the inflammatory function of microglia are the P2 purinergic receptors for which extracellular adenine nucleotides, such as ATP, are ligands. Because adenine nucleotides are abundant in the extracellular fluid following brain injury, ATP may represent an important component of the inflammatory microenvironment controlling microglial cell function. Although much work has been done examining the mechanisms whereby adenine nucleotides stimulate inflammatory mediator production, little is known concerning their complementary inhibitory effects. In this review we will focus on what is currently known about the microglial inhibitory effects of adenine nucleotides in the context of inflammation and summarize the current knowledge of their effects via purinergic receptors on microglial signal transduction pathways including transcription factors important for controlling inflammatory gene expression. The relevance of these mechanisms to microglial inflammatory function and physiology will be discussed. Further, we present data here illustrating that MAP kinase signal transduction pathways are altered in activated microglia that have been primed with or co-exposed to adenine nucleotides; effects that are stimulus- and MAPK pathway-specific. We also demonstrate the ability of P2X7 receptors to stimulate the phosphorylation of CREB, a putative inhibitory transcription factor in microglia. Together, these data indicate that ATP may be an endogenous inhibitor or neuroprotective molecule decreasing the inflammatory capacity of microglia.

Psychoneuroimmunology of stroke.

There is now considerable evidence from both experimental and clinical studies that immune and inflammatory processes can contribute to the onset of stroke and the neurologic and psychologic outcomes. Several specific therapeutic targets have been identified that may significantly improve the devastating impact of stroke.

Suppression of glial activation is involved in the protection of IL-10 on maternal E. coli induced neonatal white matter injury.

White matter damage (WMD) is an important cause of disability including cerebral palsy in preterm, low birth-weight infants. Maternal infection is now recognized as one of the risk factors for WMD. Previously we reported that intrauterine inoculation of Escherichia coli to pregnant rats resulted in WMD in offspring and interleukin-10 (IL-10) was protective against this damage. The objective of this study was to elucidate the mechanism involved in the protective effect of IL-10 against neonatal WMD. We found that E. coli treatment in dams resulted in significant apoptosis in periventricular white matter of rat pups on postnatal day 0 (P0). On P8, a remarkable increase in ED-1 immunostaining (indicating either microglial activation or macrophage infiltration) was detected in brains of pups in the E. coli-treated group. Astrogliosis was also noticed in brain white matter of pups in the E. coli-treated group. In addition to the strong activation of microglia and astrocytes, oligodendrocytes (OLs) were significantly reduced in periventricular areas in the brains of pups from the E. coli-treated group. Later, on P15, hypomyelination was also noticed in rat brains from the E. coli-treated group, using myelin basic protein (MBP) immunostaining. Treatment with IL-10 after E. coli inoculation significantly reduced TUNEL staining and caspase-3 activation, and partially restored the impaired immunostaining markers for immature and mature OLs, such as CNPase, O4, adenomatous polyposis coli (APC) and MBP. These results indicate that the protective effect of IL-10 against brain WMD is linked with suppression of microglial activation/macrophage infiltration, as shown by significantly reduced ED-1+ cells in the white matter.

Immune and autoimmune diseases in dyslexic children.

One hundred and five dyslexic and 105 control children were compared for frequency of immune diseases, autoimmune diseases, and non-right-handedness in the light of the Geschwind-Behan (1982) "testosterone hypothesis". The results showed significantly more immune- and autoimmune-diseases int he dyslexic group. There were no differences between the groups in the frequency of non-right-handedness. There were no interactions with gender, although there were more non-right-handed boys than girls in the total sample. Mothers of children who were dyslexic experienced significantly more negative life-events during pregnancy, they also experienced the pregnancy as more difficult, and they had more spontaneous abortions. In conclusion, the results support some aspects of the "testosterone hypothesis", but they also point to a more complex pattern of interaction between the factors that still remain unanswered.

Hashimoto's encephalopathy: epidemiologic data and pathogenetic considerations.

BACKGROUND: Hashimoto's encephalopathy (HE) is a condition believed to complicate Hashimoto's thyroiditis (HT). The diagnosis is suspected in the presence of high levels of serum anti-thyroid antibodies. We have recently demonstrated that in patients with HE there is an intrathecal synthesis of anti-thyroid antibodies, and concluded that the diagnosis of HE should be based on this cerebrospinal fluid (CSF) finding. OBJECTIVE: getting an estimate of the prevalence of the disease, verifying the association with HT and investigating the pathogenetic role of anti-thyroid antibodies. METHODS: 34-months prospective study in a hospital setting serving a community of 150,000 people. Patients with unexplained symptoms of acute or subacute encephalopathy or myelopathy or with a history of thyroid disorders were selected for the measurement of anti-thyroid antibodies. In the presence of high serum levels of autoantibodies, the same tests were performed in the CSF. RESULTS: Twelve patients had increased concentrations of serum autoantibodies but HE was diagnosed only in nine patients. The estimated prevalence of HE is 2.1/100,000. Only six HE patients had also HT. Four patients received corticosteroids, five patients were not treated. Five patients improved, four patients spontaneously, one patient after corticosteroids. Repeated CSF examinations showed that the titer of CSF autoantibodies did not correlate with the clinical stage of the disease nor was influenced by corticosteroids. In addition, the course of symptoms was independent of therapy. CONCLUSIONS: The association of encephalopathy and high titers of anti-thyroid antibodies is not sufficient to make a diagnosis of HE. Independent of the clinical status of the thyroid gland, the intrathecal synthesis of autoantibodies is a distinctive marker of this elusive condition.

The effects of parental immunoreactivity on pregnancy, birth, and cognitive development: maternal immune attack on the fetus?

The effects of parental immunoreactivity were tested in two ways on questionnaire data collected from 468 children and their families. (1) It was found that the presence of learning difficulties in boys was associated with pregnancy and birth complications, as well as with maternal immunoreactivity. Paternal immunoreactivity did not appear to be related to any of the variables in question. (2) The antecedent brother effect, that children, particularly males, with older brothers have higher rates of the same set of variables, was not found. Maternal immunoreactivity emerges as a risk factor for pregnancy, birth, and cognitive development, but not exclusively by the proposed mechanism of maternal immune attack on the fetus.

Antagonism of leukocyte adherence by synthetic fibronectin peptide V in a rat model of transient focal cerebral ischemia.

OBJECTIVE: Activated polymorphonuclear leukocytes (PMNs) seem to be directly involved in potentiating ischemic brain injury. Recent work in our laboratory demonstrated that synthetic fibronectin peptides significantly inhibit PMN accumulation in ischemic tissue, reduce the size of infarction, and reduce neurological dysfunction after transient focal cerebral ischemia in rats. The purpose of this study was to examine any dose-related effects (Experiment 1) and the optimal timing of the administration (Experiment 2) of synthetic fibronectin peptide V (FN-C/H-V) to further substantiate the role of the peptide in ameliorating cerebral ischemic damage. METHODS: Fifty-six animals were included in the study. We evaluated the efficacy of FN-C/H-V on PMN accumulation in ischemic tissue, infarct size, and neurological outcomes in rats subjected to 1 hour of cerebral ischemia and 48 hours of reperfusion. RESULTS: In Experiment 1, the animals receiving FN-C/H-V at a dose of 10 to 15 mg/kg of body weight per injection showed significant reduction of PMN accumulation, reduction of infarct size, and improvement of neurological outcomes at 48 hours after reperfusion compared to untreated animals (P < 0.05). In Experiment 2, the animals receiving FN-C/H-V within 3 hours after reperfusion also showed significantly better results than untreated animals (P < 0.05). Despite the treatment delay, the administration of FN-C/H-V inhibited PMN accumulation after reperfusion but did not reduce the size of infarction when administered 6 hours after reperfusion. CONCLUSION: These data suggest that relatively late postischemic administration of FN-C/H-V is effective in brain protection after ischemia/reperfusion.

Serum IgG antibody to herpes viruses in schizophrenia.

Immunoglobulin measurements have provided indirect evidence to suggest that viruses may play an etiologic role in schizophrenia. The authors review the conflicting studies and report their own measurements of serum antibody absorbance to five viral antigens using an ELISA technique in 38 schizophrenic patients and 22 matched controls. For herpes simplex virus, 12 subjects (32%) had antibody levels more than 2 SD above the control mean.

Tumor necrosis factor alpha antibody prevents brain damage of rats with acute necrotizing pancreatitis.

AIM: To study the protective effects of tumor necrosis factor alpha (TNFalpha) antibody on pancreatic encephalopathy in rats. METHODS: One hundred and twenty SD rats were randomly divided into normal control group, acute necrotizing pancreatitis group and TNFalpha antibody treated group. Acute hemorrhage necrotizing pancreatitis model in rats was induced by retrograde injection of 50 g/L sodium taurocholate into the pancreatobiliary duct. Serum TNFalpha was detected and animals were killed 12 h after drug administration. Changes in content of brain water, MDA and SOD as well as leucocyte adhesion of brain microvessels were measured. RESULTS: In TNFalpha antibody treated group, serum TNFalpha level was decreased. Content of brain water, MDA and SOD as well as leucocyte adhesion were decreased significantly in comparison with those of acute necrotizing pancreatitis group (P<0.05). CONCLUSION: TNFalpha antibody can alleviate the brain damage of rats with acute hemorrhage necrotizing pancreatitis.

Neurologic outcome of acute measles encephalitis according to the MRI patterns.

The aim of this prospective study was to clarify the ramifications of neuroimaging patterns associated with neurologic outcomes of acute measles encephalitis. Twelve patients with neurologic complications stemming from a measles outbreak were diagnosed based on characteristic clinical features, the presence of measles-specific antibodies, and abnormal cerebrospinal fluid findings. Neuroimaging studies were then performed during the acute phase of the disease. Our subject group consisted of four males and eight females (mean age: 9.9 years). Main neurologic findings were loss of consciousness, seizures, and paralysis. Serum tests for measles-specific Ig G and M antibodies were positive in eleven patients. Neuroimages of the group revealed the following three abnormalities: (1). demyelination of white matter with hypoperfusion on interictal single-photon-emission computed tomography, (2). high signal intensity of gray matter with hypoperfusion on interictal single-photon-emission computed tomography, and (3). normal MRI with hypoperfusion on single-photon-emission computed tomography. We identified a new pattern of acute measles encephalitis that involved cortical and/or deep gray matter, and this finding suggests a variant in the pathogenesis of acute measles encephalitis. Patients that demonstrated a gray matter abnormality had a higher rate of complications and required longer periods of hospitalization.

Pertussis immunization patterns in special care nursery graduates.

Controversy exists regarding immunization with pertussis vaccine of high-risk special care nursery graduates. Our study compared the immunization status of 38 high-risk, 30 low-risk, and 57 normal infants utilizing an immunization response form. Comparison of the three infant groups revealed that complete or incomplete immunization varies, depending on group status. Of 38 infants at high risk for developmental delay, 22 (57.9%) were not immunized against pertussis by age one. Physicians cited concerns related to previous neurologic injury and increased liability for vaccine-related injury as major reasons for deferring vaccination. Recommendations for improving current guidelines and practice are outlined.

Significance of the inflammatory response in brain ischemia.

Leukocytes appear to have a central role in the inflammatory response that develops during acute brain ischemia. This brief review adduces evidence that leukocytes accumulate in focal zones of acute brain ischemia at a sufficiently early stage to participate in the process of progressive ischemic brain damage and that partial inhibition of that accumulation, by various measures, can attenuate ischemic brain injury. Mechanisms of leukocyte adhesion are discussed in detail and an inference is put forward that leukocytes are an important factor in progressive ischemic injury, but almost certainly act in concert with a number of other similarly important factors. On this basis, leukocyte inhibition may have demonstrable benefit in acute stroke, but ultimately be found to only partially spare potentially salvageable tissue in the ischemic zone.

Leukocytes, macrophages and secondary brain damage following cerebral ischemia.

The involvement of white blood cells in microvascular derangement as a cause of secondary brain damage following cerebral ischemia is reviewed. Relevant data from the literature are arranged in the chronological sequence of the microvascular derangement of the brain that occurs after cerebral arterial occlusion (as based on our own experimental observations). The inflammatory processes which appeared to be elicited by polymorphonuclear leukocytes (PMNL) in the ischemic region of the brain may begin with adhesion of PMNLs to endothelial cells, followed by blood-brain barrier disruption, transudation/exudation, edema, necrosis, and scar formation. Stimulated by cytokines released from damaged neurons and axons, two types of macrophages (ameboid and ramified) appear, increase in number in the ischemic lesion, and engulf the debris of dead neurons, degenerated axons. Further, macrophages may release cytokines which stimulate healing processes, such as astroglial proliferation and revascularization, and release neurotoxins which could gradually kill surviving neurons. Even under such circumstances, individual leukocytes/macrophages are well regulated by specific mediators/cytokines. An urgent task is thus to find ways of controlling these key mediators/cytokines to reduce the inflammatory process and the extent of neuronal death for attenuating the secondary brain damage, without altering their beneficial effects.

Inflammation of the brain after ischemia.

Cytokines which promote emigration of leukocytes from the vascular lumen into the injured brain tissue are produced at the site of incipient cerebral infarction. The blood-borne invaders then accelerate the decomposition of brain cells by their toxic by-products, phagocytic action, and by the immune reaction. Recently accumulated data in our laboratories and other research facilities show that depleting the amount of circulating leukocytes or administering anti-inflammatory chemicals such as cytokine blocking agents, anti-adhesion molecule antibodies, and immunosuppressants effectively minimize the size of ischemia induced cerebral infarction. Based on the fact the leukocyte invasion of the affected brain tissue occurs 6 to 24 hours after onset of ischemia, administration of an anti-inflammatory therapy may widen the therapeutic window against stroke.

Expression of microglial markers in the human CNS after closed head injury.

The loss of neurons after severe closed head injury is not only a consequence of the primary impact but also of secondary damage mechanisms. Among the cell population of the central nervous system microglia is surely a candidate to influence secondary damage mechanisms by releasing cytotoxic cytokines [1]. About microglial reaction in closed traumatic brain injury (TBI), however, no data are available. In contrast to experiments using stab wound injury the covering of the CNS in closed TBI are still intact. We have examined 17 patients who died because of TBI after various times post injury. We studied the expression of antigens which are either permanently present on microglial cells or those which are only facultatively found on activated microglia. Low numbers of microglial cells were shown to express MHC-class II antigens immediately after TBI which is also true for CD 68 and leukocyte common antigen (LCA). Surprisingly, however, antigens such as HAM 56 were expressed not earlier than 72 hours after TBI as well as the lectin ricinus communis agglutinin-1 (RCA-1). The results indicate a delayed activation of microglia in traumatic brain injury.

Birth order and intelligence: an immunological interpretation.

The literature indicates that the IQs and school performance of children tend to decline with increasing order of birth. A hypothesis is here presented that the effect of birth order upon intellectual performance may result from an increasing probability of maternal immune attack upon the fetal brain in utero with order of parity. In support of this hypothesis, evidence is adduced from the literature that the fetal brain is antigenic, that fetal antigens may reach the immune system of the mother, that the incidence of maternal sensitization to fetal antigens increases with parity, that antibodies may readily cross the placenta and reach the fetal brain, that antibodies can be highly teratogenic, and that certain antibodies may damage, in a lasting way, the structure, function, and learning capacity of brains in experimental animals and human infants.

[Involvement of immune mechanism in the progressive brain damage].

No definitive evidence for the participation of the immune system in progressive brain damage has been previously reported. However, glial cells continue to accumulate after degeneration of neurons appears to be completed, and a recent study showed that microglia and leukocytes also accumulate after brain damage. Thus, it seemed possible that immune responses might play a role in the delayed effects. Cyclosporin A (CsA) is a cyclic undecapeptide of fungal origin with a strong immunosuppressive action but low myelotoxicity. We examined the effect of CsA administration on three different kinds of animal models for neurological deficits. Late onset reduction of muscarinic receptors after transient forebrain ischemia in gerbils was prevented by daily post-ischemic administration of CsA. This indicates that an immune mechanism may be involved in the progressive brain damage occurring after transient ischemia. On the other hand, CsA exacerbated iminodipropionitrile-induced dyskinesia both behaviorally and biochemically. CsA also mimicked pentylenetetrazol-induced seizures. These findings suggest that immune mechanisms may play important roles in the progression of brain damage and possibly that immunosuppressants might open a new chapter in the pathophysiology and treatment of chronic progressive neurodegenerative diseases. Further investigations on the immune response in the progressive brain damage are needed.

[Data on a study of the nature of secondary immunodeficient states. I. An immunophysiological analysis of the mechanisms of allergic reaction suppression in experimental lesion of the structures of the dorsal hippocampus]. / Materialy k izucheniiu prirody vtorichnykh immunodefitsitnykh sostoianii. Soob-shchenie I. Immunofiziologicheskii analiz mekhanizmov ugneteniia allergicheskikh reaktsii pri éksperimental'nom porazhenii struktur dorsal'nogo gippokampa.

Experiments on rabbits demonstrated that local electrocoagulation of the dorsal hyppocampus portions by means of the implanted electrodes caused reduction of the complementary and lysozyme activity of the blood serum, inhibited the development of Arthus' skin allergic-reaction, decreased the intensity of systemic anaphylaxis to the blood serum antigens, this being accompanied by a relative fall of the precipitating antibodies titres and a reduction of the vagus response of the heart to adrenaline.