A Study on the Humoral and Complement Immune System of Patients with Organic Acidemia.

Patients with organic acidemia are prone to different infections, which lead to acidosis episodes. Some studies have evaluated the status of immune system in acidotic phase in these patients, but to the best of our knowledge no study has evaluated the immune system in non-acidotic phase of the disease. In this study, thirty-one patients with organic acidemia were enrolled. For evaluation of humoral immunity, serum IgA, IgG, IgE, IgM, isohemaggltuinin titer, anti tetanus and anti diphtheria IgG were measured. For screening of complement deficiencies, serum C3, C4, and CH50 were assessed. Eleven patients had Maple Syrup Urine Disease (MSUD), 10 had methylmalonic acidemia, 5 had isovaleric acidemia, 4 had glutaric aciduria, and 1 had propionic acidemia. Serum IgM level was less than normal in 2 patients. Serum isohemagglutinin titer was less than 1:8 in 2 other patients. IgA, IgE, and IgG were within normal range for all patients. Anti tetanus and anti diphtheria IgG levels were low in two patients with MSUD. No significant relationship was found between any of the measured parameters and history of recurrent admissions, recurrent infections and the type of their diseases. Five patients had high C3 level, 4 had high C4 level, and 5 had high CH50 percentage. Totally, 10 patients had high complement level, but no remarkable connection was noted between the type of the disease and complement level. Minor insignificant deficiencies in humoral immunity in non-acidotic phase of organic acidemia were found. Some components of complement system showed increase in some patients, which might be due to decreased pH in extracellular fluid.

Ghrelin inhibits high glucose-induced PC12 cell apoptosis by regulating TLR4/NF-κB pathway.

Ghrelin has a protective effect on diabetic encephalopathy. To expound the protective mechanism, we investigated the effects of ghrelin on high glucose-induced cell apoptosis and intracellular signaling in cultured PC12, which is a suitable model for studying neuronal cell death. High glucose-induced PC12 apoptosis was significantly inhibited by co-treatment of ghrelin. Sustaining inflammatory response is one of the molecular mechanisms of diabetic encephalopathy and TLR4 signaling has close relationship with inflammatory response. But there is no report about the biologic role of toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) signaling in controlling high glucose-induced PC12 apoptosis by ghrelin. In this study, we found that TLR4/NF-κB pathway was activated by high glucose stimulation in PC12 and significantly alleviated by the co-treatment of ghrelin. From these findings, we made the conclusion that ghrelin could attenuate the symptoms of diabetic encephalopathy, which alleviates inflammatory reaction of diabetic encephalopathy by regulating TLR4/NF-κB pathway.

Hemorrhagic shock and encephalopathy syndrome in a child with pandemic H1N1 2009 influenza virus.

We report a case of hemorrhagic shock and encephalopathy in a child with pandemic 2009 H1N1 influenza infection. The patient succumbed within 3 days of admission.

Severe human herpesvirus 6-associated encephalopathy in three children: analysis of cytokine profiles and the carnitine palmitoyltransferase 2 gene.

Three children developed severe encephalopathy associated with human herpesvirus 6 infection. Magnetic resonance imaging of the brain showed either basal ganglia involvement or diffusion abnormalities in the cerebral white matter. Coagulopathy with hypercytokinemia was observed in 2 patients. One demonstrated thermolabile variation in carnitine palmitoyltransferase 2. These results suggest a heterogeneous pathogenic mechanism in encephalopathy associated with human herpesvirus 6 infection.

Neuropsychiatric disorders related to interferon and interleukins treatment.

Certain cytokines such as interferon-alpha and interleukin-2 are often used in the treatment certain cancers and chronic diseases such as melanoma, hepatitis C infection and multiple sclerosis. Several neuropsychiatric side effects such as depression, anxiety, psychosis, suicidal ideation, hypomanic mood and cognitive impairment were reported in those patients who received those medications. In certain patients with those neuropsychiatric side effects, the symptoms ceased when the medication was stopped. However, in some cases, the cognitive impairment persisted even for years after cessation of the medication. In animal studies, those cytokines could induce sickness behaviour, anxiety behaviour and social anhedonia. The increased in pro-inflammatory cytokines in certain neuropsychiatric disorders was widely reported. In addition, in animal studies, the treatment with interferon-alpha or interleukin-1 could induce depressive like behaviour. Recently, the role of certain pro-inflammatory cytokines that could enhance the activity of the enzyme, indoleamine 2-3, dioxygenase (IDO) which in turn would increase tryptophan degradation into kynurenine and decrease tryptophan availability of tryptophan in the brain to synthesize serotonin, a neurotransmitter which is necessary for the normal mood state became of interest in pathophysiology of psychiatric disorders. Furthermore, the imbalance in the further downward catabolic kynurenine pathway and their interactions with other neurotransmitters has been proposed to play an important role. The presence of such an imbalance in patients being treated with cytokines and in patients with psychiatric disorders and the possible consequence of those changes on the neuroprotective function in the brain are discussed in this review.

Voltage-gated potassium channel autoimmunity mimicking creutzfeldt-jakob disease.

BACKGROUND: Rapidly progressive dementia has a variety of causes, including Creutzfeldt-Jakob disease (CJD) and neuronal voltage-gated potassium channel (VGKC) autoantibody-associated encephalopathy. OBJECTIVE: To describe patients thought initially to have CJD but found subsequently to have immunotherapy-responsive VGKC autoimmunity. DESIGN: Observational, prospective case series. SETTING: Department of Neurology, Mayo Clinic, and the Memory and Aging Center, University of California, San Francisco. Patients A clinical serologic cohort of 15 patients referred for paraneoplastic autoantibody evaluation. Seven patients were evaluated clinically by at least one of us. Clinical information for the remaining patients was obtained by physician interview or medical record review. MAIN OUTCOME MEASURES: Clinical features, magnetic resonance imaging abnormalities, electroencephalographic patterns, cerebrospinal fluid analyses, and responses to immunomodulatory therapy. RESULTS: All the patients presented subacutely with neurologic manifestations, including rapidly progressive dementia, myoclonus, extrapyramidal dysfunction, visual hallucinations, psychiatric disturbance, and seizures; most (60%) satisfied World Health Organization diagnostic criteria for CJD. Magnetic resonance imaging abnormalities included cerebral cortical diffusion-weighted imaging hyperintensities. Electroencephalographic abnormalities included diffuse slowing, frontal intermittent rhythmic delta activity, and focal epileptogenic activity but not periodic sharp wave complexes. Cerebrospinal fluid 14-3-3 protein or neuron-specific enolase levels were elevated in 5 of 8 patients. Hyponatremia was common (60%). Neoplasia was confirmed histologically in 5 patients (33%) and was suspected in another 5. Most patients' conditions (92%) improved after immunomodulatory therapy. CONCLUSIONS: Clinical, radiologic, electrophysiologic, and laboratory findings in VGKC autoantibody-associated encephalopathy may be confused with those of CJD. Serologic evaluation for markers of neurologic autoimmunity, including VGKC autoantibodies, may be warranted in suspected CJD cases.

Juvenile onset central nervous system folate deficiency and rheumatoid arthritis.

Isolated cerebral folate deficiency was detected in a 13-year-old girl with cognitive and motor difficulties and juvenile rheumatoid arthritis. Her serum contains autoantibodies that block membrane-bound folate receptors that are on the choroid plexus and diminish the uptake of folate into the spinal fluid. Whereas her serum folate exceeded 21 ng/mL, her spinal fluid contained 3.2 ng/mL of 5-methyltetrahydrofolate as a consequence of the autoantibodies diminishing the uptake of this folate.

Serum and CSF levels of cytokines in acute encephalopathy following prolonged febrile seizures.

It is well known that an acute encephalopathy occasionally follows prolonged febrile seizures. We measured the concentrations of interferon-gamma, tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), IL-4, IL-6, IL-10, and soluble TNF receptor 1 (sTNFR1) in serum and CSF during the acute stage in 13 children with acute encephalopathy following prolonged febrile seizures (AEPFS) and 23 with prolonged febrile seizures without encephalopathy (PFS) to investigate the pathogenesis of AEPFS. Serum IL-6, IL-10, sTNFR1, and CSF IL-6 levels were significantly higher in AEPFS and PFS compared with control subjects. CSF IL-6 levels in AEPFS were significantly higher than those in PFS, but not serum IL-6, IL-10, or sTNFR1. The CSF IL-6 levels were significantly higher than the serum levels in AEPFS, but not PFS. The serum levels of sTNFR1 and IL-10 were significantly higher than those in the CSF in AEPFS and PFS. The serum IL-10 and sTNFR1 levels in patients who did not experience a second seizure were significantly higher than those in patients who experienced a second seizure, which was characterized by clusters of complex partial seizures several days after the initial prolonged febrile seizure. Our results suggest that serum IL-6, IL-10, TNF-alpha, and CSF IL-6 are part of the regulatory system of cytokines in AEPFS.

Acute encephalopathy associated with influenza and other viral infections.

Acute encephalopathy is the most serious complication of pediatric viral infections, such as influenza and exanthem subitum. It occurs worldwide, but is most prevalent in East Asia, and every year several hundreds of Japanese children are affected by influenza-associated encephalopathy. Mortality has recently declined, but is still high. Many survivors are left with motor and intellectual disabilities, and some with epilepsy. This article reviews various syndromes of acute encephalopathy by classifying them into three major categories. The first group caused by metabolic derangement consists of various inherited metabolic disorders and the classical Reye syndrome. Salicylate is a risk factor of the latter condition. The second group, characterized by a systemic cytokine storm and vasogenic brain edema, includes Reye-like syndrome, hemorrhagic shock and encephalopathy syndrome, and acute necrotizing encephalopathy. Non-steroidal anti-inflammatory drugs, such as diclofenac sodium and mephenamic acid, may aggravate these syndromes. Severe cases are complicated by multiple organ failure and disseminated intravascular coagulation. Mortality is high, although methylprednisolone pulse therapy may be beneficial in some cases. The third group, characterized by localized edema of the cerebral cortex, has recently been termed acute encephalopathy with febrile convulsive status epilepticus, and includes hemiconvulsion-hemiplegia syndrome and acute infantile encephalopathy predominantly affecting the frontal lobes. Theophylline is a risk factor of these syndromes. The pathogenesis is yet to be clarified, but an increasing body of evidence points to excitotoxicity and delayed neuronal death.

Hashimoto encephalopathy responding to risperidone.

This report describes a case of Hashimoto encephalopathy in an 11-year-old girl. She presented with features typical of this disorder including encephalopathy, seizures, and neuropsychiatric symptoms. Diagnosis was supported by an elevated thyroid-stimulating hormone level, a low levo-thyroxine level, and positive results for antithyroperoxidase antibody. Her response to typical treatment with levo-thyroxine was incomplete, requiring additional therapy with valproic acid and methylprednisone. Her course was further complicated by the development of acute psychosis. Treatment with risperidone was correlated with resolution of her psychosis and improvement in neuropsychiatric symptoms. Response to antipsychotic therapy has not previously been described in the pediatric population with Hashimoto encephalopathy. This case highlights the need for guidelines for the management of this rare disorder.

Childhood chorea-encephalopathy associated with human parvovirus B19 infection.

An 8-year-old female presented with a distinct clinical course characterized by an acute self-limiting chorea-encephalopathy with cerebrospinal fluid (CSF)-specific oligoclonal bands. During the clinical course, genomic human parvovirus B19 DNA was detected in her serum and CSF. It was concluded that this patient represents the first published case of childhood chorea-encephalopathy associated with, and probably caused by, human parvovirus B19 infection.

Neuropathological study of the role of mast cells and histamine-positive neurons in selective vulnerability of the thalamus and inferior colliculus in thiamine-deficient encephalopathy.

The purpose of the present study was to examine the role of histamine in the pathogenesis of experimental thiamine-deficient encephalopathy. By studying sagittal serial sections the authors were able to examine the topographical relationship between histamine-positive neurons and fibers, the number of mast cells, and localized lesions in the thalamus (TH) and inferior colliculus (IC). Adult rats were given a thiamine-deficient diet and pyrithiamine was given intraperitoneally (30 microg/100 g bodyweight per day), and the distribution of vulnerable regions and petechial bleeding was histologically examined by reconstruction of the sagittal serial sections. The distribution of mast cells and histamine-positive neurons and fibers was examined immunohistochemically in control rats, and compared between the vulnerable and non-vulnerable regions of the TH and tectum. Changes in the aforementioned measures during the thiamine-deficient state were also examined. The blood-brain barrier was examined using antibodies against rat endothelial barrier antigen (EBA) and albumin. The density of histamine-positive fibers in the vulnerable regions of the TH and IC was very low and not different from the non-vulnerable regions, and the number of mast cells was significantly higher in the lateral portion of the TH than the medial portion of the TH. The numbers of mast cells increased on days 7-10 after the start of the experiment, and significantly decreased on days 14-21. Histamine-positive neurons and fibers in the TH and IC also had the same changes. Bleeding of the IC occurred exclusively around arteries, and perivenous bleeding was absent. Albumin exudation and suppression of EBA expression of capillaries were found in the spongy lesions of the TH and IC. The role of histamine in selective vulnerability of the TH and IC in experimental thiamine-deficient encephalopathy was not supported. Findings in the present study suggest that the spongy change is a primary event, and vascular changes are secondary.

[Hashimoto encephalopathy: steroid-sensitive encephalopathy in Hashimoto thyroiditis]. / Hashimoto-Enzephalopathie. Steroid-sensitive Enzephalopathie bei Hashimoto-Thyreoiditis.

Hashimoto's encephalopathy is a steroid-responsive, relapsing or progressive encephalopathy associated with Hashimoto's thyroiditis. Characteristic clinical features are confusion, seizures, alteration in conscious level, stroke-like episodes, myoclonus, and tremulousness. High CSF protein levels without pleocytosis and a diffusely abnormal EEG are typical findings. Brain CT and MRI and cerebral angiogram are usually normal. We present two case reports of Hashimoto's encephalopathy in 55- and 77-year-old patients who both responded well to steroid therapy, and review the literature.

Serum antibodies to central nervous system antigens: an analysis of their relation with different human neurologic disorders.

In a previous paper we have presented a double ligand enzyme linked immunosorbent assay (ELISA) technique suitable for the detection of human antibodies to different brain antigens. In the present study, we have applied this technique to the analysis of 100 neurologically affected patients with regard to both a list of clinical parameters and the presence in their sera of nervous tissue specific antibodies, in an attempt to highlight the meaning of such antibodies in different neurologic disorder. We show that the presence of these antibodies cannot be used for elucidation of pathogenesis or for diagnostic purposes, but can be used as a prognostic index.