Fulminant thymomatous AMPAR-antibody limbic encephalitis with hypertonic coma, bruxism, an isoelectric electroencephalogram and temporal cortical atrophy, with recovery.

Autoimmune encephalitides are a potentially devastating group of treatable disorders with a wide variety of clinical presentations. The most studied autoimmune encephalitis is caused by antibodies to the N-methyl-D-aspartate glutamate receptor. A rarer cause is due to antibodies against the evolutionarily related α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). The full assortment of electroencephalogram (EEG) and clinical descriptions of the latter are yet to be fully described. A 44-year-old woman with impaired consciousness and subsequent coma characterised by an isoelectric EEG was diagnosed with AMPAR-antibody limbic encephalitis. MRI revealed temporal T2 hyperintensities that improved with immunosuppression, although leaving marked cortical atrophy. Gradual clinical improvement saw the development of aggressive bruxism requiring botulinum toxin injection with eventual meaningful clinical recovery. This case expands the clinical spectrum of AMPAR limbic encephalitis to include aggressive bruxism, and highlights that despite poor clinical and EEG findings at the outset, recovery is still possible.

The impact of lymphopenia on delirium in ICU patients.

BACKGROUND: Immunosuppressed states may predispose patients to development of acute brain injury during times of critical illness. Lymphopenia is a non-specific yet commonly used bedside marker of immunosuppressed states. METHODS: We examined whether lymphopenia would predict development of acute brain dysfunction (delirium and/or coma) in 518 patients enrolled in the Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU Survivors (BRAIN-ICU) study in medical and surgical ICUs of a tertiary care, university-based medical center. Utilizing proportional odds logistic regression and Cox proportional hazards survival analysis, we assessed the relationship between pre-enrollment lymphocytes and subsequent cognitive outcomes including delirium- and coma-free days (DCFDs) and 30-day mortality. RESULTS: There were no statistically significant associations between lymphocytes and DCFDs (p = 0.17); additionally, the relationship between lymphocytes and mortality was not statistically significant (p = 0.71). Among 259 patients without history of cancer or diabetes, there was no statistically significant association between lymphocytes and DCFDs (p = 0.07). CONCLUSION: lymphopenia, a commonly used bedside marker of immunosuppression, does not appear to be a marker of risk for acute brain injury (delirium/coma) or 30-day mortality in general medical/surgical ICU patients.

The effects of immunologic brainstem encephalopathy on cognitive function following awakening from a progressive autoimmune coma.

We describe a unique patient who experienced a progressive autoimmune coma from age 14 to 17. The patient awoke after treatment with immunosuppressant medication. Although alertness, verbalization, and mobilization markedly improved, the patient reported persistent cognitive difficulties. Neuropsychological assessment from age 21 showed impairments in selective attention, distractibility, and memory. Conversely, higher-order executive functions were preserved. Electrophysiological analysis also identified abnormal neural signatures of selective attention. Eighteen months after the neuropsychological assessment, voxel-based morphometry revealed reduced white matter in the medulla compared to controls. The findings are discussed in terms of the impact of brainstem encephalopathy on cognitive mechanisms.

Stage progression and neurological symptoms in Trypanosoma brucei rhodesiense sleeping sickness: role of the CNS inflammatory response.

BACKGROUND: Human African trypanosomiasis progresses from an early (hemolymphatic) stage, through CNS invasion to the late (meningoencephalitic) stage. In experimental infections disease progression is associated with neuroinflammatory responses and neurological symptoms, but this concept requires evaluation in African trypanosomiasis patients, where correct diagnosis of the disease stage is of critical therapeutic importance. METHODOLOGY/PRINCIPAL FINDINGS: This was a retrospective study on a cohort of 115 T.b.rhodesiense HAT patients recruited in Eastern Uganda. Paired plasma and CSF samples allowed the measurement of peripheral and CNS immunoglobulin and of CSF cytokine synthesis. Cytokine and immunoglobulin expression were evaluated in relation to disease duration, stage progression and neurological symptoms. Neurological symptoms were not related to stage progression (with the exception of moderate coma). Increases in CNS immunoglobulin, IL-10 and TNF-α synthesis were associated with stage progression and were mirrored by a reduction in TGF-ß levels in the CSF. There were no significant associations between CNS immunoglobulin and cytokine production and neurological signs of disease with the exception of moderate coma cases. Within the study group we identified diagnostically early stage cases with no CSF pleocytosis but intrathecal immunoglobulin synthesis and diagnostically late stage cases with marginal CSF pleocytosis and no detectable trypanosomes in the CSF. CONCLUSIONS: Our results demonstrate that there is not a direct linkage between stage progression, neurological signs of infection and neuroinflammatory responses in rhodesiense HAT. Neurological signs are observed in both early and late stages, and while intrathecal immunoglobulin synthesis is associated with neurological signs, these are also observed in cases lacking a CNS inflammatory response. While there is an increase in inflammatory cytokine production with stage progression, this is paralleled by increases in CSF IL-10. As stage diagnostics, the CSF immunoglobulins and cytokines studied do not have sufficient sensitivity to be of clinical value.

Acute hemorrhagic leukoencephalitis with atypical features.

Acute hemorrhagic leukoencephalitis (AHL) is a rare demyelinating disease mainly affecting children, characterized by acute onset, progressive course and high mortality. A 62-year-old man was admitted to our Unit for diplopia and ataxia ensuing 2 weeks after the onset of pneumonia. MRI T2-weighted images showed signal hyperintensities in the brainstem. Antibodies against Mycoplasma Pneumoniae and cold agglutinins were found. Two weeks later the patient had a worsening of his conditions: he developed left hemiplegia with motor focal seizures and the day after he was deeply comatose (GCS = 4). A second MRI scan showed extensive hyperintensities involving the whole right hemisphere white matter with a small parietal hemorrhagic area. The clinical and neuroimaging features suggested the diagnosis of AHL, Aciclovir in association with steroid therapy were administered and then plasmapheresis was started. After 30 days of coma, the patient gradually reacquired consciousness and motor functions; anyway a left hemiplegia persisted.

Spatially and genetically distinct African Trypanosome virulence variants defined by host interferon-gamma response.

We describe 2 spatially distinct foci of human African trypanosomiasis in eastern Uganda. The Tororo and Soroti foci of Trypanosoma brucei rhodesiense infection were genetically distinct as characterized by 6 microsatellite and 1 minisatellite polymorphic markers and were characterized by differences in disease progression and host-immune response. In particular, infections with the Tororo genotype exhibited an increased frequency of progression to and severity of the meningoencephalitic stage and higher plasma interferon (IFN)- gamma concentration, compared with those with the Soroti genotype. We propose that the magnitude of the systemic IFN- gamma response determines the time at which infected individuals develop central nervous system infection and that this is consistent with the recently described role of IFN- gamma in facilitating blood-brain barrier transmigration of trypanosomes in an experimental model of infection. The identification of trypanosome isolates with differing disease progression phenotypes provides the first field-based genetic evidence for virulence variants in T. brucei rhodesiense.

IgE antibodies to Plasmodium falciparum and severity of malaria in children of one ethnic group living in Burkina Faso.

Plasmodium falciparum malaria infection induces elevated blood levels of both total immunoglobulin and anti-plasmodial antibodies belonging to different isotypes. We have previously shown that donors living in areas of malaria transmission develop malaria-specific IgE antibodies that are present at highest concentrations in patients with severe disease, suggesting a role for this isotype in malaria pathogenesis. To establish the possible importance of IgE in the course and severity of this disease, we have analyzed a large and homogenous group of African children (age range = 6 months to 15 years) belonging to one ethnic group (Mossi) living in identical epidemiologic conditions in the same urban area (Ougadougo) of Burkina Faso. While IgG antibodies to P. falciparum increased to high concentrations in very young children and then remained at these levels in older patients, IgE antibodies increased with age, becoming most significantly elevated in children more than four years of age. In older children, those with severe malaria had significantly higher IgE antibody levels than those with non-severe disease. No significant differences between the patient groups were seen for IgG antibodies to P. falciparum. However, when the patients with severe malaria were divided into two groups distinguished by the presence of absence of coma, both IgG and IgE antibodies against malaria were lower in the comatous patients than in the non-comatous patients. The results support the conclusion that IgE antibodies against malaria, regardless of their possible protectivity, also contribute to disease severity in this large and homogenous group of African children.

Early immunological defects in comatose patients after acute brain injury.

OBJECT: The aim of this prospective study was to evaluate the phagocytic, humoral, and cellular arms of the immune system in comatose patients shortly after severe brain injury and to compare the findings with those reported earlier in patients in a persistent vegetative state. The study was conducted in intensive care units and immunology laboratories of university-affiliated hospitals in central Israel. METHODS: The study group consisted of 14 men aged 16 to 65 years who were comatose as a result of acute brain injury due to mechanical trauma. All were studied within 72 hours of injury. Brain damage was severe in all cases (Glasgow Coma Scale score < 8). Healthy age- and sex-matched volunteers served as simultaneous controls. Infections arose in nine (75%) of the 12 patients in whom data were available; the cumulative mortality rate was 38% (five of 13 patients in whom outcome data were available). Every patient exhibited one or more defects in at least one arm of the immune system. Significant deficiencies were noted in neutrophil superoxide release, immunoglobulin (Ig)G, IgG1, IgM, C1q, C2, properdin, alternate C pathway, T cells, T helper cells, T suppressor cells, and natural killer cells. In an earlier series of patients examined by the authors months after the primary insult, these impairments were absent in most of the patients in the vegetative state. CONCLUSIONS: Significant deficiencies of the immune system, particularly the cellular arm, are precipitated by severe brain injury within 72 hours of the event. These impairments probably play a role in the high rate of complicating infections and multiple organ failure. Together with earlier findings, the results of this study indicate that if brain-injured patients survive these hazards, their immune system will eventually recover.

Barbiturate coma may promote reversible bone marrow suppression in patients with severe isolated traumatic brain injury.

OBJECTIVES: Barbiturate coma is employed in brain-injured patients whenever increases in intracranial pressure remain unresponsive to less aggressive therapeutic regimens. Barbiturate-mediated neuroprotection, however, is weakened by an increased infection rate related to barbiturate-induced immunosuppression. Co-administration of barbiturates with antibiotics known to induce bone marrow suppression could, in turn, potentiate barbiturate-mediated immunosuppression. Adverse drug reactions and interactions of thiopental with antibiotics in terms of leukopenia, infection rate, and bone marrow suppression were investigated. METHODS: White blood cells were measured daily, tracheobronchial secretion and urine were examined for bacterial growth twice a week or if an infection was suspected. RESULTS: A total of 52 patients with severe isolated head injury were consecutively investigated. Due to increased intracranial pressure (ICP), which did not respond to analgosedation, barbiturate coma was performed in 23 cases. The other 29 patients remained analgosedated. Leukocytes and neutrophils were reversibly and significantly decreased in all patients, mostly sustained under thiopental. The pulmonary infection rate due to gram-negative organisms was nearly doubled during barbiturate coma. Reversible agranulocytosis and bone marrow suppression attributed to antibiotics developed in six patients after thiopental administration. Mortality rate, however, was not increased by these adverse effects. CONCLUSIONS: Barbiturate coma may cause reversible leukopenia and an increased infection rate. Long-term administration of thiopental may also promote reversible antibiotic-induced bone marrow suppression. The mechanisms and site of interaction between thiopental and antibiotics cannot be assessed by the present study and remain to be clarified. However, during and after barbiturate coma, close monitoring of leukocytes and infections and careful selection of antibiotics is required.

[Susceptibility to neuro-malaria and HLA-DR alleles in Senegal]. / Susceptibilité au neuropaludisme et allèles HLA-DR au Sénégal.

A prospective study was carried out in 46 patients suffering from severe malaria. The control group included 220 persons of which the HLA-DR distribution was known. The HLA-DRB1 alleles were typed by PCR-SSP (Sequence Specific Primers). The most frequent HLA-DR alleles found in patients group were: DR52 (82.8%), DR13 (57.1%), DR10 (28.6%), DR53 (25.7%), DR3 (20%), DR18 (20%). A significant difference was observed between patients with severe malaria and control group for the following alleles: DR3, DR10, DR13 (p < 0.001; Chi square with Yates' correction) and their relative risk were respectively 14.67; 6.29; 2.84. HLA-DR3 was considered as the major marker associated to severe malaria.

Cerebrospinal fluid levels of biopterin, nitric oxide metabolites, and immune activation markers and the clinical course of human cerebral malaria.

Cerebrospinal fluid samples from 130 children who presented with cerebral malaria were investigated to elucidate the impact of biopterin production, NO formation, and local immune activation on the clinical course of this disease. Biopterin levels were significantly lower in patients who were in a deeper coma (P = .02). Cerebrospinal fluid concentrations of NO were significantly higher in children who died than in survivors (P = .037); however, this was not the case for macrophage activation markers, neopterin, and soluble tumor necrosis factor receptor p75 (sTNFR-75). Biopterin, neopterin, and sTNFR-75 but not NO concentrations were significantly related to each other. Low biopterin levels in deep coma are compatible with an impaired local Th1 response, but the low levels could also be due to the scavenging of radicals or to decreased neurotransmitter synthesis. Local production of NO, most likely by nonimmune mechanisms, may be detrimental in cerebral malaria; however, this appears not to be the case for local Th1-mediated immune pathways.

Human cerebral malaria: characterization of malarial antibodies in cerebrospinal fluid.

Anti-malarial antibodies were quantified in cerebrospinal fluid (CSF) of 17 cases of cerebral malaria, 16 presumptive cases (no demonstrable parasitaemia in peripheral blood but responding to i.v. quinine therapy) of cerebral malaria, and 15 controls. A schizont-enriched Plasmodium knowlesi antigen was used in an ELISA. Anti-malarial antibodies of IgA and IgM isotypes were not detectable in most of the CSF samples analysed, although serum antibody titres were high. However, 88% of CSF from cerebral malaria and 56% of presumptive cerebral malaria cases had significant levels of IgG anti-malarial antibodies in comparison to control CSF. The antibody levels did not correlate with the severity of coma but correlated well with the duration of coma. The CSF malarial antibody titres were independent of degree of parasitaemia. The possible role of CSF anti-malarial antibodies in cerebral malaria in the light of recent demonstrations of intrathecal synthesis of immunoglobulins and deposition of immune complex in cerebral tissues is discussed.

Alterations in immune competence in outcome of coma following severe head trauma.

The homeostasis established by the interaction among the central nervous system, the immune system and the endocrine system, is radically altered by prolonged comatose state following severe head trauma. This must be taken into account when deciding on therapy and rehabilitation. In a group of post-comatose patients, we studied peripheral lymphocyte subpopulations, defined by monoclonal antibodies, and delayed hypersensitivity. Our findings are indicative of an immunological impairment originating at glioneuronal level, following head trauma. Such a temporary immune deficiency may in turn affect the equilibrium between the reconstitution of the blood-brain barrier and neuronal repair activity.

Human cerebral malaria: association with erythrocyte rosetting and lack of anti-rosetting antibodies.

Plasmodium falciparum isolates from 24 Gambian children with cerebral malaria and 57 children with mild forms of the disease were assessed for their ability to form erythrocyte rosettes. All isolates from the children with cerebral malaria were able to form rosettes, whereas those from children with mild forms of the disease did not form rosettes, or had a significantly lower rosetting rate. Plasma of children with cerebral malaria lacked anti-rosetting activity, whereas plasma of children with mild disease could often disrupt rosettes in vitro. A monoclonal antibody to P falciparum histidine rich protein (PfHRP1/KP/KAHRP) disrupted rosettes of many of the isolates in vitro indicating that the rosetting ligand is relatively conserved compared with ligands associated with endothelial cytoadherence. The findings strongly support the hypothesis that erythrocyte rosetting contributes to the pathogenesis of cerebral malaria and suggest that anti-rosetting antibodies protect against cerebral disease.

[Specific brain antigens--an index of the permeability of the hemato-encephalic barrier in comatose states in children]. / Spetsificheskie antigeny mozga--pokazatel' pronitsaemosti gematoéntsefalicheskogo bar'era pri komatoznykh sostoianiiakh u detei.

In 39 children with coma caused by infectious toxicosis, purulent meningoencephalitis and closed head trauma the brain-specific antigens (L1M and L2M globulins) contents were studied in the blood serum and cerebrospinal fluid (CSF). On days 3 to 5 after the head trauma L1M and L2M were found irregularly. In meningoencephalitis L1M and L2M were detected with a lesser delay. In infectious toxicosis L1M and L2M appeared in blood serum and CSF regularly and early. The data suggest that appearance of brain-specific antigens in blood and CSF in coma reflect a rise in the blood-brain barrier permeability to CSF-blood transport.