Distinctive clinical presentation and pathogenic specificities of anti-AK5 encephalitis.

Limbic encephalitis with antibodies against adenylate kinase 5 (AK5) has been difficult to characterize because of its rarity. In this study, we identified 10 new cases and reviewed 16 previously reported patients, investigating clinical features, IgG subclasses, human leucocyte antigen and CSF proteomic profiles. Patients with anti-AK5 limbic encephalitis were mostly male (20/26, 76.9%) with a median age of 66 years (range 48-94). The predominant symptom was severe episodic amnesia in all patients, and this was frequently associated with depression (17/25, 68.0%). Weight loss, asthenia and anorexia were also highly characteristic, being present in 11/25 (44.0%) patients. Although epilepsy was always lacking at disease onset, seizures developed later in a subset of patients (4/25, 16.0%). All patients presented CSF abnormalities, such as pleocytosis (18/25, 72.0%), oligoclonal bands (18/25, 72.0%) and increased Tau (11/14, 78.6%). Temporal lobe hyperintensities were almost always present at disease onset (23/26, 88.5%), evolving nearly invariably towards severe atrophy in subsequent MRIs (17/19, 89.5%). This finding was in line with a poor response to immunotherapy, with only 5/25 (20.0%) patients responding. IgG1 was the predominant subclass, being the most frequently detected and the one with the highest titres in nine CSF-serum paired samples. A temporal biopsy from one of our new cases showed massive lymphocytic infiltrates dominated by both CD4+ and CT8+ T cells, intense granzyme B expression and abundant macrophages/microglia. Human leucocyte antigen (HLA) analysis in 11 patients showed a striking association with HLA-B*08:01 [7/11, 63.6%; odds ratio (OR) = 13.4, 95% confidence interval (CI): 3.8-47.4], C*07:01 (8/11, 72.7%; OR = 11.0, 95% CI: 2.9-42.5), DRB1*03:01 (8/11, 72.7%; OR = 14.4, 95% CI: 3.7-55.7), DQB1*02:01 (8/11, 72.7%; OR = 13.5, 95% CI: 3.5-52.0) and DQA1*05:01 (8/11, 72.7%; OR = 14.4, 95% CI: 3.7-55.7) alleles, which formed the extended haplotype B8-C7-DR3-DQ2 in 6/11 (54.5%) patients (OR = 16.5, 95% CI: 4.8-57.1). Finally, we compared the CSF proteomic profile of five anti-AK5 patients with that of 40 control subjects and 10 cases with other more common non-paraneoplastic limbic encephalitis (five with antibodies against leucine-rich glioma inactivated 1 and five against contactin-associated protein-like 2), as well as 10 cases with paraneoplastic neurological syndromes (five with antibodies against Yo and five against Ma2). These comparisons revealed 31 and seven significantly upregulated proteins in anti-AK5 limbic encephalitis, respectively mapping to apoptosis pathways and innate/adaptive immune responses. These findings suggest that the clinical manifestations of anti-AK5 limbic encephalitis result from a distinct T cell-mediated pathogenesis, with major cytotoxicity-induced apoptosis leading to a prompt and aggressive neuronal loss, likely explaining the poor prognosis and response to immunotherapy.

Adenylate kinase 5 autoimmunity in treatment refractory limbic encephalitis.

We report two men with limbic encephalitis (LE) refractory to corticosteroids, IVIg and plasma exchange. Both patients had serum/CSF antibodies that reacted with the cytoplasm of neurons. Probing of a hippocampal cDNA library resulted in the isolation of adenylate kinase 5 (AK5). Patients' antibodies, but not those of 111 controls, recognized AK5-expressing phage plaques. Human AK5-affinity purified antibodies reproduced the neuronal immunolabeling of patients' antibodies, and co-localized with a rabbit AK5 antibody, confirming that the brain autoantigen was AK5. Detection of antibodies to AK5 in LE patients carries a poor prognosis, and suggests the prompt use of aggressive immunosuppression.

The effect of adjuvant steroid treatment on serial cerebrospinal fluid changes in tuberculous meningitis.

Three recent studies found that corticosteroids improve clinical outcome and mortality in tuberculous meningitis (TBM), although the exact mechanism of action of the drug remains speculative. A number of reports on the effect of corticosteroids on cerebrospinal fluid (CSF) findings in TBM have been published, often with conflicting results regarding serial cell counts and protein levels. As part of a controlled, randomized trial on the effect of oral prednisone on outcome in childhood TBM at our institution, CSF was collected and analysed weekly during the 1st month of treatment. We found no significant difference in serial CSF cell counts between the steroid and non-steroid groups in the study. However, the steroid group had significantly lower CSF protein and globulin levels after the 1st month of treatment, and a more steady rise in CSF glucose levels than the non-steroid group. Knowledge of the different CSF responses during the course of anti-tuberculosis therapy is important in clinical decision-making.

[Brain damage caused by hypotensive anesthesia? Both the anesthetic technique and the anesthetic agent must be chosen with care]. / Cerebrala skador av hypotensionsnarkos? Anestesiteknik och narkosmedel måste väljas med omsorg.

During the fifty years since hypotensive anaesthesia, induced hypotension to minimise intraoperative blood loss, became an established routine, there have been few reports of associated cerebral complications. However, evidence of disturbed cerebral function among patients undergoing orthognathic surgery under induced hypotension was obtained in a recent study where the level of adenylate kinase activity in cerebrospinal fluid was used as a highly sensitive biochemical marker of brain cell injury. Moreover, psychometric tests revealed persistent postoperative mental deterioration. The underlying cause of brain cell injury seems to be complex, and as in all likelihood it is not hypotension per se that is responsible, the effect of the anaesthetic agents used (isoflurane and propofol) has to be considered. It was also noted that hypotension did not improve the clinical outcome of orthognathic surgery, as compared with comparable operations performed under normotension.

Evidence of cerebral dysfunction associated with isoflurane- or propofol based anaesthesia for orthognathic surgery, as assessed by biochemical and neuropsychological methods.

A relationship has previously been described between individual mean isoflurane concentrations and the release of a marker of neuronal injury, adenylate kinase (AK), into the cerebrospinal fluid (CSF) after anaesthesia and orthognathic surgery. Likewise, reduced mental performance has been detected. Twenty-nine patients scheduled for orthognathic surgery were assigned to isoflurane- or propofol based anaesthesia, which was adjusted to a defined level with the aid of processed EEG and quantitative surface EMG. In the case of a mean arterial pressure (MAP) < 50 mmHg a phenylephrine infusion was started to keep the MAP above the minimal level, otherwise no regard was paid to the blood pressure, which never exceeded normal values. A lumbar puncture for CSF sampling was performed approximately 20 h postoperatively. The CSF sample was analysed for AK activity. Neuropsychological tests were performed the day prior to surgery and again in the period 4-8 weeks postoperatively. Five patients were re-examined by psychometry 12-30 months later. A release of AK into CSF was confirmed, equal in both groups. Correlation with the anaesthetic dose given was poor. Five patients from each group failed significantly in the postoperative neuropsychological tests. They differed in several demographic respects from the others. When five of the failed patients were re-examined 12-30 months later, three patients still performed poorly in the tests. Biochemical and neuropsychological disturbances were recorded in several patients objected to orthognathic surgery. The underlying mechanisms are unclear, including the role of the anaesthetic drugs or surgery itself.

Low frequency of adenylate kinase release into cerebrospinal fluid during balanced, normotensive anaesthesia and a non-orthognathic surgical procedure.

Activity of strictly intracellular enzymes in the cerebrospinal fluid (CSF) may indicate leakage from dysfunctional brain cells. Increased activity of adenylate kinase (AK) in the CSF is indicative of brain cell injury arising from several sources, among them orthognathic surgery. The mechanism in the latter case is obscure, but the use of an oscillating saw which generates vibrations, and the site of surgery close to the brain may be contributing factors. Anaesthesia may also play a role. In the present study, CSF-AK activity was measured after hysterectomy and was compared with activity after orthognathic surgery in two other studies. Four of 19 patients (21%) in the present study expressed pathological activity, compared with 34 of 47 (72%) orthognathic patients in the two other studies. No firm conclusion may be drawn from historical comparisons, and the difference in activity seen between the two types of surgery might not necessarily be the result of surgical factors. Until this is investigated further, however, we conclude that there may be a difference in postoperative CSF-AK activity between orthognathic and lower abdominal surgery.

Adenylate kinase activity in the cerebrospinal fluid of children with tuberculous meningitis and its relationship to neurological outcome.

Cerebrospinal fluid (CSF) adenylate kinase activity was determined in 88 children (mean age 32.6 months) at stage II (n = 40) and stage III (n = 48) tuberculous meningitis (TBM) at, or shortly after, the initiation of treatment, and at weekly intervals thereafter for the first month of treatment, and in 60 children (mean age 40 months) investigated for, but later considered not to have meningitis. CSF adenylate kinase activity in this latter group ranged from 0 to 1.27 u/l (mean 0.59 u/l). Mean CSF adenylate kinase activity during the first week of therapy in children at stage II TBM (2.95 u/l; range 0-9.22 u/l) differed significantly (p = 0.03) from that in children at stage III TBM (5.62 u/l; range 0-18.93 u/l). CSF adenylate kinase activity did not differ between children at stage II and stage III TBM during any of the 3 subsequent weeks. CSF adenylate kinase activity was not related to CSF cell count, total protein or glucose concentration or intracranial pressure at any point during the first month of treatment, but was related to CSF lactate during the first week of therapy (p = 0.001). Consecutive determinations of CSF adenylate kinase activity were available in 34 children. Although CSF adenylate kinase activity tended to increase or decrease in keeping with changes in clinical condition this was not always the case. The close relationship of CSF adenylate kinase activity and lactate concentrations suggests that adenylate kinase activity reflects hypoxic cerebral metabolism and it was unusual for children with increased CSF adenylate kinase activity at the time of diagnosis to be clinically normal on completion of 6 months of antituberculosis treatment. Any treatment modality which significantly reduced CSF adenylate kinase activity in children early in the course of TBM would probably be of clinical benefit to the patients.

MR and cerebrospinal fluid enzymes as sensitive indicators of subclinical cerebral injury after open-heart valve replacement surgery.

PURPOSE: To evaluate MR imaging and lumbar cerebrospinal fluid enzymes as potential sensitive indicators of cerebral injury after open-heart valve replacement surgery. METHODS: Thirty-four patients with cardiac valvular disease were prospectively entered into this study and then underwent valve replacement or repair under cardiopulmonary bypass using a membrane oxygenator. In 26 patients, MR head images were obtained 12 to 24 hours before surgery; repeat MR images were obtained between 1 and 2 weeks after surgery. In 18 patients, lumbar puncture cerebrospinal fluid was analyzed 24 to 48 hours after surgery; the analyses included measurement of lactic dehydrogenase, creatine phosphokinase, adenylate kinase, and neuron-specific enolase. RESULTS: After surgery, MR imaging showed new ischemic lesions in 15 (58%) of 26 patients: 7 with deep white matter hyperintense lesions; 5 with brain stem, caudate, cerebellar, or thalamic/basal ganglia infarcts; 1 with intraparenchymal hemorrhage; 1 with a subdural hematoma and cortical infarct; and 1 with a corpus callosum lesion consistent with calcium or air. These new ischemic lesions seen on MR images were associated with a focal neurologic deficit in only 4 (27%) of the 15 patients. Neuron-specific enolase and lactic dehydrogenase were abnormally elevated after surgery in 5 (28%) of 18 patients. Adenylate kinase and creatine phosphokinase (brain isozymes) were elevated in one (67%) of the patients. Two (40%) of the five patients with abnormally high neuron-specific enolase or lactic dehydrogenase after surgery also showed a new focal neurologic deficit. CONCLUSIONS: MR imaging is a sensitive measure of subclinical cerebral ischemia after cardiac valve replacement under cardiopulmonary bypass. Cerebrospinal fluid neuron-specific enolase and lactic dehydrogenase are less sensitive than MR imaging for detecting subclinical cerebral ischemia, but these values were elevated after surgery more frequently than was adenylate kinase in our patients.

Occurrence of adenylate kinase in cerebrospinal fluid after isoflurane anaesthesia and orthognathic surgery.

UNLABELLED: The study objective was, firstly, to investigate whether anaesthesia with induced arterial hypotension would cause leakage of a biochemical marker of neuronal injury, adenylate kinase (AK), into the cerebrospinal fluid (CSF). ( DEFINITION: arterial hypotension = mean arterial pressure (MAP) 50-65 mmHg during > or = 10 min). Secondly, a subgroup of patients was examined with a limited battery of psychometric tests. Patients, scheduled for orthognathic surgery, were allocated to either hypotension (n = 20) or normotension (n = 20). Seventeen patients were subjected to psychometry. Arterial blood pressure was recorded continuously and controlled by adjustments of the administered concentration of the inhalational anaesthetic isoflurane. Fentanyl, an opioid, was given equally in both groups. A lumbar puncture was performed approximately 20 h post-operatively for a CSF sample, later analysed for AK activity. Neuropsychological tests were performed the day before surgery and the fourteenth day postoperatively. The CSF-AK value was pathologically increased ( > 0.040 U/L) in 24 patients (65%), of whom 9 were normotensive. There was no significant difference between the CSF-AK values in the hypotensive and normotensive groups, mean values were 0.082 (s.d. 0.051) and 0.066 (s.d. 0.059) U/L, respectively. The overall correlation between the 10 min MAP levels and the CSF-AK values was close to zero. In the pilot neuropsychological investigation some abnormalities were observed, indicating clinically significant adverse effects in four hypotensive patients, of whom two displayed pathologically increased CSF-AK values. At the group level, the correlation between the changes in psychometry and the measured CSF-AK values was poor. Increases in CSF-AK activities may be a non-specific occurrence in the perioperative interval, possibly indicating an adverse effect on the brain. Arterial hypotension could not be proven to explain the CSF-AK outcome.

Case report: psychosis associated with hepatitis B.

An acute disintegrative disorder in a child with acute hepatitis B virus (HBV) infection is described. Both hepatitis B surface antigen (HBsAg) and HBV-DNA were detected in cerebrospinal fluid (CSF) by means of enzyme-linked immunosorbent assay (ELISA) and the polymerase chain reaction (PCR) technique respectively. A markedly elevated level of CSF adenylate kinase (AK), which normalised as the patient recovered spontaneously, suggested an organic brain disorder. Demonstration of intra-blood-brain barrier production of IgG supported the possibility of local infection by HBV within the central nervous system.

Adverse effects on the brain in connection with isoflurane-induced hypotensive anaesthesia.

As a marker of brain cell injury, adenylate kinase (AK) was measured in cerebrospinal fluid (CSF) in 10 patients given anaesthesia with isoflurane-induced hypotension for corrective surgery of dentofacial deformities. Nine out of 10 patients displayed a marked increase in CSF-AK postoperatively compared with preoperative values. The postoperative mean value displayed a 400% increase compared to the corresponding preoperative value. This difference was statistically significant (P = 0.001). The rise in CSF-AK was most probably the result of an enhanced efflux of AK into CSF subsequent to a presumed hypoxic injury to brain cells.

Adenylate kinase activity in the cerebrospinal fluid of hypoxic newborns.

Adenylate kinase (AK) activity in the cerebrospinal fluid (CSF), described as a marker of brain edema and lesions in adults, was studied in 79 newborns with severe respiratory distress within 24 h after admission to the Intensive Care Unit (ICU). The CSF-AK activity was compared with CSF lactate concentration, CSF lactate dehydrogenase activity (LDH), and CSF and serum creatine kinase isoenzyme BB (CK-BB) activity. Newborns were divided into Group I with moderate to severe brain dysfunction and Group II with mild or no detectable brain dysfunction on discharge from the ICU. Mean CSF-AK activity (11.31 U/L) in Group I was significantly (p less than 0.001) higher than in Group II (2.82 U/L). Correlation between CSF-AK and CSF lactate was r = 0.714, p less than 0.01 and between CSF-AK activity and CSF-LDH activity was r = 0.550, p less than 0.01 in Group I. Preliminary data indicate that CSF-AK activity within 24 h after ischaemia is an indicator of hypoxic brain lesions in newborns. Its prognostic value for the infant's development remains to be determined by further study.

Adenylate kinase enzyme activity in cases of brain infarction.

The adenylate kinase (AK) enzyme activity in plasma and CSF of acute brain infarctions was examined. The normal values of enzyme activity in plasma reached from 1.7-5.6 U/l, and in CSF from 0.23-0.71 U/l. According to this present classification a significant CSF increase in AK activity was found with semi-severe and severe brain infarctions. With the CCT an increased enzyme activity was shown with infarction in or close to the cortex. In no case was an alteration of AK activity in the serum sample. CSF samples showing blood contamination or pleocytosis led to false pathological results with examination of AK activity.

Reversible brain cell damage due to hypoglycemia in a patient with insulinoma.

A case of an insulinoma with hypoglycemic attacks accompanied by episodes of unconsciousness in a 57-year-old woman is described. During the hypoglycemic spells the level of adenylate kinase (AK) in the cerebrospinal fluid (CSF) was elevated 6-fold above the normalized level obtained later from the patient being in a normoglycemic condition. CSF-AK was previously found to be a sensitive marker of subtle brain cell damage due to hypoxia. The increased efflux of AK into CSF during the insulinoma-induced hypoglycemia was most probably the result of a brain cell injury caused by shortage of glycolytic fuel.

Nitrous oxide and cerebrospinal fluid markers of ischaemia following cardiopulmonary bypass.

Twenty patients with good ventricular function undergoing coronary artery bypass surgery were studied to determine whether the pre-bypass use of nitrous oxide resulted in any differences in cerebrospinal fluid markers indicative of cerebral ischaemia. All patients were anaesthetised with diazepam, fentanyl and pancuronium, after which ten patients received 50-60% nitrous oxide in oxygen until commencement of bypass, and the remaining patients 100% oxygen. Because of the known effect of nitrous oxide in expanding gaseous bubbles, any neurological dysfunction of gaseous microembolic origin may be worsened in the presence of nitrous oxide. Patients were lumbar punctured 24 hours after cardiopulmonary bypass and cerebrospinal fluid analysed for the following markers of central nervous system ischaemia: creatine kinase, lactate, total protein, noradrenaline, adrenaline and adenylate kinase. There was a statistically significant difference in cerebrospinal fluid lactate between the two groups. There were no statistically significant differences in the other cerebrospinal fluid markers of ischaemia.

Prediction of outcome after cardiac arrest.

Neurologic outcome of hypoxic ischemic coma after cardiac arrest was studied in 32 patients. Observations were made and samples collected 24 and 48 h after the ischemic insult. The Glasgow-Pittsburgh coma score was assessed for its prognostic value. Other variables studied were the EEG and adenylate kinase, lactate and glutathione in the cerebrospinal fluid (CSF). Outcome was termed good if the patients resumed an independent life within a 6-month follow-up period. The closest correlations between prediction and good outcome occurred with the Glasgow-Pittsburgh coma score (94%) and the EEG (77%) at the 48-h examination, a modified coma score (96%) at 48 h, and CSF lactate (78%) at 24 h. Some simple neurologic signs (e.g., no withdrawal response to pain) at stated points in time was 100% associated with a bad outcome, although their absence was not associated necessarily with a good prognosis.

Cerebral damage during open-heart surgery. Clinical, psychometric, biochemical and CT data.

The incidence and extent of cerebral damage following open-heart surgery were prospectively investigated in 103 patients, using clinical assessment, psychometry, adenylate kinase analysis in cerebrospinal fluid (CSF-AK) and computed tomography (CT) of the brain. The surgical mortality was 1.9%. Clinically there was obvious cerebral dysfunction in four cases, subtle evidence of brain damage (mainly undue fatigue) in 16 and no evidence in 81 cases. In the 16 patients the mean CSF-AK was substantially increased (0.122 U/l) and the psychometric performance distinctly impaired (-12 points) postoperatively; in the 81 patients the figures were 0.55 U/l and -3.4. Psychometrically, 60% of the patients showed cerebral dysfunction, which was pronounced in 16%. CSF-AK analysis indicated cerebral damage as absent or trival in 45%, moderate in 33% and marked in 22%. CT revealed postoperative cerebral infarction in two cases. Results from the various methods showed reasonable correlation, but also considerable overlap. Open-heart surgery thus can cause brain damage additional to that neurologically discernible. Fatigue is an important sign in this context. In research on postoperative brain damage, the relative insensitivity of routine neurologic investigation calls for supplementary, refined methods.

Pathophysiology of cerebrospinal fluid in head injury: Part 2. Biochemical markers for central nervous system trauma.

Many substances are released into the cerebrospinal fluid after head injury. The study of these substances and their relationship to the severity and outcome of head trauma has lead to the search for biochemical markers to aid in the quantification of the severity of the lesion and serve as a prognostic guide. The authors review the potential usefulness of biochemical markers, qualities of an ideal marker, and several potential enzymes that may be utilized as markers in central nervous system trauma.