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.

Cerebrospinal fluid markers of disturbed brain cell metabolism.

Reversibly and irreversibly disturbed brain cell metabolism may be monitored in an indirect way by the analyses of enzymes in the CSF according to the hypothesis of cell swelling induced by energy shortage. Adenylate kinase fulfils the criteria for an ideal CSF marker with the exception that it is not organspecific, which necessitates precautions to avoid influence of AK in erythrocytes and serum. When taking such limitating factors into account, AK determinations may be diagnostically useful in combination with radiological and clinical observations. Besides, it is possible that a combination of AK analyses and clinical signs are useful in the prognostication in individual patients suffering from global cerebral ischemia and cerebral infarction.

Adverse effects on the brain in cardiac operations as assessed by biochemical, psychometric, and radiologic methods.

In order to describe subclinical brain injury in conjunction with cardiac operations 94 patients were prospectively studied with three brain injury assessment methods: CSF analyses 24 hours after bypass, psychometry, and computed tomography of the brain. Adenylate kinase (AK), a marker of ischemic brain cell injury, was measured in cerebrospinal fluid (CSF) and in serum. In 13% of the patients, a considerable increase in CSF-AK was seen, in 46% there was a moderate increase, and in 41% no or trivial increase. Psychometry measured as change between preoperative scores in a test battery (SS3) revealed a moderate decrease in intellectual function after operation. There was a significant inverse correlation between CSF-AK and SS3 (r = -0.46, p less than 0.001, r2 = 0.21, n = 71). Computed tomography (CT) of the brain was performed preoperatively and postoperatively in 54 patients. Two of these had cerebral infarctions visible on the CT, despite an essentially normal postoperative state. There was no correlation between indices of brain injury and patient diagnosis and length of perfusion. It is concluded that subclinical brain injury is often seen after cardiac operations. Most often the injury appears trivial and/or reversible, but in a minority of cases there is evidence that the brain injury is irreversible. Factor analysis favors the view that the microembolism theory might no longer be a valid concept in modern cardiopulmonary bypass (CPB). Instead, circumstances in the operative field seem more likely to be important causative factors. This interpretation calls for new principles in the search for an improved cerebral protection during cardiac operations.

Hypotension induced by prostacyclin treatment during cardiopulmonary bypass does not increase the risk of cerebral complications.

High-dose prostacyclin treatment during cardiopulmonary bypass reduces platelet activation and possibly postoperative blood loss. A side-effect is arterial hypotension. We studied the incidence of cerebral complications in 79 patients requiring coronary bypass. Only patients without known cerebrovascular disease were studied. Thirty-nine patients received prostacyclin 50 ng/kg/min during cardiopulmonary bypass and 40 patients served as controls. Mean arterial blood pressure in the group given prostacyclin was below 30 mm Hg during the first 30 minutes of bypass but remained above 60 mm Hg in the control group. Postoperative neurological examination revealed transient cerebral dysfunction in six control patients and two prostacyclin-treated patients. Investigation of cerebrospinal fluid showed signs of blood-brain barrier damage in 12 control and seven prostacyclin-treated patients. Cytologic changes in cerebrospinal fluid consistent with brain tissue damage occurred in two control patients but in no patient given prostacyclin. Myelin basic protein and adenylate kinase in cerebrospinal fluid were assayed as being markers of brain damage. Myelin basic protein was within the normal range in all patients. Adenylate kinase was moderately increased (greater than 0.035 U/L) in five of 15 control patients and six of 13 prostacyclin-treated patients. We conclude that treatment with prostacyclin 50 ng/kg/min during cardiopulmonary bypass does not increase the risk of postoperative cerebral damage.

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.

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.

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.

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.

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.

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.

[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.

Cerebrospinal fluid markers in relation to outcome in patients with global cerebral ischemia.

To investigate the possibility of improving the accuracy of prognostication in early hypoxic brain damage, 12 patients with global cerebral ischemia (GCI) due to circulatory arrest outside hospital were followed until death or for 1 yr. Five who survived for more than 2 weeks displayed better values on coma scoring from 16 h-3 days, compared to those who succumbed within 2 weeks. In 2 week-survivors, lumbar puncture revealed consistently lower adenylate kinase (AK) activity in cerebrospinal fluid (CSF) at 24 h than in the other patients, whereas glutathione and lactate values overlapped to some degree. The CSF-AK activity at 48--72 h was less correlated to clinical outcome. It is concluded that the results from coma scoring, based upon clinical observation, and from determination of AK activity in CSF at 24 h reinforce each other in discriminative power to predict prognosis in these patients.

Adenylate kinase activity in cerebrospinal fluid in connection with transitory ischaemic attacks.

Adenylate kinase activity was measured in cerebrospinal fluid of healthy normal individuals and those having suffered from transitory ischaemic attacks (TIA). Normally, no adenylate kinase was present in cerebrospinal fluid. A slight but distinct activity was always registered in the 11 cases studied in connection with TIA. Cerebrospinal fluid of 2 patients was also analysed in a symptom-free interval (at least 2 weeks after the stroke) and no adenylate kinase activity was found.

Bioluminescent assay of total and brain-specific creatine kinase activity in cerebrospinal fluid.

A bioluminescent assay based on the firefly luciferase reaction has been used for determination of creatine kinase activity in CSF. Activities as low as 0.1 U/L can be measured. The coefficient of variation at an activity level of 0.3-0.4 U/L was between 5 and 6%. The assay conditions optimized for serum specimens can be used for CSF. The adenylate kinase activity is almost completely inhibited, which simplifies the procedure. The creatine kinase/(CK) isoenzyme distribution was obtained using the bioluminescent assay in combination with immunoinhibition or ion exchange chromatography. All specimens contained both MM and BB activity, but no MB was found. The study indicates that the bioluminescent assay is useful in the determination of CK isoenzymes in CSF. The clinical importance of the observed CK levels will be reported in a separate communication.

Cerebrospinal fluid enzymes in neurological diseases.

The activities of adenylate kinase, creatine kinase and lactate dehydrogenase were measured in cerebrospinal fluid and serum from 127 patients admitted to the Department of Neurology. All cerebrospinal fluid samples with hemoglobin greater than 1 mg/l were excluded. Upper reference limits for the enzyme determinations were established, using samples from patients without objective criteria of organic involvement of the nervous system. High enzyme activities did not correlate to any particular group of diseases and were also found in patients without organic brain diseases. We conclude that determination of the three enzymes in cerebrospinal fluid is of limited value in the diagnosis of neurological diseases.

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.

Studies of biochemical markers in cerebrospinal fluid in patients with meningoencephalitis.

Several biochemical markers in the cerebrospinal fluid (CSF) of 120 patients with serous meningoencephalitis (SM) of viral origin were compared with those of 74 patients with viral or bacterial infections accompanied by neck stiffness but no CSF abnormality (i.e., meningism). CSF adenylate kinase was higher (P less than 0.025) in SM and correlated with lactate concentration (r = 0.37; P less than 0.01). CSF hypoxanthine was lower (P less than 0.001) in SM, whereas CSF xanthine was similar in the two conditions. The xanthine/hypoxathine ratio correlated with the CSF leukocyte count (r = 0.32; P less than 0.01), and especially with the mononuclear cell count (r = 0.45; P less than 0.001). CSF adenylate kinase correlated with fever in SM (r = 0.28; P less than 0.01). CSF urate and protein displayed a mutual correlation in both conditions (r = 0.26 and P less than 0.05 for SM; r = 0.55 and P less than 0.001 for meningism). These results support the hypothesis of impaired brain cell metabolism, probably of ischemic nature, in viral meningoencephalitis, causing leakage of adenylate kinase into the CSF, where hypoxanthine may be reutilized by mononuclear leukocytes.

Cerebrospinal fluid content of adenylate kinase, lactate and glutathione in patients with meningitis.

Adenylate kinase activity and lactate concentration were measured in the cerebrospinal fluid (CSF) of 5 patients with bacterial meningitis, of 4 patients with probable bacterial meningitis, and of 18 patients with serous meningitis. Furthermore, for comparison measurements were also performed in CSF of 27 patients with meningism. Concomitantly glutathione was measured in CSF in most of the patients. Significantly higher values of these 3 parameters were found in the CSF of patients with bacterial and probable bacterial meningitis compared with those having serous meningitis and meningism. Adenylate kinase activity and lactate concentration in patients with serous meningitis were significantly higher than in those with meningism. All patients with a clinical diagnosis of meningitis studied so far also displayed an adenylate kinase activity in their CSF. The determination of adenylate kinase, lactate and glutathione levels in CSF might be a useful aid for the diagnosis not only of meningitis but also for the discrimination between bacterial and serous meningitis.