Jan Hillman

Sudden onset headache: a prospective study of features, incidence and causes

Sudden onset headache is a common condition that sometimes indicates a life- threatening subarachnoid haemorrhage (SAH) but is mostly harmless. We have performed a prospective study of 137 consecutive patients with this kind of headache (thunderclap headache = TCH). The examination included a CT scan, CSF examination and follow-up of patients with no SAH during the period between 2 days and 12 months after the headache attack. The incidence was 43 per 100 000 inhabitants > 18 years of age per year; 11.3% of the patients with TCH had SAH. Findings in other patients indicated cerebral infarction (five), intracerebral haematoma (three), aseptic meningitis (four), cerebral oedema (one) and sinus thrombosis (one). Thus no specific finding indicating the underlying cause of the TCH attack was found in the majority of the patients. A slightly increased prevalence of migraine was found in the non-SAH patients (28%). The attacks occurred in 11 cases (8%) during sexual activity and two of these had an SAH. Nausea, neck stiffness, occipital location and impaired consciousness were significantly more frequent with SAH but did not occur in all cases. Location in the temporal region and pressing headache quality were the only features that were more common in non-SAH patients. Recurrent attacks of TCH occurred in 24% of the non-SAH patients. No SAH occurred later in this group, nor in any of the other patients. It was concluded that attacks caused by a SAH cannot be distinguished from non-SAH attacks on clinical grounds. It is important that patients with their first TCH attack are investigated with CT and CSF examination to exclude SAH, meningitis or cerebral infarction. The results from this and previous studies indicate that it is not necessary to perform angiography in patients with a TCH attack, provided that no symptoms or signs indicate a possible brain lesion and a CT scan and CSF examination have not indicated SAH.

A microdialysis technique for routine measurement of macromolecules in the injured human brain.

OBJECTIVE: To evaluate a new intracerebral microdialysis catheter with a high-cutoff membrane and its potential for the study of macromolecules in the human brain. METHODS: Paired intracerebral microdialysis catheters were inserted in 10 patients who became comatose after subarachnoid hemorrhage or traumatic brain injury and were then treated in our neurosurgical unit. The only differences from the routine use of microdialysis in our clinic were the length (20 mm) and cutoff properties of the catheter membranes (100 kD) and the perfusion fluids used (standard perfusion fluid, 3.5% albumin, or Ringer-dextran 60). Samples were weighed (for net fluid fluxes) and analyzed at bedside (for routine metabolites) and later in the laboratory (for total protein and interleukin-6). The in vitro recovery of glucose, glutamate, and glycerol were also investigated under different conditions. RESULTS: Even brief perfusion with standard perfusion fluid resulted in a significant loss of volume from the microdialysis system. For albumin and Ringer-dextran 60 fluid, recovery was comparable to standard settings. Interleukin-6 (highest value close to 25,000 pg/ml) was sampled from all catheters, and total protein was analyzed from catheters perfused with Ringer-dextran 60 (average concentration, 234 &mgr;g protein/ml). There were detectable patterns of variations in the concentration of interleukin-6, seemingly related to concomitant variations in intracerebral conditions. In the present study, no direct comparison was made with the standard CMA 70 catheter (CMA Microdialysis, Stockholm, Sweden), but in vivo, the measured mean concentrations of glucose, glycerol, lactate, and pyruvate were comparable to those previously reported from standard catheters. In vitro, the recovery of metabolites was better when using Ringer-dextran 60 compared with albumin. CONCLUSION: Microdialysis catheters with high-cutoff membranes can be used in routine clinical practice, allowing for sampling and analysis of cytokines and other macromolecules.

Changes in extracellular concentrations of some cytokines, chemokines, and neurotrophic factors after insertion of intracerebral microdialysis catheters in neurosurgical patients.

OBJECTIVEThe extracellular levels of eight different inflammatory agents were analyzed during the initial 36 hours after insertion of microdialysis catheters in patients. METHODSCerebral extracellular fluid from 38 patients who were treated in a neurosurgical intensive care unit for severe brain injury was collected every 6 hours for 36 hours. The concentration of interleukin (IL)-1β, IL-6, IL-8, macrophage inflammatory protein-1β, regulated on activation, normal T-cell expressed and secreted (RANTES), fibroblast growth factor-2, and vascular endothelial growth factor was determined by a multiplex assay, and IL-10 was determined by enzyme-linked immunosorbent assay. RESULTSThis is the first report regarding the presence of IL-10, IL-8, macrophage inflammatory protein-1β, regulated on activation, T-cell expressed and secreted, vascular endothelial growth factor, and fibroblast growth factor-2 in the tissue level proper of the living human brain. The study also provides new information regarding the response of IL-1β and IL-6 after insertion of a microdialysis catheter. The study confirms that the intriguing patterns of interplay between different components of the inflammatory response studied in laboratory settings are present in the human brain. This was most clearly observed in the variations in response between the three different chemokines investigated, as well as in the rapid and transient response of fibroblast growth factor-2. CONCLUSIONThe data presented illustrate the opportunity to monitor biochemical events of possible importance in the human brain and indicate the potential of such monitoring in neurosurgical intensive care. The study also underlines that any analysis of events in the brain involving mechanical invasiveness needs to take into account biochemical changes that are directly related to the manipulation of brain tissue.

Expression and Growth Dependency of the Insulin-Like Growth Factor I Receptor in Craniopharyngioma Cells: A Novel Therapeutic Approach

Craniopharyngioma is a rare benign intracranial epithelial tumor that, however, often recurs and sometimes kills the affected patients, one-third of which are children. In many cases, the patients acquire growth hormone deficiency and postoperatively need substitution. Generally, growth hormone promotes local release of insulin-like growth factor I (IGF-I), which in turn activates the IGF-I receptor (IGF-IR) if present. Together, these circumstances raise the question whether IGF-IR may be involved in craniopharyngioma growth. To address this issue, we analyzed phenotypically well-characterized primary low-passage craniopharyngioma cell lines from nine different patients for IGF-IR expression and IGF-I dependency. Two of the cell lines showed no/very low expression of the receptor and was independent on IGF-I, whereas five cell lines exhibited a strong expression and was clearly contingent on IGF-I. The two remaining cell lines had low receptor expression and IGF-I dependency. Upon treatment with an IGF-IR inhibitor, cells with high IGF-IR expression responded promptly with decreased Akt phosphorylation followed by growth arrest. These responses were not seen in cells with no/very low receptor expression. Growth of cell lines with low IGF-IR expression was only slightly affected by IGF-IR inhibition. Taken together, our data suggest that IGF-IR may be involved in the growth of a subset of craniopharyngiomas and points to the possibility of the involvement of IGF-IR inhibitors as a treatment modality to obtain complete tumor-free conditions before growth hormone substitution.

Differences in cerebral extracellular response of interleukin-1β, interleukin-6, and interleukin-10 after subarachnoid hemorrhage or severe head trauma in humans.

BACKGROUND:Microdialysis has become a routine method for biochemical surveillance of patients in neurosurgical intensive care units. OBJECTIVE:To analyze the intracerebral extracellular levels of 3 interleukins (ILs) during the 7 days after major subarachnoid hemorrhage or traumatic brain injury). METHODS:Microdialysate from 145 severely injured neurosurgical intensive care unit patients (88 with subarachnoid hemorrhage, 57 with traumatic brain injury) was collected every 6 hours for 7 days. The concentrations of IL-1β and IL-6 were determined by fluorescence multiplex bead technology, and IL-10 was determined by enzyme-linked immunosorbent assay. RESULTS:Presented are the response patterns of 3 ILs during the first week after 2 different types of major brain injury. These patterns are different for each IL and also differ with respect to the kind of pathological impact. For both IL-1β and IL-6, the initial peaks (mean values for all patients at day 2 being 26.9 ± 4.5 and 4399 ± 848 pg/mL, respectively) were followed by a gradual decline, with IL-6 values remaining 100-fold higher compared with IL-1β. Female patients showed a stronger and more sustained response. The response of IL-10 was different, with mean values less than 23 pg/mL and with no significant variation between any of the postimpact days. For all 3 ILs, the responses were stronger in subarachnoid hemorrhage patients. The study also indicates that under normal conditions, IL-1β, IL-6, and IL-10 are present only at very low concentrations or not at all in the extracellular space of the human brain. CONCLUSION:This is the first report presenting in some detail the human cerebral response of IL-1β, IL-6, and IL-10 after subarachnoid hemorrhage and traumatic brain injury. The 3 ILs have different reaction patterns, with the response of IL-1β and IL-6 being related to the type of cerebral damage sustained, whereas the IL-10 response was less varied.

Intracerebral microdialysis in neurosurgical intensive care patients utilising catheters with different molecular cut-off (20 and 100 kD)

SummaryObjective. To compare the properties of a new intracerebral micro-dialysis catheter with a high cut-off membrane (molecular cut-off 100 kDalton) with a standard catheter (CMA70, molecular cut-off 20 kDalton).Methods. Paired intracerebral microdialysis catheters were inserted in fifteen comatose patients treated in a neurosurgical intensive care unit following subarachnoid haemorrhage or traumatic brain injury. The high-cut-off catheter (D100) differed from the CMA 70 catheter by the length (20 mm) and cut-off properties of the catheter membranes (100 kDalton) and the perfusion fluids used (Ringer-Dextran 60). Samples were collected every 4–6 hours, analyzed bedside (for glucose, glutamate, glycerol, lactate, pyruvate and urea) and later in the laboratory (for total protein).Results. Fluid recovery was similar for the two types of catheters, but significantly more protein was recovered by the D100 catheter. The recovery of glycerol and pyruvate did not differ, while minor differences in recovery of glutamate and glucose were observed. The recovery of lactate was considerably lower in the D100 catheter (p < 0.01), influencing the lactate/pyruvate-ratio. The patterns of concentration changes over time were consistent for all metabolites, and independent of type of catheter.Conclusion. Microdialysis catheters with high cut-off membranes can be used in routine clinical practice in the NSICU, adding the possibility of macro-molecule sampling from the extracellular space during monitoring.

Release of VEGF and FGF in the extracellular space following severe subarachnoidal haemorrhage or traumatic head injury in humans

Microdialysate fluid from 145 severely injured NSICU-patients, 88 with subarachnoidal haemorrage (SAH), and 57 with traumatic brain injury (TBI), was collected by microdialysis during the first 7 days following impact, and levels of the neurotrophins fibroblast growth factor-2 (FGF2) and vascular endothelial growth factor (VEGF) were analysed. The study illustrates both similarities and differences in the reaction patterns of the 2 inflammatory proteins. The highest concentrations of both FGF2 and VEGF were measured on Day 2 (mean (± SE) values being 47.1 ± 15.33 and 116.9 ± 41.85 pg/ml, respectively, in the pooled patient material). The VEGF concentration was significantly higher in TBI-patients, while the FGF2 showed a tendency to be higher in SAH-patients. This is the first report presenting in some detail the human cerebral response of FGF2 and VEGF following SAH and TBI. Apart from increasing the understanding of the post-impact inflammatory response of the human brain, the study identifies potential threshold values for these chemokines that may serve as monitoring indicators in the NSICU.

Aneurysmal Subarachnoid Haemorrhage: Overall outcome and incidence of early recurrent haemorrhage despite a policy of acute stage operation

A series of 480 patients who were alive upon admission following an aneurysmal subarachnoid haemorrhage (SAH) is reported. These patients represented 40% of the total Swedish incidence during a 3-year period. The three neurosurgical referral centres covering this population had a similar policy of early diagnosis and acute state surgery in all patients considered of having a potential to survive without permanent disabling cerebral malfunction. At 2-year follow up 45% showed a good neurological recovery, the morbidity was 25% and the mortality was 30%. Some more lives might have been saved with an improved ultra-early referral system since there were 21 initially good-to-fair risk patients (4% of the total SAH population) who rebled fatally before surgery and within 48 h. For comparison, in the Kingdom of Denmark, with a general policy of delayed operation, out of 1076 patients who were alive upon admission, 27.5% made a good recovery, while the morbidity was 27%, and the mortality was 45.5%.

Human neuroblastoma (SH-SY5Y) cells are highly sensitive to the lysosomotropic aldehyde 3-aminopropanal

3-Aminopropanal (3-AP), a degradation product of polyamines such as spermine, spermidine and putrescine, is a lysosomotropic small aldehyde that causes apoptosis or necrosis of most cells in culture, apparently by inducing moderate or extensive lysosomal rupture, respectively, and secondary mitochondrial changes. Here, using the human neuroblastoma SH-SY5Y cell line, we found simultaneous occurrence of apoptotic and necrotic cell death when cultures were exposed to 3-AP in concentrations that usually are either nontoxic, or only cause apoptosis. At 30 mM, but not at 10 mM, the lysosomotropic base and proton acceptor NH3 completely blocked the toxic effect of 3-AP, proving that 3-AP is lysosomotropic and suggesting that the lysosomal membrane proton pump of neuroblastoma cells is highly effective, creating a lower than normal lysosomal pH and, thus, extensive intralysosomal accumulation of lysosomotropic drugs. A wave of internal oxidative stress, secondary to changes in mitochondrial membrane potential, followed and gave rise to further lysosomal rupture. The preincubation of cells for 24 h with a chain-breaking free radical-scavenger, alpha-tocopherol, before exposure to 3-AP, significantly delayed both the wave of oxidative stress and the secondary lysosomal rupture, while it did not interfere with the early 3-AP-mediated phase of lysosomal break. Obviously, the reported oxidative stress and apoptosis/necrosis are consequences of lysosomal rupture with ensuing release of lysosomal enzymes resulting in direct/indirect effects on mitochondrial permeability, membrane potential, and electron transport. The induced oxidative stress seems to act as an amplifying loop causing further lysosomal break that can be partially prevented by alpha-tocopherol. Perhaps secondary brain damage during a critical post injury period can be prevented by the use of drugs that temporarily raise lysosomal pH, inactivate intralysosomal 3-AP, or stabilize lysosomal membranes against oxidative stress.

Education of referring doctors about sudden onset headache in subarachnoid hemorrhage

Objectives – Forty percent of patients with aneurysmal subarachnoid hemorrhage have prodromal warning episodes and difficulties in identifying these events are repeatedly documented. Modifications of diagnostic and referral patterns through educational programs of local doctors may help to identify such patients before a major devastating rupture occurs. Materials and methods– A teaching program about sudden onset headache, targeting referring doctors, was systematically applied and its impact on early misdiagnosis of ruptured aneurysms was prospectively studied. Results– Forty percent of all studied patients experienced a warning episode, manifested as apoplectic headache, prior to hospitalization. An initial diagnostic error was evident in 12% of the patients. Diagnostic errors were reduced by 77% as a result of continuous interaction between neurosurgeons and local physicians. Conclusion– Misdiagnosed warning episodes cause greater loss of lives and higher morbidity on a population basis than does delayed ischemic complications from vasospasm in aneurysmal SAH. Teaching programs focused on local physicians have a profound impact on outcome at low cost.