Differences between intracranial vascular malformation types in the characteristics of their presenting haemorrhages: prospective, population-based study.

OBJECTIVE: To determine the imaging and demographic characteristics of intracranial haemorrhages, which are subsequently found to be due to an underlying intracranial vascular malformation (IVM). METHODS: We compared the demographic and brain imaging characteristics of adults presenting with intracranial haemorrhage, subsequently found to be due to a brain arteriovenous malformation (BAVM), dural arteriovenous fistula (DAVF) or cavernous malformation (CM) in a prospective, population-based cohort of adults diagnosed for the first time with an IVM (The Scottish IVM Study (SIVMS)). RESULTS: Of the 141 adults in SIVMS who presented with intracranial haemorrhage, those with CMs presented at a younger age and were less handicapped. A total of 115 (82%) had intracerebral haemorrhage (ICH) with or without subarachnoid, intraventricular or subdural extension. ICH without extension into other compartments accounted for all CM bleeds, but only 50% of BAVM and DAVF bleeds. Median haematoma volumes differed (Kruskal-Wallis, p<0.0001): ICH due to BAVM (16.0 cm3, inter-quartile range (IQR) 4.7 to 42.0) and DAVF (14.1 cm3, IQR 4.9 to 21.5) were similar, but CM haematoma volumes were smaller (median 1.8 cm3, IQR 1.3 to 4.3). These findings were robust in sensitivity analyses. Small haematoma volumes occurred among all IVM types; the largest haematoma volume due to CM was 12 cm3, and volumes of >34 cm3 were only due to BAVM. CONCLUSIONS: Intracranial haemorrhages found to be due to IVMs differ in adults' age of presentation and clinical severity, as well as the volume and distribution of the haematoma within the brain compartments.

HSV1716 injection into the brain adjacent to tumour following surgical resection of high-grade glioma: safety data and long-term survival.

Following standard treatment, the prognosis remains poor in patients with high-grade glioma and new therapies are urgently required. Herpes simplex virus 1716 (HSV1716) is an ICP34.5 null mutant that is selectively replication competent and shown to be safe and to replicate following injection into high-grade glioma. We demonstrate that following surgical resection, HSV1716 is safe when injected into the brain adjacent to excised tumour. In all, 12 patients with recurrent or newly diagnosed high-grade glioma underwent maximal resection of the tumour. HSV1716 was injected into eight to 10 sites around the resulting tumour cavity with the intent of infecting residual tumour cells. As clinically indicated, patients proceeded to further radiotherapy or chemotherapy. There has been no clinical evidence of toxicity associated with the administration of HSV1716. Longitudinal follow-up has allowed the assessment of overall survival compared to that of similar patients not treated with HSV1716. Three patients remain alive and clinically stable at 15, 18 and 22 months postsurgery and HSV1716 injection. Remarkably, the first patient in the trial, who had extensive recurrent disease preprocedure, is alive at 22 months since injection of HSV1716 and 29 months since first diagnosis. Imaging has demonstrated a reduction of residual tumour over the 22-month period despite no further medical intervention since the surgery and HSV1716 injection. In this study, we demonstrate that on the basis of clinical observations, there has been no toxicity following the administration of HSV1716 into the resection cavity rim in patients with high-grade glioma. The survival and imaging data, in addition to the lack of toxicity, give us confidence to proceed to a clinical trial to demonstrate efficacy of HSV1716 in glioma patients.

Leptomeningeal spinal spread of glioblastoma multiforme: report of two cases and review of the literature

Extracranial metastasis of glioblastoma multiforme (GMB) are extremely rare, developing clinically in less than 2 pert cent of case, but probably increasingas patients live longer. It has been reported from necropsic series that microscopic metastasis occur in approximately 6 pert cent and 60 pert cent of supratentorial and infratentorial glioblastomas respectively but patient usually die before they become symptomati. We report two patients with supratentorial glioblastoma multiforme who developed leptomeningeal seeding at the thoracolumbar region as part of their natural history. Clinical and radiographic features and the usefulness of magnetic resonance imaging and CSF fluid analysis is discussed as well as a brief review of the literature

HSV1716 persistence in primary human glioma cells in vitro.

HSV1716 is a selectively replication competent mutant of herpes simplex virus which is in trial in glioma patients. We have demonstrated that HSV1716 is non-toxic when delivered into tumour or into brain adjacent to tumour, yet replicates within tumour cells. Tumour tissue, from one patient treated 2.5 years previously with intra-tumoural HSV1716, was put into culture. The cultured cells were shown to be glial in origin with no evidence of residual HSV1716. These cells were subsequently infected at a MOI of 0.1 with either HSV1716 or wild-type HSV17(+). The HSV17(+) infected cells were completely rounded up or lysed within 72 h. Although the cells supported HSV1716 replication and also became rounded or lysed, a proportion (approximately 20%) remained viable. These cells continued to divide and shed low levels of HSV1716 up to 31 days after infection when there was evidence of rapid virus replication resulting in complete cell lysis. These data demonstrate that HSV1716 can 'persist' in human glioma cells at least in vitro and gives credence to the possibility that in tumours in vivo a similar phenomenon may take place. If this were the case, then HSV1716 has the potential to kill tumour cells over a prolonged period of time.

The potential for efficacy of the modified (ICP 34.5(-)) herpes simplex virus HSV1716 following intratumoural injection into human malignant glioma: a proof of principle study.

We have previously demonstrated the safety of intratumoural administration of the selectively replication-competent herpes simplex virus mutant HSV1716 in patients with high-grade glioma (HGG). Here we show its potential for efficacy by demonstrating that the virus survives and replicates when injected into the tumours of patients. Since HSV replication is a cytolytic process it must result in tumour cell killing. Twelve patients with biopsy-verified HGG received an intratumoural injection of 10(5) plaque-forming units (p.f.u.) of HSV1716. Four to 9 days after inoculation, tumours were removed and assayed for evidence of viral replication. In two patients, HSV1716, in excess of the input dose was recovered from the injection site. HSV DNA was detected by PCR at the sites of inoculation in 10 patients and at distal tumour sites in four. HSV-specific antigen was detected in tumour tissue from two patients. In five patients an immunological response to HSV1716, as detected by changes in levels of IgG and IgM, was demonstrated. This study demonstrates that HSV1716 replicates in HGG without causing toxicity in both HSV-seropositive and -seronegative patients.

Identification of a human olfactory ensheathing cell that can effect transplant-mediated remyelination of demyelinated CNS axons.

The olfactory ensheathing cell (OEC) has attracted much interest recently because of its potential for transplantation-based therapy of CNS disease. Rat OECs are able to remyelinate demyelinated axons and support regeneration of damaged axons. Although OECs can be grown readily from the rat, a macrosmatic species, it has been uncertain whether it would be similarly straightforward to obtain these cells from the human, a microsmatic species with a relatively poorly developed olfactory system. In this study, we have identified a human OEC which shares many properties with its rat counterpart, including expression of the low-affinity nerve growth factor receptor (L-NGFr) and similar growth factor requirements. Purified populations of human OECs obtained by selection with L-NGFr antibodies have extremely high viability in tissue culture, and are capable of remyelinating persistently demyelinated CNS axons following transplantation into experimentally induced demyelinating lesions in the rat spinal cord. Thus, the human OEC represents an important new cell for the development of transplant therapy of CNS diseases.

Toxicity evaluation of replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients with recurrent malignant glioma.

The herpes simplex virus (HSV) ICP34.5 null mutant 1716 replicates selectively in actively dividing cells and has been proposed as a potential treatment for cancer, particularly brain tumours. We present a clinical study to evaluate the safety of 1716 in patients with relapsed malignant glioma. Following intratumoural inoculation of doses up to 10(5) p.f.u., there was no induction of encephalitis, no adverse clinical symptoms, and no reactivation of latent HSV. Of nine patients treated, four are currently alive and well 14-24 months after 1716 administration. This study demonstrates the feasibility of using replication-competent HSV in human therapy.

Actions of 5-HT on human neocortical neurones in vitro.

Using intracellular recordings, we have studied the action of 5-hydroxytryptamine (5-HT) on slices of human temporal, occipital and frontal cortex maintained in vitro. The recordings were usually made 1.2 to 1.5 mm down from the pial surface, in or around layer III. The action of 5-HT (30-50 microM) was studied on 21 cells (from 12 individuals) which had electrophysiological characteristics of glutamatergic pyramidal neurones. 5-HT depolarised the majority (11) of these cells with a median response of 5 mV. It produced a hyperpolarising response in five neurones (median=-4 mV) and a combined hyperpolarising/depolarising response in two others. No response was detected in three cells. The depolarising response was probably mediated by reducing a resting potassium conductance. Ketanserin (0.1 and 1.0 microM) and spiperone (1 microM) reduced the response indicating that it was likely mediated by 5-HT2A receptors. The hyperpolarising response was associated with the opening of ion channels and was blocked by the selective 5-HT1A receptor antagonist WAY-100635 (100 nM). 5-HT inhibited spontaneous synaptic potentials. This effect was reduced by ketanserin (1 microM) but not by WAY-100635 (100 nM). It is concluded that human neocortical neurones in vitro can be depolarised via 5-HT2A receptors and hyperpolarised via 5-HT1A receptors.

Dose escalation with repeated intrathecal injections of 131I-labelled MAbs for the treatment of central nervous system malignancies.

We have previously demonstrated a 33% response rate in patients with primitive neurectodermal tumours after the direct injection of 131I-monoclonal antibodies (MAbs) into the cerebrospinal fluid (CSF). Dose-limiting toxicity is myelosuppression due to the passage of the radioimmunoconjugate from the CSF to the blood compartment. This occurs at doses of 2220 MBq of 131I-MAb and above, although this is not seen in all patients studied and appears to be related to the degree of prior therapy received. Rather than attempting to improve the efficacy of this approach to the treatment of disseminated disease within the CSF compartment by dose escalation and haemopoietic rescue, we have explored the possibility of repeatedly administering the radioimmunoconjugate. Eight patients were recruited to the study, two of whom received two and six of whom received three injections of 131I-MAb. After repeated administration of 131I-MAb pharmacokinetic data revealed that, with one exception, the radioimmunoconjugate cleared from the CSF compartment with similar kinetics, while its residence time in the blood decreased with each injection. This was due to the development of an anti-mouse Ig response in the blood. Clearance of 131I-MAb from the ventricular CSF appears to be independent of the presence of an anti-mouse Ig response in this compartment. The differential clearance of the radioimmunoconjugate from the ventricular CSF and from the blood results in a marked increase in the therapeutic index that can be achieved. Up to 5920 MBq of 131I-MAb was administered as the third injection of radioimmunoconjugate and combined doses of up to 12,500 MBq were given without either haematological or neurological toxicity. These data illustrate that dose escalation and thus an increase in the dose rate delivered to tumour cells within the CSF is possible if ways are found to reduce the residence time of the radioimmunoconjugate in the blood compartment. Suggestions as to how this can best be achieved are reviewed in detail.

Use of the Radionics Image Fusiontrade mark and Stereoplantrade mark programs for target localization in functional neurosurgery.

We describe the use of Radionics Image Fusiontrade mark and Stereoplantrade mark in defining the target for thalamotomy and pallidotomy in functional surgery for parkinsonism and tremor. Using this to fuse and spatially correct magnetic resonance imaging (MRI) to computed tomography (CT) images our calculated targets were a mean of 0.6 +/- 1.5 mm from the end target determined physiologically by stimulation. This is significantly better than the values of 2.6 +/- 1.6 mm for thalamic targets and 7.1 +/- 3.7 mm for pallidal targets using CT alone. As a consequence, determination of the target and the lesion making are routinely performed in one pass of the electrode allowing for faster, more accurate and, we believe, safer functional procedures.

Benign intracerebral cysts with ependymal lining: pathological and radiological features.

Cerebral intraparenchymal cysts without communication with the ventricles are very rare. We report four such cases with no relevant past history or evidence of infection, haemorrhage, trauma, tumour or congenital neural tube defect. At operation smooth wailed cysts with an ependymal-type lining were found. To the best of our knowledge, we present the first correlation of their pathological and radiological features (including magnetic resonance imaging). We also review the literature on these cysts.

A model to estimate the dose to tumour following intracavity administration of radioimmunoconjugates to patients with malignant gliomas.

Patients who have relapsed following primary treatment for malignant glioma and have undergone further surgical debulking have been treated with an anti-human neural cell adhesion molecule (NCAM) MoAb linked to either Iodine-131 or Yttrium-90. These reagents are introduced into the tumour resection cavity via an Ommaya reservoir. Pharmacokinetic and imaging studies indicate that the radioimmunoconjugate remains within the cavity for a protracted period of time. In this manuscript we develop a dosimetric model to predict the dose delivered to the rim of tissue surrounding the resection cavity. The model takes into account variables such as the diameter of the cavity and the degree of antibody binding which is achieved. Whilst the calculated doses to the wall of the cavity are relatively inaccurate due to our inability to measure factors such as diffusion and heterogeneity in antibody uptake, the model illustrates the potential benefits and pitfalls that can result from targeting the two radionuclides. It is hoped that as increasing interest is shown in this type of "liquid brachytherapy" other groups will find it useful to apply the model to allow comparisons to be made between our targeting strategy and those developed by other individuals.

Contralateral cerebellar hemorrhagic infarction after pterional craniotomy: report of five cases and review of the literature.

OBJECTIVE AND IMPORTANCE: Five cases of cerebellar hemorrhagic infarction complicating pterional craniotomy are presented. Recognition of this rare complication may be delayed, with catastrophic consequences, because clinicians are unaware of the possibility. We suggest that the mechanism of this complication is dislocation of the dependent part of the cerebellum and venous obstruction causing hemorrhagic infarction. CLINICAL PRESENTATION: Five patients undergoing pterional craniotomies for benign conditions (four unruptured aneurysms and one meningioma) developed hemorrhagic infarction of the contralateral cerebellum in the postoperative period. This resulted in obstructive hydrocephalus and brain stem compression. A review of the literature revealed only one previous report of a similar complication in patients with gross coagulopathy. This was not a problem in our patients. INTERVENTION: The time of onset of symptoms varied from immediately postoperative to 24 hours later. Once the diagnosis was made, the hydrocephalus was drained and the posterior fossa was decompressed. CONCLUSION: The outcome depended on two variables: 1) the rate of development of hemorrhagic infarction and the associated complications and 2) the amount of time that elapsed before remedial action was taken. Two patients with the first signs of deterioration in the immediate postoperative period had the worst outcome; one died and the other remained severely disabled. In two patients with good neurological recovery, problems were identified and corrected within 4 hours of the first sign of deterioration. Rapid overdrainage of cerebrospinal fluid during supratentorial surgery should be avoided, and the fluid volume should be replaced before closure. Postoperative evaluation of patients whose conditions deteriorate after supratentorial craniotomy should include adequate imaging studies of the posterior fossa.

Pharmacokinetics and dose estimates following intrathecal administration of 131I-monoclonal antibodies for the treatment of central nervous system malignancies.

PURPOSE: Treatment of malignant disease in the central nervous system (CNS) with systemic radiolabeled monoclonal antibodies (MoAbs) is compromised by poor penetration into the cerebrospinal fluid (CSF), limited diffusion into solid tumors, and the generation of anti-mouse antibodies. To attempt to avoid these problems we have treated patients with diffuse neoplastic meningitis with radioimmunoconjugates injected directly into the intrathecal space. METHODS AND MATERIALS: Tumor-specific MoAbs were conjugated to Iodine-131 (131I) (629-3331 MBq) by the Iodogen technique, and administered via an intraventricular reservoir. A clinical response rate of approximately 33% was achieved, with better results in more radiosensitive tumors. Here, we present detailed pharmacodynamic data on patients receiving this intracompartmental targeted therapy. RESULTS: Elimination from the ventricular CSF appeared biphasic, with more rapid clearance occurring in the first 24 h. Radioimmunoconjugate entered the subarachnoid space and subsequently the vascular compartment. From this information, the areas under the effective activity curves for ventricular CSF, blood, and subarachnoid CSF were calculated to permit dosimetry. Critical organ doses were calculated using conventional medical internal radiation dose (MIRD) formalism. Where available, S-values were taken from standard tables. To calculate the doses to CSF, brain, and spinal cord, S-values were evaluated using the models described in the text. CONCLUSION: A marked advantage could be demonstrated for the dose delivered to tumor cells within the CSF as compared to other neural elements.

Treatment of recurrent and cystic malignant gliomas by a single intracavity injection of 131I monoclonal antibody: feasibility, pharmacokinetics and dosimetry.

A pilot study was undertaken to determine the feasibility of infusing 131I labelled monoclonal antibodies (MoAbs) into either the cavity remaining after resection of malignant glioma or into glioma cysts. Of the seven patients recruited into the study, two had cystic lesions and five resection cavities. Six of the seven were treated after relapse from primary therapy. All patients apart from one, were given a single injection of 131I conjugated to a MoAb (ERIC-1) recognising the human neural cell adhesion molecule (NCAM). One patient received a further injection of 131I-MoAb after regrowth of their disease. Pharmacokinetic studies revealed that the MoAb remained predominantly in the tumour cavity with little leakage into the systemic compartment. This resulted in a high calculated dose of radiation being delivered to the tumour cells either lining or within close proximity to the cavity/cyst wall. In such a small study, it is not possible to determine accurately response rates, but individual patient responses were observed. This, along with the low toxicity noted, demonstrates the feasibility of using 131I-MoAbs in this way. With 131I, radiation dose is deposited in tissue to a depth of 1 mm from the source. The possibility of applying isotopes such as 90Yttrium which will irradiate tumour/tissue to a greater depth (6 mm) is discussed in context with the biology of glioma infiltration into normal brain parenchyma.

Immunoreactivity, pharmacokinetics and bone marrow dosimetry of intrathecal radioimmunoconjugates.

Ten patients with neoplastic meningitis were treated with a variety of 131I-monoclonal antibody (MAb) conjugates, chosen to bind to their particular malignancy. Pharmacokinetic studies revealed that MAbs leave the ventricular compartment, enter the sub-arachnoid space and then pass into the blood. Once the MAbs enter the blood compartment, their clearance is determined by factors such as circulating anti-mouse Ig and circulating antigens. These lead to complex formations and the clearance of the conjugate by the reticuloendothelial system. In one individual, the anti-mouse Ig response observed systemically was not mirrored within the CSF, which has implications for planning future therapy of this type. In other patients, formation of immune complexes was due to binding to circulating antigen within the blood. The major toxicity associated with the intrathecal administration of 131I-MAbs was bone-marrow suppression. The doses to the bone marrow, resulting from the form of therapy, were calculated but showed no direct correlation with WHO grade 3/4 toxicity. Doses to the ventricular lining were also calculated, but due to the complex geometry of the compartment, calculation of potential tumour doses was not practicable.