Image-guided system with miniature robot for precise positioning and targeting in keyhole neurosurgery.

This paper describes a novel image-guided system for precise automatic targeting in minimally invasive keyhole neurosurgery. The system consists of the MARS miniature robot fitted with a mechanical guide for needle, probe or catheter insertion. Intraoperatively, the robot is directly affixed to a head clamp or to the patient's skull. It automatically positions itself with respect to predefined targets in a preoperative CT/MRI image following an anatomical registration with an intraoperative 3D surface scan of the patient's facial features and registration jig. We present the system architecture, surgical protocol, custom hardware (targeting and registration jig), and software modules (preoperative planning, intraoperative execution, 3D surface scan processing, and three-way registration). We also describe a prototype implementation of the system and in vitro registration experiments. Our results indicate a system-wide target registration error of 1.7 mm (standard deviation = 0.7 mm), which is close to the required 1.0-1.5 mm clinical accuracy in many keyhole neurosurgical procedures.

Molecular analysis of two putative tumour suppressor genes, PTEN and DMBT, which have been implicated in glioblastoma multiforme disease progression.

The transition from low grade astrocytoma to glioblastoma multiforme is almost always accompanied by the loss of genetic markers from chromosome 10. Recently two genes, PTEN/MMAC1/TEP1 and DMBT, have been isolated from chromosome 10q. We have analysed these two genes for mutations in 21 primary glioblastomas. An exon by exon screen of the PTEN gene using SSCP failed to identify any mutations in this tumour series. In contrast, 38% of tumours showed intragenic homozygous deletions in the DMBT gene. The fact that the majority of gliomas do not carry mutations in either of these genes suggests that there may still be other genes on chromosome 10 which are important in the development of glioblastoma multiforme.

The role of automatic computer-aided surgical trajectory planning in improving the expected safety of stereotactic neurosurgery.

PURPOSE: Minimal invasion computer-assisted neurosurgical procedures with various tool insertions into the brain may carry hemorrhagic risks and neurological deficits. The goal of this study is to investigate the role of computer-based surgical trajectory planning tools in improving the potential safety of image-based stereotactic neurosurgery. METHODS: Multi-sequence MRI studies of eight patients who underwent image-guided neurosurgery were retrospectively processed to extract anatomical structures-head surface, ventricles, blood vessels, white matter fibers tractography, and fMRI data of motor, sensory, speech, and visual areas. An experienced neurosurgeon selected one target for each patient. Five neurosurgeons planned a surgical trajectory for each patient using three planning methods: (1) conventional; (2) visualization, in which scans are augmented with overlays of anatomical structures and functional areas; and (3) automatic, in which three surgical trajectories with the lowest expected risk score are automatically computed. For each surgeon, target, and method, we recorded the entry point and its surgical trajectory and computed its expected risk score and its minimum distance from the key structures. RESULTS: A total of 120 surgical trajectories were collected (5 surgeons, 8 targets, 3 methods). The surgical trajectories expected risk scores improved by 76% ([Formula: see text], two-sample student's t test); the average distance of a trajectory from nearby blood vessels increased by 1.6 mm ([Formula: see text]) from 0.6 to 2.2 mm (243%). The initial surgical trajectories were changed in 85% of the cases based on the expected risk score and the trajectory distance from blood vessels. CONCLUSIONS: Computer-based patient-specific preoperative planning of surgical trajectories that minimize the expected risk of vascular and neurological damage due to incorrect tool placement is a promising technique that yields consistent improvements.

Radiation-induced meningioma: a distinct molecular genetic pattern?

Radiation-induced meningiomas arise after low-dose irradiation treatment of certain medical conditions and are recognized as clinically separate from sporadic meningioma. These tumors are often aggressive or malignant, they are likely to be multiple, and they have a high recurrence rate following treatment compared with sporadic meningiomas. To understand the molecular mechanism by which radiation-induced meningioma (RIM) arise, we compared genetic changes in 7 RIM and 8 sporadic meningioma (SM) samples. The presence of mutations in the 17 exons of the neurofibromatosis type 2 (NF2) gene, which has been shown to be inactivated in sporadic meningiomas, was analyzed in RIM and SM using single-strand conformation polymorphism (SSCP) and DNA sequencing. In contrast to SM, which showed NF2 mutations in 50% of specimens, no mutations were found in RIM. In addition, Western blot analysis of schwannomin/merlin protein, the NF2 gene product, demonstrated protein levels comparable to normal brain in 4/4 RIM tumor samples analyzed. Loss of heterozygosity (LOH) of genomic regions, which were reported for SM, was also analyzed in all cases of RIM using 22 polymorphic DNA markers. Allele losses were found on chromosomes 1p (4/7), 9p (2/7), 19q (2/7), 22q (2/7), and 18q (1/7). From these observations we conclude that unlike sporadic meningiomas, NF2 gene inactivation and chromosome 22q deletions are far less frequent in RIM, and their role in meningioma development following low dose irradiation is less significant. Other chromosomal lesions, especially loss of 1p, possibly induced by irradiation, may be more important in the development of these tumors.

Control of vasogenic edema in a brain tumor model: comparison between dexamethasone and superoxide dismutase.

OBJECTIVE: The production of prostaglandin (PG) within brain tumors probably generates excessive amounts of oxygen free radicals that may disrupt microvessel permeability within the tumor and in the adjacent brain. We evaluated the effect of systemic therapy with recombinant human manganese-superoxide dismutase (r-hMnSOD) and with dexamethasone on the vascular permeability (VP) of a brain tumor and the adjacent brain. Treatment effect was also evaluated in control animals subjected to mild penetration injury. METHODS: Fischer rats were injected stereotactically with either 10(5) cells of malignant sarcoma or with vehicle into the right parietal hemisphere. Nine days later, the animals were treated with r-hMnSOD (50 mg/kg of body weight every 12 h [one intravenous, then two intraperitoneal injections]; serum levels, 1100-1800 micrograms/ml), dexamethasone (2 mg/kg every 12 h [one intravenous, then two intraperitoneal injections]), or vehicle and were killed after 30 hours for evaluation of VP and PG production. RESULTS: The VP was markedly increased within the tumor (P < 0.001), in the brain adjacent to it, and in the vehicle injection site. The VP of the normal brain was unaffected by r-hMnSOD or dexamethasone treatment, unlike the VP in the tumor, the adjacent brain, and the injection sites of control animals, where it was reduced by 50, 54, and 23%, respectively (P < 0.04), for r-hMnSOD and 50, 41, and 71%, respectively (P < 0.05), for dexamethasone. A one- to threefold increase in synthesis of thromboxane and PGE2 was measured within the tumor, the adjacent brain, and the injection sites of control animals (P < 0.0001). Treatment with r-hMnSOD had no effect on tumor PG production, but it reduced the synthesis in the brain tissue adjacent to the tumor and in traumatized control animals (P < 0.04). Immunohistochemical evaluation revealed vascular proliferation with abnormal basal membrane, atypical astrocytes, and large numbers of reactive macrophages present in the adjacent brain and at the injection sites of control animals but not within the tumor mass. CONCLUSION: Oxygen free radicals probably enhance vasogenic brain edema resulting from tumor and penetration injury. The edema can be attenuated by systemic r-hMnSOD therapy, which has been proven to be as effective as steroid treatment. An inflammatory response may account for oxygen free radical production in brain tissue adjacent to the tumor and at the injection site of vehicle solution, but other mechanisms probably generate oxygen free radicals within the tumor mass.

Safety of perioperative minidose heparin in patients undergoing brain tumor surgery: a prospective, randomized, double-blind study.

OBJECT: Thromboembolic phenomena (TEPs) continue to be a significant source of morbidity and mortality in patients undergoing neurosurgery. Although the efficacy of low-dose heparin in preventing TEPs in neurosurgical patients is well established, neurosurgeons are reluctant to use it perioperatively because of concern for increased bleeding complications. To clarify this issue, the authors used a prospective, randomized, double-blind design to evaluate the safety of minidose heparin treatment in patients undergoing surgery for supratentorial brain tumors. METHODS: One hundred three patients, all 40 years of age or older, were treated with either 5000 U of heparin (55 patients) or placebo (48 patients) starting 2 hours before surgery and continuing until full mobilization or for 7 days. Both groups were well matched for sex, weight, duration of surgery, and tumor diagnosis. Subjective and objective parameters were used to estimate and calculate the perioperative bleeding tendency in all patients. Red blood cell mass loss was calculated by assessing the preoperative and postoperative hematocrit and the patient's weight. Intraoperative blood loss was determined by measuring the quantity of blood in the suction containers and subtracting the amount of irrigation fluids. Postoperative bleeding was measured by determining the amount of fluid in the subgaleal drain, and blood cell replacement was monitored during and after the procedure. Intracranial bleeding was graded according to findings on the postoperative computerized tomography scan obtained 48 to 72 hours after surgery. In addition, the senior surgeon in each case was asked to assess each patient's bleeding tendency during the operation. The results showed that perioperative administration of heparin did not significantly alter bleeding tendency by any measured parameter. The surgeon was blinded to which group individual patients had been allocated. CONCLUSIONS: Perioperative minidose heparin is safe for use in patients undergoing craniotomy for supratentorial tumors. This relatively simple and inexpensive measure is recommended as a routine regimen for the prevention of TEPs in patients undergoing neurosurgery.

Molecular alterations in the neurofibromatosis type 2 gene and its protein rarely occurring in meningothelial meningiomas.

OBJECT: The neurofibromatosis Type 2 (NF2) gene is the only tumor suppressor gene that has been clearly implicated in the development of benign meningiomas. Interestingly, previous data obtained by the authors indicate that reduced NF2 protein expression seldom occurs in meningothelial meningiomas, the most common histological type of meningioma. The goal of the current study was to explore further the hypothesis of NF2 gene-independent tumorigenesis of meningothelial meningiomas. METHODS: The authors performed a mutational analysis of all 17 exons of the NF2 gene by using single-stranded conformational polymorphism (SSCP). In addition, expression levels of the NF2 protein and mu-calpain, a protease suggested to inactivate the NF2 protein, were determined by immunoblotting analysis of 27 meningiomas (20 meningothelial and seven nonmeningothelial). Mutations of the NF2 gene were found in only one (5%) of 20 meningothelial meningiomas and three (43%) of seven nonmeningothelial tumors (Fisher's exact test, p = 0.042). The levels of NF2 protein were severely reduced in six (28.5%) of 21 meningothelial meningiomas, in contrast to six (86%) of seven nonmeningothelial meningiomas (Fisher's exact test, p = 0.023). Activation of IL-calpain did not correlate with the status of NF2 protein expression in the meningiomas analyzed, demonstrating that mu-calpain activation does not account for the loss of NF2 protein in meningiomas with apparently normal NF2 genes. CONCLUSIONS: These results clearly demonstrate that NF2 gene mutations and decreased NF2 protein expression rarely occur in meningothelial meningiomas compared with other histological types of meningiomas. The clinical behavior of meningothelial meningiomas, however, is similar to that of other benign meningiomas. It is likely, therefore, that the tumorigenesis of meningothelial meningiomas is the result of deleterious alterations of genes that have final phenotypical effects similar to inactivation of the NF2 gene.

[Surgery for craniopharyngioma].

We present a series of 20 patients (11 males) operated on for craniopharyngioma through a frontal craniotomy during an 11-year period. They ranged in age from 7 months to 58 years (mean 20 years). The most common symptoms were headaches, blurred vision and endocrine disorders. The perioperative mortality was 5% and morbidity 25%. 5 (25%) patients need reoperation; 13 (65%) received additional radiation therapy. In 94% visual function improved. 65% continued to have or developed endocrine problems, although all were well controlled with supplemental therapy. These results, similar to those reported from other centers, justify a combination of radical surgery and radiation therapy for this condition.

[Stereotactic brain biopsy].

During a 3-year period starting in 1991, 49 patients with brain lesions underwent 50 stereotactic brain biopsy procedures. The average age was 46 years (range 4-74). Specimens were taken from various brain regions, particularly from the deep aspect of the cerebral hemispheres and midline structures. The pathologic entities included 27 gliomas (13 glioblastomas, 6 astrocytomas, 3 anaplastic astrocytomas, 1 pilocytic astrocytoma and 4 oligodendrogliomas), 5 lymphomas, 2 germinomas, 1 primitive neuroectodermal tumor, 2 metastatic tumors and 11 non-neoplastic lesions (4 demyelination, 2 infarcts, 1 hematoma, 1 brain abscess, 1 radiation necrosis, 1 Alzheimer's disease and in 1 case no diagnosis). The diagnostic success of the stereotactic brain biopsies in this series was 96% (in 98% of the patients). The mean hospital stay was 3 days. 1 patient with a multifocal bilateral glioblastoma died due to early postoperative hematoma of the basal ganglia (2%). Another 2 patients underwent craniotomy due to post-biopsy hematoma. They continued to suffer from hemiparesis after discharge. Transient Horner's syndrome was noted in 1 patient. Thus the permanent morbidity rate was 4%. We conclude that stereotactic brain biopsy can be performed relatively safely, has a high diagnostic yield, and facilitates planning of treatment.

Do cranial subdural hematomas migrate to the lumbar spine?

We report a patient with minor head trauma-related bilateral hemispheric subdural hematoma (SDH) and subsequent delayed spinal SDH or presumed migration to the lumbar spine. An acutely confused 88-year-old man presented to the Emergency Department after minor head trauma. Head CT scan revealed a small hemispheric SDH. The patient was admitted for observation. CT scan 6 hours later showed bilateral SDH with extension to the tentorium. Three days later SDH had resolved leaving bilateral subdural hygromas. Local leg weakness localized to the lumbar spine developed on day 6; spinal CT scan and MRI revealed a posterior L5-S1 collection. A pure subacute subdural hematoma compressing the cauda equina was drained after an L5 laminectomy. His lower leg weakness improved. The patient was discharged to rehabilitation two weeks after surgery. Patients with traumatic SDH who develop late-onset neurological deterioration attributable to any region of the spine should be evaluated for spinal SDH.

Robot-assisted image-guided targeting for minimally invasive neurosurgery: planning, registration, and in-vitro experiment.

This paper present a novel image-guided system for precise automatic targeting in keyhole minimally invasive neurosurgery. The system consists of a miniature robot fitted with a mechanical guide for needle/probe insertion. Intraoperatively, the robot is directly affixed to a head clamp or to the patient skull. It automatically positions itself with respect to predefined targets in a preoperative CT/MRI image following an anatomical registration with a intraoperative 3D surface scan of the patient facial features. We describe the preoperative planning and registration modules, and an in-vitro registration experiment of the entire system which yields a target registration error of 1.7 mm (std = 0.7 mm).

Accelerated Fas-mediated apoptosis of monocytes and maturing macrophages from patients with systemic lupus erythematosus: relevance to in vitro impairment of interaction with iC3b-opsonized apoptotic cells.

Impaired handling of apoptotic cells has been suggested as an important factor in the development of systemic lupus erythematosus (SLE), and a role for complement in the removal of apoptotic cells was shown recently. We studied the in vitro function of macrophages from 40 patients with SLE and their matched controls in the removal of heterologous apoptotic cells opsonized by iC3b. Interaction index of apoptotic cells opsonized by iC3b was significantly lower in patients with SLE and averaged 71% +/- 37 of that of healthy individuals (p < 0.002) and 69% +/- 35 of patients with rheumatoid arthritis (p < 0.007). SLE patients had increased apoptosis of both freshly isolated monocytes (p < 0.001) and maturing macrophages (p < 0.04) that led to decreased density of monocyte-derived macrophages. Apoptosis was inhibited by adding soluble Fas receptor indicating Fas-mediated apoptosis. As demonstrated in both healthy controls and patients with SLE, decreased macrophage density by itself caused significant decreased uptake of apoptotic cells by the remaining macrophages. Maintaining normal density in SLE patients either by an increased initial density or by using soluble Fas restored the interaction capacity of the individual macrophages in the majority of patients. We concluded that impaired in vitro interaction of iC3b-opsonized apoptotic cells with macrophages from patients with SLE was mainly associated with Fas-dependent accelerated apoptosis of the monocytes/macrophages. Accelerated apoptosis of phagocytes may represent a novel in vitro mechanism of impairment of interaction with apoptotic cells that, apart from reducing the number of professional phagocytes, alters the function of the remaining macrophages.

Huge acoustic neurinomas presenting in the late stage of pregnancy. Treatment options and review of literature.

BACKGROUND: Even though vestibular schwannomas rarely present during pregnancy, symptoms may appear or worsen particularly in this period. The clinical picture may include tinnitus, hearing abnormalities, and in large tumors, brain-stem and cerebellar compression with involvement of additional cranial nerves. Large vestibular schwannomas (also known as Acoustic Neurinomas) present a great challenge in peripartum management of both the mother and the fetus. MATERIAL AND METHOD: We present a case of a 24-year old woman, with headache, papilledema, ataxia, and multiple cranial nerve weakness, diagnosed in the 35th week of pregnancy. MRI demonstrated a huge vestibular schwannoma compressing the brainstem and causing obstructive hydrocephalus. RESULT: In the presence of high intra-cranial pressure a ventriculo-peritoneal shunt was first inserted, enabling delay of tumor surgery until after delivery. A successful elective cesarean section followed at 37 weeks, and radical tumor surgery was performed a week later. Maternal and fetal outcome were excellent. DISCUSSION: The options, sequence and timing of the neurosurgical and obstetrical interventions are discussed. Other reports of large vestibular schwannomas that presented during pregnancy are reviewed. Advances in neurosurgery, neuroradiology, neuroanesthesiology and obstetrics are highlighted, and their impact on outcome is discussed in comparison to the poor results reported in the past. Emphasis is made on the importance of early diagnosis, that necessitates high-index of suspicion by the obstetrician, in any pregnant woman presenting abnormal neurological signs. CONCLUSION: We conclude that with a cooperative team approach, maternal and fetal prognosis can today be excellent, even in cases of large vestibular schwannomas diagnosed in the late stage of pregnancy.

Anaplastic and atypical meningiomas express high levels of Fas and undergo apoptosis in response to Fas ligation.

In this study we characterized the expression of Fas and Fas ligand in different types of meningiomas and examined the effect of Fas ligation on the death of meningioma cells in culture. Using Western blot analysis, we found that extracts derived from anaplastic and atypical meningiomas expressed high levels of Fas, whereas benign meningiomas did not express detectable levels of this protein. All of the meningiomas examined expressed low levels of Fas ligand. Cultures of anaplastic meningiomas also expressed Fas and treatment of these cells with anti-Fas antibody induced cell death. The results of this study indicate that Fas is preferentially expressed in atypical and anaplastic meningiomas and suggest that it is involved in the increased apoptosis observed in these tumors.

Thoracic hematomyelia secondary to coumadin anticoagulant therapy: a case report.

A case of thoracic hematomyelia secondary to anticoagulant therapy is presented. Clinical features, similar to 2 other previously reported cases, are discussed. A high index of suspicion may lead to a quick diagnostic procedure and successful decompressive surgery.

Identification of the promoter, genomic structure, and mouse ortholog of LGI1.

The human LGI1 gene is a leucine-rich, repeat-containing gene that was cloned from the t(10:19) breakpoint of the T98G glioblastoma cell line. The LGI1 gene maps to 10q24, a region of peak LOH in malignant gliomas, and is inactivated during the transition from low to high-grade brain tumors. Here we report detailed studies of the genomic structure of the LGI1 gene and its promoter. We have also cloned and characterized the mouse lgil gene, which is 97% homologous to the human gene at the amino acid level and 91% homologous at the nucleotide level. LGI1 contains 8 exons, where each of the four leucine-rich repeat units is contained in an individual 72-bp exon. The cysteine-rich regions flanking the LRR and the single trans-membrane domain do not occupy individual exons. Approximately 5-kb of the genomic region 5' to LGI1 was sequenced, but conventional CAAT and TATA motifs were not present within this sequence. A 597-bp fragment of this 5' sequence was cloned upstream of a promoterless luciferase gene and was shown to be sufficient to drive transcription. SSCP analysis of the coding region of LGI1 in 20 glioblastomas and five cell lines did not reveal any mutations. Because LGI1 expression is considerably downregulated in gliomas, we also investigated whether this was owing to changes in the methylation status of the promoter. Southern blot analysis and 5-azacytidine treatment did not show any appreciable difference in methylation status between normal brain and glioblastomas.

Rathke's cleft cyst abscess.

Pituitary abscesses are rare. Occasionally they will arise in pre-existing pituitary pathology. We report such an occurrence within a Rathke's cleft cyst. On the basis of history and imaging, this was indistinguishable from more commonly encountered pituitary pathology.

Expression of oligodendrocyte progenitor cell antigens by gliomas: implications for the histogenesis of brain tumors.

The early events in neoplastic transformation can be understood only by comparison of the neoplastic cell with its nontransformed counterpart. The most common central nervous system gliomas traditionally are thought to arise from mature astrocytes and oligodendrocytes. We examined the possibility that gliomas arise from a population of glia that has properties of oligodendrocyte progenitors. These glial cells express the NG2 chondroitin sulfate proteoglycan and the alpha receptor of platelet-derived growth factor in vivo. We identified NG2 and the alpha receptor of platelet-derived growth factor expression in tissue from seven of seven oligodendrogliomas, three of three pilocytic astrocytomas, and one of five glioblastoma multiforme. These data provide evidence that glial tumors arise from glial progenitor cells. Molecules expressed by these progenitor cells should be considered as targets for novel therapeutics.

Coincidental supraorbital neuralgia and sinusitis.

Headache interpreted as treatment failure may be encountered after FESS or pharmacological treatment for chronic sinusitis. This persistent symptom may lead, even in the presence of minimal sinus disease, to frequent office visits, medical treatment, primary surgery, and revision procedures. A prospective study of patients with a documented history and imaging-verified sinus disease with persistent atypical refractory headache were evaluated. Diagnostic measures included injection of local anesthetic and response to carbamazepine. Severe neuralgia of the supraorbital nerve was identified in 11 patients with chronic sinusitis, treated either medically or surgically before inclusion in the study. Eight of the patients underwent surgery for sinus disease, and five of them had revision surgery because of persisting complaints. All patients responded favorably to the local injection, and eight were treated with carbamazepine. In certain cases, headache in sinusitis patients may be caused or aggravated by supraorbital neuralgia. Sinus disease is possibly a causative factor but conceivably plays the role of a "red herring." This readily diagnosed and treated coexistence may be more prevalent than recognized formerly.