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Ian R. Piper, J. Douglas Miller, N. Mark Dearden, James R. S. Leggate and Ian Robertson

✓ In an observational study in head-injured patients, cerebrovascular pressure transmission was investigated using a systems analysis approach whereby the blood pressure (BP) waveform was used as a measure of an input stimulus to the cerebrovascular bed (CVB) and the intracranial pressure (ICP) waveform as the response to that stimulus. The transfer function is a measure of how much pressure is transmitted through the CVB at a given frequency and is calculated using Fourier analysis of the pressure waveforms. The transfer function allows quantification of the pressure transmission performance of the CVB, thus providing a basis for comparison between normal and abnormal function.

Fifteen hundred samples of ICP and BP waveforms were collected from 30 head-injured patients via microcomputer. Off-line spectral analysis of the waveform database revealed four main classes of transfer function: those with an overall flat transfer function (curve type 1); those with an elevated low-frequency response (curve type 2); those with an elevated high-frequency response (curve type 3); and those exhibiting both an elevated low- and high-frequency response (curve type 4). Curve types 2 and 4 were most often associated with raised ICP (> 20 mm Hg), whereas curve types 1 and 3 were most often affiliated with ICP less than 15 mm Hg. Studies of this type may provide insight into the pathophysiology of the CVB and ultimately aid in the prediction and treatment of raised ICP.

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Sanjiv Bhatia, Faiz Ahmad, Ian Miller, John Ragheb, Glenn Morrison, Prasanna Jayakar and Michael Duchowny


Refractory status epilepticus (RSE) is a life-threatening neurological emergency associated with high morbidity and mortality. Affected patients often require prolonged intensive care and can suffer multiple complications. Surgical intervention to control RSE is rarely used but can obviate the risks of prolonged seizures and intensive care treatment. Authors of the present study analyzed their experience with the surgical management of patients suffering from RSE.


The Epilepsy Surgery Database at Miami Children's Hospital was reviewed for patients who had undergone surgery for RSE. Clinical presentation, electrophysiological profile, radiological data, surgical details, and postoperative course were evaluated.


Between 1990 and 2012, 15 patients underwent surgery for uncontrolled seizures despite high-dose medical suppressive therapy. The mean preoperative duration of status epilepticus was 8 weeks. Ictal SPECT and FDG-PET imaging in conjunction with intraoperative electrophysiological studies helped to outline the extent of resection. Surgical intervention controlled seizures in all patients and facilitated the transition out of intensive care. Adverse events related to a prolonged intensive care unit stay included sepsis and respiratory complications. Four patients had worsened neurological function, developing hemiparesis and dysphasia. There was no operative mortality.


Surgical intervention can successfully control refractory partial status epilepticus, prevent associated morbidity, and decrease intensive care unit stay. Ictal SPECT and PET are valuable in guiding resection.

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Thomas H. Milhorat, David E. Adler, Ian M. Heger, John I. Miller and Joanna R. Hollenberg-Sher

✓ The pathology of hematomyelia was examined in 35 rats following the stereotactic injection of 2 µl blood into the dorsal columns of the thoracic spinal cord. This experimental model produced a small ball-hemorrhage without associated neurological deficits or significant tissue injury. Histological sections of the whole spinal cord were studied at intervals ranging from 2 hours to 4 months after injection. In acute experiments (2 to 6 hours postinjection), blood was sometimes seen within the lumen of the central canal extending rostrally to the level of the fourth ventricle. Between 24 hours and 3 days, the parenchymal hematoma became consolidated and there was an intense proliferation of microglial cells at the perimeter of the lesion. The cells invaded the hematoma, infiltrated its core, and removed erythrocytes by phagocytosis. Rostral to the lesion, the lumen of the central canal was found to contain varying amounts of fibrin, proteinaceous material, and cellular debris for up to 15 days. These findings were much less prominent in the segments of the canal caudal to the lesion. Healing of the parenchymal hematoma was usually complete within 4 to 6 weeks except for residual hemosiderin-laden microglial cells and focal gliosis at the lesion site. It is concluded that the clearance of atraumatic hematomyelia probably involves two primary mechanisms: 1) phagocytosis of the focal hemorrhage by microglial cells; and 2) drainage of blood products in a rostral direction through the central canal of the spinal cord.

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Ian R. Whittle, Janet S. MacPherson, J. Douglas Miller and John F. Smyth

✓ Tauromustine (TCNU), 130 mg/sq m, was administered intraoperatively by nasogastric tube to 10 patients with malignant glioma (seven glioblastomas and three anaplastic astrocytomas). High-performance liquid chromatography analysis of 32 tumor specimens for TCNU revealed that tissue concentrations ranged from 0 to 554 ng/gm; TCNU was not detected in necrotic regions of the tumor. Levels of TCNU in brain adjacent to tumor were similar to those recorded within the gliomas (range 0 to 635 ng/gm). The variability in the tissue level of TCNU was partly attributable to variable absorption of the drug, since peak plasma TCNU levels ranged from 164 to 3333 ng/ml. There were close quantitative and temporal relationships between the times of peak plasma levels (median 456 ng/ml at 45 minutes after administration), peak tumor levels (median 250 ng/gm tissue at 55 minutes), and brain adjacent to tumor levels (median 256 ng/gm tissue at 50 minutes). Linear regression analysis of the ratio between tissue and plasma TCNU levels at particular times after drug administration suggest that plasma concentrations can be used to estimate tissue concentrations. This study demonstrates that TCNU enters malignant glioma. In view of the activity of TCNU against a range of tumors, a full clinical evaluation of this new nitrosourea in malignant glioma seems justified.

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Alexander G. Weil, Ngoc Minh D. Le, Prasanna Jayakar, Trevor Resnick, Ian Miller, Aria Fallah, Michael Duchowny and Sanjiv Bhatia


Seizure onset in the insular cortex as a cause of refractory epilepsy is underrepresented in the pediatric population, possibly due to difficulties localizing seizure onset in deep anatomical structures and limited surgical access to the insula, a complex anatomical structure with a rich overlying vascular network. Insular seizure semiology may mimic frontal, temporal, or parietal lobe semiology, resulting in false localization, incomplete resection, and poor outcome.


The authors retrospectively reviewed the records of all pediatric patients who underwent insular cortical resections for intractable epilepsy at Miami Children's Hospital from 2009 to 2015. Presurgical evaluation included video electroencephalography monitoring and anatomical/functional neuroimaging. All patients underwent excisional procedures utilizing intraoperative electrocorticography or extraoperative subdural/depth electrode recording.


Thirteen children (age range 6 months–16 years) with intractable focal epilepsy underwent insular-opercular resection. Seven children described symptoms that were suggestive of insular seizure origin. Discharges on scalp EEG revealed wide fields. Four patients were MRI negative (i.e., there were no insular or brain abnormalities on MRI), 4 demonstrated insular signal abnormalities, and 5 had extrainsular abnormalities. Ten patients had insular involvement on PET/SPECT. All patients underwent invasive investigation with insular sampling; in 2 patients resection was based on intraoperative electrocorticography, whereas 11 underwent surgery after invasive EEG monitoring with extraoperative monitoring. Four patients required an extended insular resection after a failed initial surgery. Postoperatively, 2 patients had transient hemiplegia. No patients had new permanent neurological deficits. At the most recent follow-up (mean 43.8 months), 9 (69%) children were seizure free and 1 had greater than 90% seizure reduction.


Primary insular seizure origin should be considered in children with treatment-resistant focal seizures that are believed to arise within the perisylvian region based on semiology, widespread electrical field on scalp EEG, or insular abnormality on anatomical/functional neuroimaging. There is a reasonable chance of seizure freedom in this group of patients, and the surgical risks are low.

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Aria Fallah, Alexander G. Weil, Samir Sur, Ian Miller, Prasanna Jayakar, Glenn Morrison, Sanjiv Bhatia and John Ragheb


Pediatric brain tumors may be associated with medically intractable epilepsy for which surgery is indicated. The authors sought to evaluate the efficacy of epilepsy surgery for seizure control in pediatric patients with brain tumors.


The authors performed a retrospective review of consecutive patients undergoing resective epilepsy surgery related to pediatric brain tumors at Miami Children’s Hospital between June 1986 and June 2014. Time-to-event analysis for seizure recurrence was performed; an “event” was defined as any seizures that occurred following resective epilepsy surgery, not including seizures and auras in the 1st postoperative week. The authors analyzed several preoperative variables to determine their suitability to predict seizure recurrence following surgery.


Eighty-four patients (47 males) with a mean age (± standard deviation) of 8.7 ± 5.5 years (range 0.5–21.6 years) were included. The study included 39 (46%) patients with gliomas, 20 (24%) with dysembryoplastic neuroepithelial tumors (DNETs), 14 (17%) with gangliogliomas, and 11 (13%) with other etiologies. Among the patients with gliomas, 18 were classified with low-grade glioma, 5 had oligodendroglioma, 6 had uncategorized astrocytoma, 3 had pilocytic astrocytoma, 3 had pleomorphic xanthoastrocytoma, 3 had glioblastoma, and 1 had gliomatosis cerebri. Seventy-nine (94.0%) resections were guided by intraoperative electrocorticography (ECoG). The mean time (± standard deviation) to seizure recurrence was 81.8 ± 6.3 months. Engel Class I outcome was achieved in 66 (78%) and 63 (75%) patients at 1 and 2 years’ follow-up, respectively. Patients with ganglioglioma demonstrated the highest probability of long-term seizure freedom, followed by patients with DNETs and gliomas. In univariate analyses, temporal location (HR 1.75, 95% CI 0.26–1.27, p = 0.171) and completeness of resection (HR 1.69, 95% CI 0.77–3.74, p = 0.191) demonstrated a trend toward a longer duration of seizure freedom.


ECoG-guided epilepsy surgery for pediatric patients with brain tumors is highly effective. Tumors located in the temporal lobe and those in which a complete ECoG-guided resection is performed may result in a greater likelihood of long-term seizure freedom.

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Michel Lacroix, Dima Abi-Said, Daryl R. Fourney, Ziya L. Gokaslan, Weiming Shi, Franco DeMonte, Frederick F. Lang, Ian E. McCutcheon, Samuel J. Hassenbusch, Eric Holland, Kenneth Hess, Christopher Michael, Daniel Miller and Raymond Sawaya

Object. The extent of tumor resection that should be undertaken in patients with glioblastoma multiforme (GBM) remains controversial. The purpose of this study was to identify significant independent predictors of survival in these patients and to determine whether the extent of resection was associated with increased survival time.

Methods. The authors retrospectively analyzed 416 consecutive patients with histologically proven GBM who underwent tumor resection at the authors' institution between June 1993 and June 1999. Volumetric data and other tumor characteristics identified on magnetic resonance (MR) imaging were collected prospectively.

Conclusions. Five independent predictors of survival were identified: age, Karnofsky Performance Scale (KPS) score, extent of resection, and the degree of necrosis and enhancement on preoperative MR imaging studies. A significant survival advantage was associated with resection of 98% or more of the tumor volume (median survival 13 months, 95% confidence interval [CI] 11.4–14.6 months), compared with 8.8 months (95% CI 7.4–10.2 months; p < 0.0001) for resections of less than 98%. Using an outcome scale ranging from 0 to 5 based on age, KPS score, and tumor necrosis on MR imaging, we observed significantly longer survival in patients with lower scores (1–3) who underwent aggressive resections, and a trend toward slightly longer survival was found in patients with higher scores (4–5). Gross-total tumor resection is associated with longer survival in patients with GBM, especially when other predictive variables are favorable.

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Michael G. O'Sullivan, Patrick F. Statham, Patricia A. Jones, J. Douglas Miller, N. Mark Dearden, Ian R. Piper, Shirley I. Anderson, Alma Housley, Peter J. Andrews, Susan Midgley, Jane Corrie, Janice I. Tocher and Robin Sellar

✓ Previous studies have suggested that only a small proportion (< 15%) of comatose head-injured patients whose initial computerized tomography (CT) scan was normal or did not show a mass lesion, midline shift, or abnormal basal cisterns develop intracranial hypertension. The aim of the present study was to re-examine this finding against a background of more intensive monitoring and data acquisition.

Eight severely head-injured patients with a Glasgow Coma Scale score of 8 or less, whose admission CT scan did not show a mass lesion, midline shift, or effaced basal cisterns, underwent minute-to-minute recordings of arterial blood pressure, intracranial pressure (ICP), and cerebral perfusion pressure (CPP) derived from blood pressure minus ICP. Intracranial hypertension (ICP ≥ 20 mm Hg lasting longer than 5 minutes) was recorded in seven of the eight patients; in five cases the rise was pronounced in terms of both magnitude (ICP ≥ 30 mm Hg) and duration. Reduced CPP (≤ 60 mm Hg lasting longer than 5 minutes) was recorded in five patients.

Severely head-injured (comatose) patients whose initial CT scan is normal or does not show a mass lesion, midline shift, or abnormal cisterns nevertheless remain at substantial risk of developing significant secondary cerebral insults due to elevated ICP and reduced CPP. The authors recommend continuous ICP and blood pressure monitoring with derivation of CPP in all comatose head-injured patients.