To assess the feasibility, toxicity, and local control of stereotactic radiosurgery followed by accelerated external beam radiotherapy (AEBR) for patients with glioblastoma multiforme.

Six males and eight females, with a median age of 67.5 years (range 45-78 years), entered the study. Karnofsky performance status was 90 for five, 80 for six, and 60 for three patients. Following surgery, the patients were left with a residual mass 4 cm. Radiosurgery was delivered with a single dose of 20 Gy to the 90% isodose surface corresponding to the contrast-enhancing edge of the tumour. A total AEBR dose of 60 Gy in 30 fractions was delivered using a concomitant boost technique over four weeks.

Median survival time was 40 weeks (range 17-80 weeks). Actuarial survivals at 12 and 18 months were 43% and 14%, respectively. The median time to progression was 25 weeks (range 2-77 weeks). One patient developed a seizure on the day of stereotactic radiosurgery. Two patients experienced somnolence at 47 and 67 days post-radiotherapy. Eight patients remained steroid-dependent. Radiological evidence of leukoencephalopathy was observed in one patient, and brain necrosis in two additional patients at 30 and 63 weeks. One of these two patients with brain necrosis developed complete loss of vision in one eye, and decreased vision in the contralateral eye at 63 weeks.

Stereotactic radiosurgery followed by AEBR was feasible but was associated with late complications. The use of such radiosurgical boost for patients with glioblastoma multiforme should be reserved for those patients entering controlled clinical trials.

To determine the epidemiological profile for pediatric pseudotumor cerebri.

A retrospective case series was identified from a geographically limited region of 205,765 children aged 2-15 years at the only tertiary care pediatric hospital with all pediatric neurologists and ophthalmologists. Health records identified 35 children with ICD9 code 348.2 (benign intracranial hypertension) presenting between April 1, 1979 and March 31, 1994. After chart review, 29 cases were identified which satisfied modified Dandy's diagnostic criteria for pseudotumor cerebri.

The 29 cases ranged in age from 3-15 years. The annual incidence of symptomatic disease was 0.9 per 100,000 children (95% Cl 0.6, 1.4). Cases were 2.7 times more likely to be female (21/29, X² p = .01) and twice as likely to be adolescent (age 12-15 years), (X² p = .04). Based upon these distinctions, the following estimates of age and sex specific disease incidence were derived (based upon 100,000 child years of exposure): male age 2-11 years: 0.4; male age 12-15 years: 0.8; female age 2-11 years: 1.1; female age 12-16 years: 2.2.

These data appear to be unique for its the estimation of age and sex specific incidence rates for pediatric pseudotumor cerebri.

To utilize the diagnostic criteria of frontal lobe dementia (FLD).

We studied 12 patients with FLD diagnosed clinically, with radiological confirmation in 10 and autopsy confirmation in 2; sixteen patients with Alzheimer's disease matched for stage and severity to FLD and 11 patients with depressive dementia were used as control groups. A 24-item Frontal Behavioral Inventory (FBI) using the most relevant behavioral manifestations of FLD was administered in these populations.

FLD patient scores on the FBI were much higher compared with control groups (AD and DD). Item analysis showed loss of insight, indifference, distractibility, personal neglect and apathy as the most frequent negative symptoms. Perseveration, disinhibition, inappropriateness, impulsivity, and irresponsibility were the most significant positive symptoms. An operational definition of FLD included a minimum FBI score of 27. Only one false positive was shown in the depressive group and none among the AD group, indicating little overlap between patient groups, and a high discriminating value of the FBI.

The FBI appears to be a useful diagnostic instrument and a method to operate the behavioral criteria of FLD. Further prospective studies are warranted to establish validity.

Currently, decreases in seizure frequency are the accepted efficacy outcome measure of therapeutic interventions in the management of patients with epilepsy. In a longitudinal randomized controlled trial of 10 subjects with intractable complex partial seizures who received left vagal nerve stimulation (VNS) to control seizures, it was found that the total number of consecutive seizure-free days is a significant efficacy outcome measure. Unlike measures in which percentage decreases in seizure frequency are calculated, measures of consecutive seizure days indicate improvement in the amount of time for which patients may function at a higher level in activities of daily living.

Fourteen day blocks of consecutive seizure-free days and 14 day blocks of consecutive days in which subjects had seizures were tabulated.

A Pearson correlation coefficient showed that prior to VNS subjects had few, if any, seizure free blocks of time and after VNS they had more blocks of time seizure free r = -1.00 and r = -0.99. The blocks of seizure-free days increased tenfold (x̄ 0.85 to x̄ 8.00) from 1991-1995 while mean seizure frequency in those blocks in which subjects had seizures only decreased from (x̄ 20.14 to x̄ 17.59) for the same time period. Correlations between total number of seizures after 24 months of VNS and after 50 months of VNS were r = 0.85 showing a consistency in the effect of VNS.

Monitoring the number of consecutive seizure-free days is a significant clinical outcome measure of VNS.

To assess the ease and reliability of routine use of somatosensory evoked potentials (SSEPs) for identification of sensorimotor cortex in brain tumour removal and to document its influence on the performance and outcome of surgery.

SSEPs in response to contralateral median nerve stimulation were recorded from the cortical surface by means of a four lead electrode strip. Polarity reversal of short latency SSEP waves was used to identify the position of the central sulcus in 46 consecutive craniotomies for removal of metastases, gliomas, or meningiomas located in, near, or overlying sensorimotor cortex.

SSEPs were successfully recorded in 43/46 cases (94%) with demonstration of polarity reversal in 42/43 (98%). SSEP localization led to modification of 14/42 (33%) procedures, most frequently because of either displacement or involvement of sensorimotor cortex by tumour. Six patients (14%) developed new neurological deficits but none of these was attributable to incorrect identification of sensorimotor cortex.

SSEP polarity reversal is a simple, reliable, accurate, and inexpensive method of localizing sensorimotor cortex under general anaesthesia. Correct identification is possible when sensorimotor cortex is displaced or when surface anatomy is obscured by tumour. Routine use of this technique should be considered in all procedures for lesions located near the central sulcus.

Alfentanil is a potent, short-acting opioid agent which has been used during balanced anaesthesia in children undergoing the surgical excision of epileptic foci. After the observation that this agent had the potential to induce epileptic seizures, we questioned the frequency of this occurrence in this group of patients.

Twelve patients (6 males, 6 females) undergoing surgical excision of an epileptic foci were prospectively followed. For each patient an electrocorticogram was recorded for 30 minutes before and after receiving alfentanil 20 pg/kg intravenously. The frequency of epileptiform abnormalities before and after drug administration was evaluated. When the electrocorticogram no longer showed the effects of alfentanil administration, methohexital 0.5 ug/kg was given intravenously.

Alfentanil induced significant activation of epileptiform discharges among 83% of these patients. Twenty-five per cent had an electrographic seizure. In comparison, methohexital induced significant activation of epileptiform discharges in 50% of these patients. None experienced electrographic seizures.

As alfentanil can induce electrographic seizures in patients known to have epilepsy, caution is advised in its use in this group of patients.

Early studies of cognitive motor control have shown deficits in complex reaction time tests of epileptic subjects. The purpose of this efficacy study was to determine whether chronic (28 months) stimulation of the left vagus nerve (VNS) to control seizures increased these deficits in 6 epileptic subjects with intractable complex partial seizures.

Subjects were assessed for simple reaction time, Test A, and subsequent Tests B and C which involved more complex cognitive strategies. Tests were done pre-operatively (S1) and at intervals, 6-8 weeks (S2-S3), and at 6 month intervals (S4-S6) over a 28 month period. Data were collected and collated on an Apple II E computer (Apple, Cupertino CA. U.S.A.) and on electronic switch pad. Data were analyzed using a repeated measures analysis of covariance technique with 2 within subject factors, day, and time of day.

2/11 cognitive measures showed a statistically significant difference. Error rate associated with Test A (simple reaction time) significantly decreased for the factor of day (repeated visits) p = .01. For Test C, error rates decreased in the afternoon (p = .03). This test involved the subjects ability to respond quickly to one signal while simultaneously ignoring a second signal. Data analysis of the covariate showed that the effects of VNS are weak in comparison to baseline differences and the frequency of nerve stimulation negatively predicts the number of wrong errors. High frequency stimulation results showed fewer errors than low frequency stimulation T = -2.31, p = .03.

Chronic stimulation of the left vagus nerve to control seizure activity does not impair cognitive motor control.

The cortical changes resulting from chronic hydrocephalus in adults are not well defined.

Retrospective analysis of twenty-one patients (age 64-88 years) with a clinical diagnosis of “normal pressure hydrocephalus” who underwent cortical biopsy at the time of intracranial pressure monitoring or shunt insertion, and eight patients who were biopsied but not shunted. Eleven brains (age 26-92 years), seven from patients who could be considered to have “normal pressure hydrocephalus”, were also examined following autopsy. Age- and sex-matched control brains with small ventricles and no history of dementia were compared to the hydrocephalic brains. Senile plaques and neurofibrillary tangles were assessed semiquantitatively and a non-parametric statistical analysis was employed.

Five biopsies exhibited both senile plaques and rare neurofibrillary tangles, while two had only neurofibrillary tangles. Neurofibrillary tangles were more prevalent in hydrocephalic brains than in controls. There was no difference in the prevalence of senile plaques between the two groups. Grumose bodies in the substantia nigra were identified in five autopsy brains, a prevalence higher than in control brains.

These pathological features are not specific for hydrocephalus; however, they suggest that long-standing ventriculomegaly is associated with degenerative brain changes in sites beyond the periventricular white matter. The presence of senile plaques in cortical biopsies from hydrocephalic patients does not appear to be a contraindication to shunting; however a prospective study in patients undergoing intracranial pressure monitoring would better address the issue.

To help investigators decide if new therapies for glioma warrant definitive evaluation in randomized studies we have been developing a method for assessing the degree to which patient selection may have enhanced the results of uncontrolled treatment trials. In this study, we analyzed the impact of case selection on the survival of patients with malignant glioma receiving adjuvant stereotactic radiosurgery, a promising therapy reserved for those with small tumors and good performance status.

Following published eligibility criteria we simulated the patient selection process for stereotactic radiosurgery given as a boost at the conclusion of conventional radiotherapy. Eligible patients were culled from a pre-existing clinical/imaging database of 101 consecutive conventionally-treated patients with biopsy-proven malignant glioma and known survival times. Median durations of survival and 2- and 3-year survival rates were determined for those judged eligible or ineligible for stereotactic radiosurgery.

Twenty-seven percent of patients were deemed eligible for stereotactic radiosurgery, eligible patients had more favorable prognostic factors and significantly longer median survival than ineligible patients (23.4 vs. 8.6 months; 2-year rate, 48% vs. 15%; 3-year rate, 30% vs. 7%); eligible patients also had a longer median survival than the entire group of unselected patients (23.4 vs. 11.4 months). Radiosurgery-eligible, conventionally-treated patients with glioblastoma multiforme and a group of radiosurgery-treated patients at a special referral center had similar median survival times (16.4 vs. 19.7 months).

We provide additional evidence for selection bias in uncontrolled trials of stereotactic radiosurgery and by simulating the selection process accurately have detected a larger bias effect than noted previously. Judging from experience with interstitial radiation and intraarterial chemotherapy where substantial selection bias also occurred and randomized controlled trials proved disappointing, we conclude that a phase III study of stereotactic radiosurgery for malignant glioma is unlikely to yield a positive result and may not be necessary.

We studied the incidence and clinical significance of early post-traumatic seizures after severe closed head injury.

This prospective study is based on clinical observation of 3340 adult patients with severe closed head injuries, each of them having a Glasgow Coma Scale (GCS) 3 to 8 after trauma. Anticonvulsant agents were not given to these patients unless there was evidence of seizure.

One hundred and twenty-one patients (3.6%) experienced seizures within 1 week after head injury; 42 of these (1.26% of the series) had seizures within 24 hours after trauma. The incidence of intracerebral parenchymal damage was found to be higher among those patients who developed seizures in the first week (66.1%) than in those who did not (62.7%). However this result did not reach statistical significance. The patients with early seizures had a lower mortality rate (p < 0.01). In patients who survived from the initial injury, the occurrence of early post-traumatic seizures did not appear to influence the neurological recovery at 6 months after injury.

Presence of intracerebral parenchymal damage on CT scan after severe closed head injury does not increase the risk of early post-traumatic seizures. With proper treatment, patients presenting with early seizures may have a lower mortality rate. However, the occurrence of early seizures does not influence the neurological recovery in patients who survive the initial severe closed head injury.

Stimulation of the left vagus nerve (VNS) has been shown to control seizures in double blinded crossover studies in man. Animal studies have reported vagal afferent induced depression of nociceptive and motor reflexes which may be caused by an effect on the descending reticular system controlling spinal cord function. Anticonvulsant drug therapy may cause postural instability. The effects of VNS are assessed not only from the perspective of seizure control but also from the view of potential harm to other bodily systems. Long term (2¼ years) effects of VNS were compared to postural stability analyses.

8 subjects, 2 were females, mean age 34.5 ± 8.23 SD years, with intractable complex partial seizures, taking 3 anticonvulsant drugs were assessed for postural stability in quiet standing and while moving forwards, backwards and sideways with eyes open (EO) and eyes closed (EC). Data were collected and collated using an AMTI Biomechanics immovable forceplate, Newton M.A. U.S.A. The study design was longitudinal with pre-operative baseline data collected prior to neurostimulation and at intervals post operatively.

4/8 balance measures showed significant changes from pre-operative values and after 2¼ years of stimulation. Area of sway (EO) in quiet standing p = .022 and total sway (EC) in the moving state p = .019 and total sway (EC) in quiet standing showed an increase in sway p = .003. Area of sway (EC) p = .004 tended to decrease. Regression analysis for frequency of stimulation showed an increase in sway with higher frequencies T = 1.99, P = .05.

Chronic VNS does not augment postural instability.

Previous studies demonstrated that destabilizing responses to slow perturbations were enhanced in patients with Parkinson's disease (PD). Our objectives were to investigate the influence of PD on responses to faster whole head-and-body tilts in the standing position, and to establish whether any modification of tilt-evoked responses in PD patients was related to possible changes in the modulation of soleus (SO) H-reflex.

Ten PD patients and 10 age-matched normal subjects assumed a standing position on an L-shaped tilting apparatus. Their head and shoulders were firmly attached to the back support of the apparatus, while their feet were fixated to the standing platform. With their vision occluded, the subject's whole head-and-body was suddenly tilted forward to 20°, at a peak head acceleration of 0.7g ± 0.lg. Tilt-evoked responses were recorded from the lower limb muscles bilaterally. In addition, 40 H-reflexes were elicited in the SO muscle at 30-190 ms intervals after the onset of head acceleration. The M response amplitude was kept within ±15% of its control value.

PD patients demonstrated an abnormally high responsiveness to whole head-and-body tilts in comparison with age-matched normal subjects. This was shown by the significantly larger proportion of PD patients manifesting responses in the SO, biceps femoris and vastus lateralis muscles (p<0.05), as well as their significantly larger SO response area (413%; p<0.01). In contrast, the amplitude of the SO H-reflex was significantly increased by only 14% (p<0.05) in these patients, and only at 30-70 ms after head acceleration onset.

The overexcitable tilt-evoked responses of PD patients could originate from a reduced ability to suppress responses when the body is supported. This enhanced excitability of tilt-evoked responses was probably not due to motoneuronal hyperexcitability or decreased presynaptic inhibition of the group la terminals involved in the mainly monosynaptic H-reflex pathway. Thus, we hypothesize that the control of spinal interneurons involved in the tilt-evoked responses may be defective in PD.

A reliable marker for tumor oligodendroglial cells is not yet available, so that the histological recognition of the tumor still encounters uncertainties. There is no general agreement also on prognostic factors in oligodendroglioma. The inconsistency concerns mainly the histopathological factors. The aim of the study was recognition of prognostic factors in oligodendroglioma.

In a series of ninety-eight oligodendrogliomas, including twenty mixed oligoastrocytomas, clinical [sex, age at surgery, tumor location, symptoms at presentation], therapeutic [extent of resection, year of surgery, post-operative Karnofsky score, post-operative radiotherapy, post-operative chemotherapy], histological [cell density, nuclear pleomorphism, vascular endothelial proliferation, necrosis, microcysts, mitoses, mitotic index (MI), apoptosis, apoptotic index (AI)] and immunohistochemical parameters [MIB-1 and PCNA Labeling Indexes (Lis), staining for GFAP, positivity for p53] were correlated with survival in uni- and multivariate analysis in order to identify their prognostic significance.

Age at surgery, extent of surgical resection, year of surgery, postoperative Karnofsky score and MIB-1 LI were associated with survival in both uni- and multivariate analysis. Location, symptoms at presentation, mitoses, MI, AI, and PCNA LI showed a significant correlation with survival in uni- but not in multivariate analysis. The twenty cases of oligoastrocytomas did not show any difference in survival from pure oligodendrogliomas.

Some clinical and therapeutic factors together with MIB-1 LI play a prognostic role. MIB-1 LI is prognostic with a cutoff of 8%. Histology gives a limited contribution to the prognosis. Oligoastrocytomas had the same outcome and prognostic factors as pure oligodendrogliomas.

Parkinson's disease (PD) patients frequently report a family history of PD and this may provide etiological clues to PD. It has also been suggested that a report of a negative family history is reliable. We studied the prevalence of PD in relatives of PD patients to assess the reliability of family history and to evaluate possible explanations of “familial PD”(fPD).

81 of 650 (12.5%) PD probands (all PD patients seen at clinic in 4 years) reported a positive family history of PD. Each fPD proband was matched with non-familial PD (nfPD) proband by gender and year of birth. Screening and follow-up questionnaires were mailed to relatives to obtain information concerning pedigree and presence of neurodegenerative disease. Available family members (regardless of disease status) were examined.

On examination, 8 persons, said to be “normal” by probands, relatives and themselves, had definite or possible PD (5 fPD, 3 nfPD). The prevalence rate of PD among first and second degree living relatives of probands varied significantly between fPD and nfPD groups (6269/100 000 versus 1190/100 000; p < 0.001). The weighted prevalence (taking into account the proportions of fPD and nfPD within the clinic) was 1822/100 000, a value more than 5 times higher than reported prevalence rates of PD in the general population (p < 0.001). The prevalence rate was greater in first degree relatives than second degree.

“Familial parkinsonism” cannot be explained merely by size of or advanced age within families. Significant numbers of previously unrecognized PD patients may be identified despite a “negative” family history. That is, the patient's report of an absence of familial parkinsonism is frequently inaccurate. The prevalence rate in relatives of PD patients appears to be higher than the general population – regardless of the family history reported by a PD patient. We believe our study suggests that genetic influences or early life environmental exposures are likely to be of etiological importance in PD.

Observation of physiological changes during motion sickness is required to quantify the degree of sickness. The review of the literature does not show unifying results. An objective symptom of motion sickness is facial pallor. It reflects changes in skin microcirculation which have not been measured so far.

Eleven healthy volunteers susceptible to motion sickness were subjected to eccentric vertical axis rotation. The dynamics and the correspondence of the changes in skin blood flow in two segments, forehead and finger, were measured by laser Doppler flowmeter.

The difference in the microcirculatory skin blood flow across the phases of motion sickness is significant for the forehead but not for the fingertip; the established dynamics of the forehead blood flow during motion sickness will be of benefit in quantifying the degree of sickness; there is no correlation between the blood flow changes in both measured areas; the rhythmic blood flow fluctuation increases during motion sickness; there is a difference between the blood flow responses to vestibular stimulation before the appearance of motion sickness and in the course of the sickness. Laser Doppler flowmetry is a reliable method in quantifying the degree of motion sickness.

The assessment of thalamocortical function in comatose patients in the intensive care unit (ICU) can be difficult to determine. Since the electroencephalogram (EEG) affords such assessment, we have developed an EEG classification for comatose patients in our general ICU.

One hundred EEGs were classified in a blinded fashion by two EEGers, using our method and that of Synek. Interobserver agreement was assessed using kappa score determination.

Kappa scores were 0.90 for our system and 0.75 for the Synek system. (The Kappa score represents the inter-rater agreement that is beyond chance; 0.90 is almost perfect agreement, while 0.75 is substantial agreement).

Our system for classifying EEGs in comatose patients has a higher interobserver reliability than one that was previously published. This EEG classification scheme should be useful in clinical electrophysiological research involving ICU patients, allowing for internal consistency and comparisons among centres.

In many countries, neurosurgical care is concentrated in regional centres, which often necessitates the inter-hospital transfer of patients with head injury for optimal treatment. The aim of this study was to evaluate the role of teleradiology in the management of head-injured patients when referred from a district general hospital to a tertiary neurosurgical centre.

Prospective data were collected over a fifteen month period from March '95 to May '96. Head-injured patients referred without the facility of teleradiology (Group 1), were compared to similar patients referred with teleradiologie images (Group 2), with particular regard to therapeutic intervention before transfer and adverse events during transfer.

There were 28 patients in Group 1 and 35 in Group 2, of which 31 were transferred. Both groups were comparable with respect to age, admission Glasgow Coma Scale score, and intracranial pathology. For patients transferred with teleradiology consultation (Group 2), therapeutic interventions were more (32.1% vs. 10.7%, p = 0.06), adverse events during transfer were significantly lower (6.4% vs. 32.1%, p = 0.01), and transfer time was reduced (72 vs. 80 minutes, p = 0.38). Four patients in Group 2 were treated by a mobile neurosurgical team at the referring hospital because of rapid clinical deterioration.

Our findings indicate that teleradiology has an important role in improving inter-hospital management of head-injured patients.

Pallidotomy helps parkinsonian symptoms. We tested the hypothesis that this might be due to changes in inhibition in the motor cortex.

We examined 15 patients with parkinsonism before and after posteroventral pallidotomy. Magnetic stimuli were delivered over the motor cortex, while subjects maintained a 30% maximum voluntary contraction of the contralateral first dorsal interosseus (FDI).

Weak stimuli inhibited voluntary muscle activity, while slightly stronger stimuli caused short latency facilitation from activation of the corticospinal neurons. After pallidotomy magnetic stimulation, at the threshold for the short latency facilitation, resulted in more inhibition than before.

Pallidotomy increases cortical inhibition. This may be associated with improved control of movements.