Adjuvant nitrosourea chemotherapy fails to prolong survival significantly as many tumors demonstrate resistance to these drugs. It has been documented in cell lines that O6-methylguanine DNA methyltransferase (MGMT) plays an important role in chloroethylnitrosourea (CENU) drug resistance.

We evaluated MGMT expression in 22 glioma specimens by using an immunofluorescence assay and compared the results with clinical responses of the patients to CENU-based chemotherapy.

Eight tumor samples had no detectable MGMT, whereas other samples had from 9,989 to 982,401 molecules/nucleus. In one group (12 patients), the tumor decreased in size or was stable (effective group), whereas in the other group (10 patients), the tumor demonstrated continuous growth during chemotherapy (progressive group). The Mer- patients (MGMT < 60,000 molecules/nucleus) appeared to have more chance of stable disease or response to CENU therapy than the Mer+ patients (MGMT > 60,000 molecules/nucleus) (X2 = 4.791, p = 0.0286). In patients with glioblastomas multiforme (GBMs), the median time to progression (TTP) of Mer+ patient was shorter than that of Mer- patient (t = 2.04, p = 0.049). As a corollary, the MGMT levels were significantly higher in GBM tumors from the progressive group than those from the effective group (t = 2.26, p = 0.029). However, there was no significant correlation between MGMT levels and either the survival time (r = 0.04, p = 0.8595) or TTP (r = 0.107, p = 0.6444).

This study suggests that being MGMT positive is indicative of a more aggressive disease that progresses more rapidly with CENU therapy. However, MGMT negative tumors are not always sensitive to CENU agents, suggesting that other factors are also important.

To study the effectiveness and safety of topiramate in clinical practice, for a group of patients with childhood onset epilepsy.

All patients treated with topiramate at the three study centers between November 1995 and December 31, 1997 were analyzed retrospectively, using a standardized study protocol. Data were gathered on demographic features, seizure response and medication related adverse events.

Eighty-seven patients were treated with topiramate. Over 90% seizure reduction was achieved in 8 (9%) patients, 50%-90% in 21 (24%), <50% in 54 (62%) patients. Four patients (5%) had a deterioration in seizure control. Adverse events required topiramate discontinuation in 36 (41%). Of these 27 (31%) complained of unacceptable cognitive dulling. The rate of dose escalation and final dose in mg/kg were similar in those who remained on topiramate and those who were intolerant because of cognitive side effects.

Although topiramate resulted in >50% seizure reduction in 29 (33%) of this group of patients with difficult epilepsy, its usefulness was limited by a high incidence of adverse effects. Adverse events prevented ongoing therapy for 36 (41%) and cognitive dulling resulted in topiramate discontinuation by 27 (31%) of the group.

We set out to determine the rate of response of low-grade (WHO Grade II) gliomas to radiotherapy and analyze the relationship between radiographic response, symptom control and patient survival.

Patients were eligible for this study if they had received radiotherapy for pathologically confirmed, residual, supratentorial low-grade astrocytoma, oligodendroglioma, or mixed glioma, and imaging studies (baseline and follow-up) were available for review. Percent change in tumor size and rate and timing of response were determined by maximum linear measurement, area measurement, volume measurement using an ellipsoid model, and volume measurement by image segmentation. For each method, response to radiotherapy was defined firstly as a ≥50% decrease in tumor size (partial response), and secondly as a decrease equivalent to a 50% area decrease (normalized partial response). Relationships between radiographic response, clinical improvement and progression-free survival were analyzed using a Cox Proportional Hazard's model.

Twenty-one patients in a database (13 male, 8 female; ages 22-66 years) met the eligibility criteria. Twenty were imaged by computed tomography, 18 had an astrocytoma and 15 were irradiated soon after surgery. Responses were common and not felt to be due to a steroid effect. Use of normalized response criteria improved agreement between assessment of response as determined by the 4 methods. Median time to maximum radiographic improvement was 2.8 months (range, 1.5-11). Sixteen patients (76%) were improved neurologically, the median time to progression was 4.8 years and the 5-year progression-free survival rate was 43%. We did not detect a statistically significant association between response (as measured by any method), symptomatology and progression-free survival.

Low-grade gliomas are moderately radioresponsive. Use of volume measurement may over-estimate the number of partial responses unless a volume reduction equivalent to a 50% area decrease is used to define response. The best way to measure response remains uncertain because neither visual, area, nor volume changes confidently predicted clinical outcomes.

To determine the etiology, early mortality, predictors of prognosis and diagnostic yields of EEG and CT scans of the head in new-onset seizures in elderly patients.

EEG records for the north-central region of Saskatchewan, between 01/94 and 12/95 were reviewed to identify all adults aged 60 years or older with new-onset seizures. Information on demographics, seizure type, etiology, EEG and neuroimaging studies, anti-epileptic treatment and course of epilepsy was obtained by review of medical records and interview with the patient and/or family member.

Of 88 eligible subjects, 61 (69%) were contacted for follow-up, 19 (22%) were deceased (12 of whom who had a serious underlying etiology to their seizures, which was obvious at the time of initial presentation and led shortly to their demise), 4 (5%) were lost to follow-up and 4 (5%) refused participation. Excluding those refusing participation, 74/84 (88%) patients presented with partial or secondarily generalized seizures. Seizures were cryptogenic in 38/84 (45%), and due to stroke in 19/84 (23%). EEGs were abnormal in 61/84 (73%) cases, with epileptiform discharge in 33/84 (39%). CT scans were abnormal in 57/84 (68%) cases with acute pathology in 29/84 (35%). Of the 61 patients participating in the follow-up interview, 54 (89%) were treated with anti-epileptic medication and seizure control was usually successful. Predictors for ongoing seizures were more than 3 seizures at presentation, epileptiform activity on initial EEG and discontinuation of anti-epileptic medication for lack of efficacy.

Prognosis of new-onset seizures in elderly patients is favorable if seizures are not symptomatic of a life-threatening disorder.

Access to multiple sclerosis (MS) diagnosis in Canada has never been assessed. This study was designed to examine the pattern of MS diagnosis in Canada, including neurologists' diagnostic approach and waiting times for investigations.

A mail survey was forwarded to every registered neurologist in Canada (n = 479) in late 1996. Questions included their diagnostic approach to MS including perceived waiting times for various investigations including MRI. Actual MRI waiting periods were separately obtained from booking clerks or neuroradiologists from every MRI unit in Canada.

153 responses were received. Neurological assessment is obtained, on average, 1 month after referral. MRI is routinely ordered by 92% of neurologists for suspected MS followed by evoked potentials (EP) (36%) and lumbar puncture (LP) (17%). The perceived waiting period for EP and LP is less than one month but 3 months for MRI. This is very similar to the actual waiting periods obtained from the MRI units surveyed (mean of 101 days). There is a trend for longer waiting periods as one moved east to west (Eastern provinces — mean of 62 days, Ontario — 95 days, Quebec — 102 days and 122 days in the Western provinces). Private MRI units have appeared in the Western provinces and have the shortest waiting periods (2 weeks maximum). The current MRI/million population ratio in Canada is 1.8, far below the ratios of other developed nations.

Canadian neurologists prefer MRI of the brain to confirm an MS diagnosis and desire greater access to it. Access to neurological assessment, EP and LP is probably adequate but the average wait for MRI of 3 months is relatively long. The perceived average waiting period for MRI is similar to the actual waiting times of 3 months, with the Western provinces of Canada having the longest waits. Canada continues to have one of the lowest MRI/population ratios in the developed world.

The Canadian Burden of Illness Study Group reported that the quality of life (QoL) of multiple sclerosis (MS) patients falls drastically, early in the disease. With disability progression, the physical functioning scales of the Short Form 36 (SF-36) showed further decreases in QoL. The objective of this study is to describe the QoL of MS patients treated with interferon beta-1b (IFNB-1b) and to compare it to the QoL observed in a group of patients who had not been treated with IFNB-1b.

Treated patients were prospectively recruited and were seen at their regular visit to the MS clinic. They self-completed the SF-36 questionnaire and their QoL was described and retrospectively compared to that of historical controls.

When IFNB-1b treated patients were compared to historical control patients with the same relapsing forms of MS, the treated patients with an Expanded Disability Status Scale (EDSS) score lower than 3.0 had a significantly better QoL. This was significant for four of the eight SF-36 domains: Physical Function (+22%, p=0.0102), Role-Physical (+100%, p=0.0022), General Health (+27%, p=0.0070) and Social Function (+19%, p=0.0287). The average QoL difference was 8% in the EDSS 3.0-6.0 group and 10% in the EDSS >6 group.

Patients with relapsing forms of MS treated with IFNB-1b have better QoL than patients who are not treated, especially those with an EDSS < 3.0.

To determine if hypoperfusion abnormalities on single photon emission computed tomography (SPECT) are associated with poorer cognitive function at baseline or increased risk of decline in cognitive function and progression to dementia in memory-impaired but non-demented elderly subjects meeting the criteria for aging associated cognitive decline (AACD).

Cross sectional study of 36 AACD subjects comparing hexamethyl propylene-amine oxime (HMPAO) SPECT results rated by visual inspection with base line cognitive functioning. Prospective study of these AACD subjects with clinical and neuropsychological follow-up over 35 months.

The memory clinic and nuclear medicine unit of a university teaching hospital.

Thirty-six subjects meeting the criteria for AACD recruited from patients seen on a physician referral basis.

1) Baseline cognitive function as measured by the Mini Mental State Examination (MMSE), Boston naming, Logical Memory I subtest of the WAIS-R, and verbal fluency, correlated with SPECT status. 2) Decline in cognitive function as measured by clinical exam and the MMSE, with progression to dementia on follow-up being correlated with SPECT status at baseline.

18 of the 36 subjects progressed to dementia (probable Alzheimer's Disease) over follow-up. No correlation was found between the presence or absence of SPECT abnormality and MMSE or other cognitive measures. There was no correlation between the presence or absence of SPECT abnormality at initial examination, and cognitive decline according to the MMSE, or with the occurrence of clinical dementia on follow-up.

We conclude that SPECT abnormalities assessed by visual inspection do not correlate with severity of impairment in AACD individuals, and are not useful in predicting progression to dementia in AACD subjects.

Clinical experience suggests that young multiple sclerosis patients may have herpes zoster (HZ) earlier and more often than the general population. As there is evidence of a relationship between varicella zoster virus (VZV) and MS, a study of HZ and MS was undertaken.

Eight hundred and twenty-nine patient-members of the Manitoba Chapter of the Canadian Multiple Sclerosis Society were surveyed by mail. Six hundred and thirty-three (76%) responded. Questions included: age at diagnosis of MS, history of HZ (yes, no, probably), number of episodes of HZ and age at each occurrence, date of birth, and sex of respondent. The controls were consecutive patients with other neurological diseases (OND) attending local neurological or neurosurgical clinics, plus practice-based and population-based surveys of herpes zoster without reference to any other disease. The OND controls were assessed at the time of their outpatient visits.

In the MS group with a positive/probable history of HZ, the HZ/MS rate was 106/633 (16.8%); in the practice-based survey the rate was 192/3534 (5.4%); and among the patients with OND it was 42/616 (6.8%). The HZ occurred at an earlier age in the MS group. The majority of male patients had HZ prior to the diagnosis of MS. The date of diagnosis is more likely to be a precise memory as opposed to the onset of symptoms. More than one attack of HZ was also more common in the MS group.

This survey adds to the evidence that patients with MS have a unique relationship with the herpes zoster virus.

The Scripps neurologic rating scale (SNRS) is a summary measure of individual components comprising a neurological examination, designed for use in multiple sclerosis (MS). Our objective is to evaluate the responsiveness of the SNRS, within the context of a 2-year, randomized, double-blind crossover study of the efficacy of cladribine for treatment of secondary progressive MS.

Effect sizes were determined for the SNRS and its components, separately for each treatment group (initial placebo, and initial cladribine) over both years of the clinical trial, using a standard random effects model.

Individual components tended to show positive effect sizes (improvement) during periods of active therapy in both treatment groups, and negative effect sizes (deterioration) during periods of no active therapy. Summation indices derived from the individual components of the SNRS seemed somewhat more stable than the individual components. The two components mentation and mood, and bladder, bowel, or sexual dysfunction, were rather unresponsive in our clinical trial.

Changes in the components of the SNRS over the course of our clinical trial were consistent between the two treatment groups. Most components were moderately responsive; and, the summary SNRS score appropriately summarized the moderate magnitudes of change evinced in the individual components.

Malignant spinal cord astrocytomas are rare tumors and their specific MR characteristics have not been previously described. We present a detailed MR analysis of four children with malignant astrocytoma.

A review of the clinical database at the Hospital for Sick Children, Toronto revealed four patients with histologically-verified malignant spinal cord astrocytomas (WHO Grade 3 or 4) with pre-operative MR available for retrospective review.

There were three boys and one girl with a mean age at presentation of four years (range 7 months - 12 years). Mean duration of symptoms prior to presentation was six weeks (range 3 days - 5 months). Pre-operative MR analysis revealed that all tumors were located in the cervical or cervico-thoracic regions and expanded the cord over an average of 6.5 vertebral levels. The signal was usually hypointense on T1-weighted and hyperintense or mixed intensity on T2-weighted images. In the three cases where gadolinium was given, all demonstrated enhancement (one rim enhancement with a discrete border and two with inhomogeneous central enhancement). One tumor appeared to be exophytic, one had a significant cystic component, and none showed evidence of hemorrhage. Pre-operative leptomeningeal spread of tumor was documented in two of four cases and involved intracranial spread in both cases.

There did not appear to be any specific MR characteristics to help differentiate a malignant astrocytoma from a low-grade tumor, except for the high rate of leptomeningeal spread at presentation. It is recommended that full neuraxis MR imaging be performed pre-operatively in children in whom a rapidly progressive clinical course suggests a malignant lesion. This will likely have a high positive yield and provide valuable information prior to surgical intervention.