Prospective evaluation of delayed central nervous system (CNS) toxicity of hyperfractionated total body irradiation (TBI).

PURPOSE: Prospective evaluation of chronic radiation effects on the healthy adult brain using neuropsychological testing of intelligence, attention, and memory. METHODS AND MATERIALS: 58 patients (43 +/- 10 yr) undergoing hyperfractionated total body irradiation (TBI) (TBI, 14.4 Gy, 12 x 1.2 Gy in 4 days) before bone marrow or peripheral blood stem cell transplantation were prospectively included. Twenty-one recurrence-free long-term survivors were re-examined 6-36 months (median 27 months) after completion of TBI. Neuropsychological testing included assessment of general intelligence, attention, and memory using normative, standardized psychometric tests. Mood status was controlled, as well. Test results are given as IQ scores (population mean 100) or percentiles for attention and memory (population mean 50). RESULTS: The 21 patients showed normal baseline test results of IQ (101 +/- 13) and attention (53 +/- 28), with memory test scores below average (35 +/- 21). Test results of IQ (98 +/- 17), attention (58 +/- 27), and memory (43 +/- 28) showed no signs of clinically measurable radiation damage to higher CNS (central nervous system) functions during the follow-up. The mood status was improved. CONCLUSION: The investigation of CNS toxicity after hyperfractionated TBI showed no deterioration of test results in adult recurrence-free patients with tumor-free CNS. The median follow-up of 27 months will be extended.

Neurobehavioral toxicity of total body irradiation: a follow-up in long-term survivors.

PURPOSE: Total body irradiation (TBI) in preparation for bone marrow transplantation (BMT) is a routine treatment of hematological malignancy. A retrospective and a prospective group study of long-term cerebral side effects was performed, with a special emphasis on neurobehavioral toxicity effects. METHODS AND MATERIALS: Twenty disease-free patients treated with hyperfractionated TBI (14.4 Gy, 12 x 1.2 Gy, 4 days), 50 mg/kg cyclophosphamide, and autologous BMT (mean age 38 years, range 17-52 years; age at TBI 35 years, 16-50 years; follow-up time 32 months, 9-65 months) participated in a neuropsychological, neuroradiological, and neurological examination. Data were compared to 14 patients who were investigated prior to TBI. Eleven patients with renal insufficiencies matched for sex and age (38 years, 20-52 years) served as controls. In a longitudinal approach, neuropsychological follow-up data were assessed in 12 long-term survivors (45 years, 23-59 years; follow-up time 8.8 years, 7-10.8 years; time since diagnosis 10.1 years, 7.5-14.2 years). RESULTS: No evidence of neurological deficits was found in post-TBI patients except one case of peripheral movement disorder of unknown origin. Some patients showed moderate brain atrophy. Neuropsychological assessment showed a subtle reduction of memory performance of about one standard deviation. Cognitive decline in individual patients appeared to be associated with pretreatment (brain irradiation, intrathecal methotrexate). Ten-years post disease onset, survivors without pretreatment showed behavioral improvement up to the premorbid level. CONCLUSION: The incidence of long-term neurobehavioral toxicity was very low for the present TBI/BMT regimen.

Acute central nervous system (CNS) toxicity of total body irradiation (TBI) measured using neuropsychological testing of attention functions.

PURPOSE: The purpose of this study was to investigate acute normal tissue damage of low irradiation doses to the healthy, adult central nervous system (CNS) using neuropsychological testing of attention functions. METHODS AND MATERIALS: Neuropsychological testing (IQ, attention [modified Trail-Making Test A, Digit Symbol Test, D2 Test, Wiener Determination Machine]) was used to examine 40 patients (43 +/- 10 years) before and immediately after the first fraction (1.2 Gy) of hyperfractionated total body irradiation (TBI) at the University of Heidelberg. The patients received antiemetic premedication. Test results are given as mean percentiles +/- standard deviation, with 50 +/- 34 being normal. Thirty-eight control patients (53 +/- 15 years) were studied to quantify the influence of hospitalization, stress, and repeated testing. RESULTS: The patients showed normal baseline test results (IQ = 101 +/- 14, attention = 54 +/- 28) and no decrease in test results after 1.2 Gy TBI. Attention functions improved (66 +/- 25) corresponding to a practice effect of repeated testing that was seen in the control group, although alternate versions of the tests were used (IQ = 104 +/- 10, attention before = 42 +/- 29, attention after = 52 +/- 31). CONCLUSION: Our data show no deterioration of neuropsychologic test results acutely after 1.2 Gy whole body exposure in adult patients without CNS disease receiving antiemetic medication.

Assessment of neuropsychological changes in patients with arteriovenous malformation (AVM) after radiosurgery.

PURPOSE: The purpose of this study was to investigate neuropsychological effects of radiosurgery in patients with cerebral arteriovenous malformation (AVM), with special focus on attention and memory. This report describes the study setup and presents the first results during a follow-up of up to 1 year. MATERIALS AND METHODS: Seventy-nine patients were studied before, acutely after radiosurgery, and during the regular follow-up (subacute phase: Weeks 6-12, chronic phase: Months 6-12). Radiosurgery was performed using a modified linear accelerator (minimum doses to the target volume: 15-22 Gy, median 20 Gy). Estimated whole brain dose was 0.5 to 2 Gy. Neuropsychological testing included assessment of general intelligence (Wechsler Adult Intelligence Scale), attention (modified Trail-Making Test A, Digit Symbol Test, D2 Test, Wiener Determination Machine) and memory (Rey Auditory Verbal Learning Test, Benton Visual Retention Test). During follow-up, alternate test versions were used. Neuropsychological deficits were defined as a test score of at least one standard deviation (SD) below the mean of the normal distribution. RESULTS: The pretherapeutic evaluation revealed marked deviations from the normal population; 24% had deficits in intelligence (range 23-31% in different subtests), attention (35%, 23-59%) and memory (48%, 31-61%). The overall percentage of aberrant results was reduced by 12% (memory) to 14% (attention) in the chronic phase up to 12 months after therapy. The improvement in test scores was significant (p < 0.05) in 3 of 4 subtests of attention functions. CONCLUSIONS: The acute tolerance of radiosurgery seems to be very good in these patients, showing no relevant increase in number of patients with neuropsychological deficits. Although the long-term follow-up needs to be further increased, our data indicate a tendency to slight improvement in the overall neuropsychological performance of AVM patients in the chronic phase after radiosurgery.

Pallidal stimulation: an alternative to pallidotomy?

A resurgence of interest in the surgical treatment of Parkinson's disease (PD) came with the rediscovery of posteroventral pallidotomy by Laitinen in 1985. Laitinen's procedure improved most symptoms in drug-resistant PD, which engendered wide interest in the neurosurgical community. Another lesioning procedure, ventrolateral thalamotomy, has become a powerful alternative to stimulate the nucleus ventralis intermedius, producing high long-term success rates and low morbidity rates. Pallidal stimulation has not met with the same success. According to the literature pallidotomy improves the "on" symptoms of PD, such as dyskinesias, as well as the "off" symptoms, such as rigidity, bradykinesia, and on-off fluctuations. Pallidal stimulation improves bradykinesia and rigidity to a minor extent; however, its strength seems to be in improving levodopa-induced dyskinesias. Stimulation often produces an improvement in the hyper- or dyskinetic upper limbs, but increases the "freezing" phenomenon in the lower limbs at the same time. Considering the small increase in the patient's independence, the high costs of bilateral implants, and the difficulty most patients experience in handling the devices, the question arises as to whether bilateral pallidal stimulation is a real alternative to pallidotomy.

Quantitation of herpes simplex virus type 1 DNA in cells of cerebrospinal fluid of patients with herpes simplex virus encephalitis.

We used a nested polymerase chain reaction assay to quantitate the number of viral copies in cells of CSF of eight patients with herpes simplex virus encephalitis (HSVE). The viral load was monitored in serial CSF samples during the course of disease and correlated to clinical symptoms, radiologic manifestations, efficacy of acyclovir treatment, and overall clinical outcome. Before treatment, HSV type 1 (HSV-1) copies were detected at a mean value of 1,786/10(5) (range, 5 to 8,333/10(5) cells; median, 81/10(5) cells). During therapy, HSV-1 DNA decreased gradually to a mean value of 6 copies/10(5) cells (range, 0 to 33 copies/10(5) cells; median, 0 copies/10(5) cells) within 6 to 21 days and disappeared or was barely detectable before treatment completion in most cases. The HSV-1 burden in the CSF did not clearly correlate with the severity of clinical signs or the degree of cranial imaging findings and overall outcome. Quantitation of HSV-1 copies allows rapid and reliable monitoring of antiviral therapy. The absence of a clear correlation between viral load in the CSF and morbidity may suggest a role for indirect mechanisms of brain injury in HSVE.

Pallidal stimulation: an alternative to pallidotomy?

A resurgence of interest in the surgical treatment of Parkinson's disease (PD) came with the rediscovery of posteroventral pallidotomy by Laitinen in 1985. Laitinen's procedure improved most symptoms in drug-resistant PD, which engendered wide interest in the neurosurgical community. Another lesioning procedure, ventrolateral thalamotomy, has become a powerful alternative to stimulate the nucleus ventralis intermedius, producing high long-term success rates and low morbidity rates. Pallidal stimulation has not met with the same success. According to the literature pallidotomy improves the "on" symptoms of PD, such as dyskinesias, as well as the "off" symptoms, such as rigidity, bradykinesia, and on-off fluctuations. Pallidal stimulation improves bradykinesia and rigidity to a minor extent; however, its strength seems to be in improving levodopa-induced dyskinesias. Stimulation often produces an improvement in the hyper- or dyskinetic upper limbs, but increases the "freezing" phenomenon in the lower limbs at the same time. Considering the small increase in the patient's independence, the high costs of bilateral implants, and the difficulty most patients experience in handling the devices, the question arises as to whether bilateral pallidal stimulation is a real alternative to pallidotomy.

Is the medial globus pallidus a site for stimulation or lesioning in the treatment of Parkinson's disease?

After the encouraging report on bilateral pallidal stimulation by Siegfried in 1994, we started this procedure in 1995 and will report our experience in 6 patients with a mean follow-up of 1 year. In contrast to the good results of pallidotomy reported in the literature improving the 'on' symptoms as dyskinesias as well as 'off' symptoms such as rigidity, bradykinesia and on-off fluctuations, our results indicate that pallidal stimulation improves the 'off' symptoms only to a minor extent and L-dopa-induced dyskinesias remain the main indication. Considering the overall functional outcome, the question arises whether the medial globus pallidus should be lesioned or stimulated.