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Scientific Meeting of the Netherlands Society of Child Neurology held in Groningen, 29th November 1985
Meeting reports
Scientific meeting of the Netherlands Society of Child Neurology held in Groningen, 29th November 1985. During this meeting the Cornelia de Lange medallion was awarded to Dr. J. Aicardi (Paris) for his outstanding work in the field of Child Neurology. The symposium was devoted to neuro-oncological problems in children.
Pathogenetic mechanisms in embryonal tumours, in particular those of neural origin. C.H.C.M. Buys (Groningen). In the etiology of a number of early childhood turnout types a genetic component may play an important role as illustrated by the occurrence of familial as well as sporadic cases of e.g. retinoblastoma, neuroblastoma, medulloblastoma, and Wilm's tumour. Presumably, these tumours originate from mutations predisposing for a certain cancer or group of cancers. A small percentage of retinoblastoma and Wilm's tumour patients are heterozygous for a microscopically visible deletion of specific chromosome regions (13q14 and l l p 1 3 , respectively) either in the turnout cells or in all tissues. These deletions not only indicate where the predisposing mutant genes may be located, but also suggest that they are recessive cancer genes, i.e. the presence of a normal allele prevents tumour development. Loss of the normal allele as a consequence of deletion implies loss of protection against tumourigenesis. Other types of chromosome or gene mutations involving the normal allele, or loss of the whole chromosome, will have the same result. These presumptions are supported by the results of D N A analyses comparing restriction fragment length polymorphisms - naturally occurring variations that can be detected with D N A probes - in turnout and
constitutional D N A from the same patient. In retinoblastoma, Wilm's tumour, and osteosarcoma patients where heterozygosity at certain loci was demonstrated in D N A isolated from normal tissues, turnout D N A appeared to be homozygous, in agreement with the suggested chromosomal mechanisms. Thus, for development of these childhood turnouts at least two genomic alterations have to occur: mutation of one allele and loss or inactivation of the remaining normal allele. This explains why these tumours occur in both hereditary and nonhereditary forms with involvement of the same locus. In the hereditary forms all cells will carry an originally germinal first alteration at the relevant locus. A second alteration at this locus in one of the cells of a target tissue will result in tumour development. In nonhereditary forms two somatic alterations involving the same locus have to coincide in the same cell to result in tumour formation. In our own studies we did not only find loss of heterozygosity (of chromosome 13) in isolated cases of retinoblastoma and osteosarcoma, but also (of chromosome 3) in small cell lung cancer. This might indicate that the suggested mechanism of tumour development is a common one, also for cancers where the involvement of a genetic component is not known.
313
Patient's and doctor's delay. R.I. H o o g e n E s c h and J.H. Begeer (Groningen). The diagnosis of a tumour of the central nervous system is a serious matter, especially when the complaints have been existing a long time before the final diagnosis is made. A long delay can cause psychological harm and irreversible neurological damage. We studied the diagnostic delay in a group of 111 patients (101 patients with a tumour cerebri and 10 patients with a spinal cord tumour) who were examined and discussed in the Child Neuro-oncology group of the University Hospital Groningen (from 1975-1985). More than 30% of the patients had had complaints for a period of more than 6 months before the tumour
in the nervous system was diagnosed. We divided the 101 patients with a tumour cerebri in two groups: group A with a delay in diagnosis of less than 6 months and group B with a longer delay. We compared the symptoms in these two groups. Especially in group B wrong diagnoses were made. In one patient, e.g,, the wrong diagnosis Anorexia Nervosa was made, in another Spasmus Mutans. The initial symptoms were for both groups remarkably similar, so the difference in diagnostic delay could not be explained by difference in symptomatology. We state on the basis of our material that a CT scan is necessary in all children suspected of anorexia nervosa, before psychiatric treatment is started.
Epileptic seizures as a presenting manifestation of supratentorial tumors in children. J. Aicardi (Paris). Supratentorial tumors producing epileptic seizures in children are mainly benign lesions and their removal, even without sacrifice of the neighbouring cortex, appears to give gratifying results from both the epileptologic and oncologic points of view. It is therefore imperative to diagnose and treat them early. Experience with CT scan, however, has shown that similar images, apparently not due to tumors, were rather frequently found in epileptic children. As a result, neurosurgical exploration of all such images does not seem warranted and decision to operate must be carefully pondered over. Because some pseudotumoral images are transient and because most benign tumors of childhood have a very slow progression it is
generally reasonable to delay surgical exploration by 3-4 months after repeating the neuroradiological examinations. Only in unchanged (or growing) images will exploration be considered. For persistent lesions the use of new techniques will certainly help but nothing will replace careful reflexion and experience. In order to limit the magnitude of the problems posed by neuroradiological images suggestive of tumors but of a different nature, we think it reasonable to avoid systematic CT examination of all epileptic children but to restrict it to those cases for which a brain lesion is likely. Thus, CT scan should not be done, in our view, for generalized epilepsies clinically and electroencephalographically typical, not for patients with classical benign rolandic epilepsy.
Childhood medulloblastoma: Second cooperative therapeutic study of the International (SIOP) and the West German (GPO) Societies of Paediatric Oncology. M.K. Neidhardt (Augsburg). This study, which started in 1984, is based on the interposition of an intensive course of chemotherapy between surgery and irradiation 314
in one of the most frequent and most highly malignant brain tumours in children. Such 'sandwich' chemotherapy offers a number of
theoretical advantages: 1) Chemotherapy may be more effective because the physiological barriers are broken down due to surgery; neovascularisation occurs as part of the healing process, and fibrosis following irradiation is absent. 2) Certain drugs like methotrexate may be administered more safely before than after irradiation. Experience of the first SlOP study (Bloom et al.) shows that a delay by a few weeks of the onset of radiotherapy does not jeopardize overall treatment results. The first (one-arm) GPO study (Neidhardt et al.) has demonstrated that the administration of a combination of procarbazine, vincristine, and intermediate-dose methotrexate with citrovorum factor rescue is well tolerated by the patients. De Kraker, Vofite et al. have obtained very promising results in a pilot study employing vincristine, prednisolone and 2000 mg/m 2 of methotrexate with folinic acid administration. The joint study of both societies aims to test the 'sandwich' principle in a prospective, randomised fashion. Half of the patients receive a combination of procarbazine, vincristine, and 2000 mg/m; of methotrexate with CF-rescue between surgery and irradiation, the other half receive immediate postoperative radiotherapy. Moreover, patients at high risk for relapse (i.e. those having had incomplete resection of their
turnout or proof of metastases present at diagnosis) receive maintenance chemotherapy with vincristine and CCNU following radiotherapy for an overall duration of one year. Moreover, about one half of the participating centers will randomize 'low risk' patients (with complete macroscopic turnout resection and without metastases at diagnosis) into a group receiving reduced doses of radiotherapy (25 gy instead of the usual 35 gy) to the brain and spine (with the exception of the posterior fossa) and another one receiving conventional doses (35 gy). This part of the study will test the hypothesis that such a dose reduction is possible without compromising survival and, hopefully, will lead to a reduction of deficits in long-term survivors. All patient data are being reviewed by independent expert committees analysing results of surgery, CT scans, and quality of radiotherapy and chemotherapy. By 31 August, 1985, 97 patients had been entered by 62 participating centers (34 high risk and 63 low risk). Another 34 patients had been registered but for various reasons were excluded from the trial. It is far too early to present any conclusive results of this recent trial but tolerance of the therapeutic regimen appears to be quite good and thus far the reduction of the radiotherapy dose has not resulted in an increase of early relapses.
Repetitive courses of radiotherapy and chemotherapy for primary CNS relapse of childhood ALL. W . A . Kamps, D . M . Mehta, J.A. L e e u w and G . B . H u m p h r e y (Groningen). Intrathecal 'triple therapy' (IT-f) with methotrexate, hydrocortisone and cytosine arabinoside (15, 30 and 60 mg/m 2 resp.) followed by craniospinal irradiation (1 Gy) one week later was given once in 7 weeks to children with a primary isolated central nervous system (CNS) relapse of acute lymphocytic leukemia (ALL). Remission induction was achieved before by weekly ITT (x6). The protocol also included 4-drug systemic remduction and maintenance therapy. From June 1980 to November 1985 17 patients were entered; all had had 25 Gy 'prophylactic' cranial irradiation I> 6 months
earlier. They all attained a second complete remission at 6 weeks after CNS relapse. Four patients, who subsequently received an allogeneic bone marrow graft, were excluded. After a follow-up of 2-49 months (median 15) 7/13 patients are disease-free; 3/7 are off all therapy. The second remission ended in 5/13 patients by another CNS relapse and in 1/13 by a bone marrow relapse; 5/6 died. One patient refused further therapy while in second remission and subsequently died. The actuarial disease-free survival for these 13 patients is 68% at 15 months and 41% at 4 years; the median disease-free survival time is 21/z year. Three out of 7 survivors have a reduced cognitive ability. No overt encephalopathy or other 315
CNS toxicity was seen. Long term disease-free survival without major toxicity can be achieved by repetitive courses of radioand
chemotherapy in primary isolated CNS relapse of childhood ALL.
Some complications after chemo- and radiotherapy. J . H . van der H o e v e n and J . H . B e g e e r (Groningen). Different neurological problems associated with cancer therapy in children were described. Three examples of neurological complications with different therapeutic agents were presented. A patient with a cerebral infarct during L-asparaginase treatment in acute lymphoblastic leukemia. A temporary deficiency of the clotting factors fibrinogen and AT-III was detected.
A patient with a subacute encephalopathy associated with aphasia due to high dose methotrexate (MTX) intravenously for treatment of osteosarcoma without known metastasis. The symptoms disappeared within one week. The possible pathological mechanism was discussed (pulmonary micrometastasis?). A patient with necrotizing encephalopathy during combined MTX (intravenously and intrathecally) and radiotherapy. Radiotherapy after combined chemotherapy has proved to be less toxic for the nervous system than the reverse way.
Late effects of vincristine neuropathy in children. M.J. Plods van Amstel, M . M . van den Briel, and W . A . K a m p s (Groningen). We examined 31 patients, age 5 to 19 years (median 11), for the presence of residual clinical symptoms of vincristine neuropathy in the lower extremity. All patients had 2 to 3 years of chemotherapy for acute lymphoblastic leukemia and they were off-treatment for more than 9 months at the time of this study. We found a normal strength of the muscles around the knee. The patients did not show any loss of deep tendon refexes nor
insufficient touch and pain sensation. However, 6/31 patients had an abnormal gait with incomplete unrolling of the foot. Also a decrease of the motion of dorsiflexion and of plantar flexion at the talocrural joint was noticed in this group of patients. The incomplete unrolling of the foot during walking is probably due to this reduced dorsiflexion ability. Patients should be regularly seen by a physiotherapist during and after treatment with vincristine for prevention or early intervention of potential physical disabilities.
Cognitive functions and quality of life of children treated for a brain tumor - a prospective study. A. Kingma (Groningen). To investigate the effects of a brain tumor and its treatment (i.e. surgery and/or irradiation and/or chemotherapy) on higher cerebral functioning, our pediatric brain tumor patients are being followed in a prospective neuropsychological study. The results of 22 children (median age 9.6 years) could be evaluated with a 316
median follow-up of 1.7 years. The group comprised ten different tumor types, including eight patients with medulloblastoma. Cognitive functions (i.e. intelligence, memory, attention, cognitive speed, visual-motor integration, fine motor functioning and academic abilities) were evaluated by serial neuropsychological assessment. Physical and emotional status were also
evaluated. The results show an impairment in cognitive functions in 10/22 patients, a delay in emotional development in 7/22 patients and physical disabilities in 15/22 patients. Severe and multiple impairment with a seriously affected quality of life existed in 7/22 children. Adjustments in teaching were necessary for 50% of the children; however, a good setting for
cognitive and social rehabilitation is hard to find. Our conclusion is that the majority of children with a brain tumor will suffer at least some degree of cerebral dysfunctioning. We have to inform and support both patients and parents, regarding these potential adverse effects of a brain tumor and its treatment.
Scientific meeting of the Amsterdamsche Neurologenvereeniging held in Amsterdam, 1st May 1986.
The significance of Herpes Virus encephalitis animal models. A . C . B . Peters (Leiden). With respect to diagnosis, the most challenging viral infection of the human CNS is herpes simplex type 1 (HSV-1) encephalitis. Without treatment the disease has a high mortality and morbidity rate. A first message from antiviral drug trials is clear: for optimum effect specific therapy has to be started as early as possible. At present the only conclusive way to diagnose HSV encephalitis rapidly is by demonstrating the virus or its specific antigens in a brain biopsy specimen. Laboratory diagnosis of a viral infection requires the detection of: a) an immune response to the virus, or b) the virus itself, or c) components of the virus. The time interval from presentation of clinical symptoms to a demonstrable immune response (e.g. HSV IgM) takes too long to allow a diagnosis to be established within the first days of the disease. Attempts to isolate the herpes virus from the CSF have rarely
proved successful. Intracellular demonstration of HSV-antigen in CSF cells by an indirect immunofluorescence technique has given conflicting results. Lack of specificity and low sensitivity have been the major problems. Another approach to develop a reliable, rapid and noninvase method of diagnosis is to demonstrate viral components: structural proteins (VP 1757), virus induced enzymes (HSV specific kinases), or viral nucleic acids (HSV specific nucleic acids). Experimental study of herpes encephalitis in animals is a prerequisite to develop diagnostic tests as mentioned above in CSF. We compared the advantages and disadvantages of the rabbit, mouse and pig (Aujeszky's disease) herpes encephalitis model with respect to reproducibility of the infection, volume of CSF available, costs, etc. The CSF studies have been and will be focused on HSV-antigen detection in CSF cells and in situ hybridization techniques.
Aujeszky's disease in pigs; an animal model for herpes encephalitis. W. B o o g e r d , A . C . B . Peters, J. Pol*, J.T. van Oirschot* (Leiden, Lelystad*). The advantages of the pig model (intranasally infected with herpes virus suis), compared to rabbit and mice herpes models, are the clinical and histological similarities between pigs herpes encephalitis and human HSV encephalitis and
the amount of CSF that can be obtained without killing the animal, thus enabling a longitudinal study. A new procedure was developed for obtaining CSF by puncturing the cisterna magna. All 8 infected animals developed a severe meningo-encephalitis with a mortality rate of 60%. The histological changes and the distribu317
Scientific meeting of the Netherlands Society of Child Neurology held in Groningen, 29th November 1985. During this meeting the Cornelia de Lange medallion was awarded to Dr. J. Aicardi (Paris) for his outstanding work in the field of Child Neurology. The symposium was devoted to neuro-oncological problems in children.
Pathogenetic mechanisms in embryonal tumours, in particular those of neural origin. C.H.C.M. Buys (Groningen). In the etiology of a number of early childhood turnout types a genetic component may play an important role as illustrated by the occurrence of familial as well as sporadic cases of e.g. retinoblastoma, neuroblastoma, medulloblastoma, and Wilm's tumour. Presumably, these tumours originate from mutations predisposing for a certain cancer or group of cancers. A small percentage of retinoblastoma and Wilm's tumour patients are heterozygous for a microscopically visible deletion of specific chromosome regions (13q14 and l l p 1 3 , respectively) either in the turnout cells or in all tissues. These deletions not only indicate where the predisposing mutant genes may be located, but also suggest that they are recessive cancer genes, i.e. the presence of a normal allele prevents tumour development. Loss of the normal allele as a consequence of deletion implies loss of protection against tumourigenesis. Other types of chromosome or gene mutations involving the normal allele, or loss of the whole chromosome, will have the same result. These presumptions are supported by the results of D N A analyses comparing restriction fragment length polymorphisms - naturally occurring variations that can be detected with D N A probes - in turnout and
constitutional D N A from the same patient. In retinoblastoma, Wilm's tumour, and osteosarcoma patients where heterozygosity at certain loci was demonstrated in D N A isolated from normal tissues, turnout D N A appeared to be homozygous, in agreement with the suggested chromosomal mechanisms. Thus, for development of these childhood turnouts at least two genomic alterations have to occur: mutation of one allele and loss or inactivation of the remaining normal allele. This explains why these tumours occur in both hereditary and nonhereditary forms with involvement of the same locus. In the hereditary forms all cells will carry an originally germinal first alteration at the relevant locus. A second alteration at this locus in one of the cells of a target tissue will result in tumour development. In nonhereditary forms two somatic alterations involving the same locus have to coincide in the same cell to result in tumour formation. In our own studies we did not only find loss of heterozygosity (of chromosome 13) in isolated cases of retinoblastoma and osteosarcoma, but also (of chromosome 3) in small cell lung cancer. This might indicate that the suggested mechanism of tumour development is a common one, also for cancers where the involvement of a genetic component is not known.
313
Patient's and doctor's delay. R.I. H o o g e n E s c h and J.H. Begeer (Groningen). The diagnosis of a tumour of the central nervous system is a serious matter, especially when the complaints have been existing a long time before the final diagnosis is made. A long delay can cause psychological harm and irreversible neurological damage. We studied the diagnostic delay in a group of 111 patients (101 patients with a tumour cerebri and 10 patients with a spinal cord tumour) who were examined and discussed in the Child Neuro-oncology group of the University Hospital Groningen (from 1975-1985). More than 30% of the patients had had complaints for a period of more than 6 months before the tumour
in the nervous system was diagnosed. We divided the 101 patients with a tumour cerebri in two groups: group A with a delay in diagnosis of less than 6 months and group B with a longer delay. We compared the symptoms in these two groups. Especially in group B wrong diagnoses were made. In one patient, e.g,, the wrong diagnosis Anorexia Nervosa was made, in another Spasmus Mutans. The initial symptoms were for both groups remarkably similar, so the difference in diagnostic delay could not be explained by difference in symptomatology. We state on the basis of our material that a CT scan is necessary in all children suspected of anorexia nervosa, before psychiatric treatment is started.
Epileptic seizures as a presenting manifestation of supratentorial tumors in children. J. Aicardi (Paris). Supratentorial tumors producing epileptic seizures in children are mainly benign lesions and their removal, even without sacrifice of the neighbouring cortex, appears to give gratifying results from both the epileptologic and oncologic points of view. It is therefore imperative to diagnose and treat them early. Experience with CT scan, however, has shown that similar images, apparently not due to tumors, were rather frequently found in epileptic children. As a result, neurosurgical exploration of all such images does not seem warranted and decision to operate must be carefully pondered over. Because some pseudotumoral images are transient and because most benign tumors of childhood have a very slow progression it is
generally reasonable to delay surgical exploration by 3-4 months after repeating the neuroradiological examinations. Only in unchanged (or growing) images will exploration be considered. For persistent lesions the use of new techniques will certainly help but nothing will replace careful reflexion and experience. In order to limit the magnitude of the problems posed by neuroradiological images suggestive of tumors but of a different nature, we think it reasonable to avoid systematic CT examination of all epileptic children but to restrict it to those cases for which a brain lesion is likely. Thus, CT scan should not be done, in our view, for generalized epilepsies clinically and electroencephalographically typical, not for patients with classical benign rolandic epilepsy.
Childhood medulloblastoma: Second cooperative therapeutic study of the International (SIOP) and the West German (GPO) Societies of Paediatric Oncology. M.K. Neidhardt (Augsburg). This study, which started in 1984, is based on the interposition of an intensive course of chemotherapy between surgery and irradiation 314
in one of the most frequent and most highly malignant brain tumours in children. Such 'sandwich' chemotherapy offers a number of
theoretical advantages: 1) Chemotherapy may be more effective because the physiological barriers are broken down due to surgery; neovascularisation occurs as part of the healing process, and fibrosis following irradiation is absent. 2) Certain drugs like methotrexate may be administered more safely before than after irradiation. Experience of the first SlOP study (Bloom et al.) shows that a delay by a few weeks of the onset of radiotherapy does not jeopardize overall treatment results. The first (one-arm) GPO study (Neidhardt et al.) has demonstrated that the administration of a combination of procarbazine, vincristine, and intermediate-dose methotrexate with citrovorum factor rescue is well tolerated by the patients. De Kraker, Vofite et al. have obtained very promising results in a pilot study employing vincristine, prednisolone and 2000 mg/m 2 of methotrexate with folinic acid administration. The joint study of both societies aims to test the 'sandwich' principle in a prospective, randomised fashion. Half of the patients receive a combination of procarbazine, vincristine, and 2000 mg/m; of methotrexate with CF-rescue between surgery and irradiation, the other half receive immediate postoperative radiotherapy. Moreover, patients at high risk for relapse (i.e. those having had incomplete resection of their
turnout or proof of metastases present at diagnosis) receive maintenance chemotherapy with vincristine and CCNU following radiotherapy for an overall duration of one year. Moreover, about one half of the participating centers will randomize 'low risk' patients (with complete macroscopic turnout resection and without metastases at diagnosis) into a group receiving reduced doses of radiotherapy (25 gy instead of the usual 35 gy) to the brain and spine (with the exception of the posterior fossa) and another one receiving conventional doses (35 gy). This part of the study will test the hypothesis that such a dose reduction is possible without compromising survival and, hopefully, will lead to a reduction of deficits in long-term survivors. All patient data are being reviewed by independent expert committees analysing results of surgery, CT scans, and quality of radiotherapy and chemotherapy. By 31 August, 1985, 97 patients had been entered by 62 participating centers (34 high risk and 63 low risk). Another 34 patients had been registered but for various reasons were excluded from the trial. It is far too early to present any conclusive results of this recent trial but tolerance of the therapeutic regimen appears to be quite good and thus far the reduction of the radiotherapy dose has not resulted in an increase of early relapses.
Repetitive courses of radiotherapy and chemotherapy for primary CNS relapse of childhood ALL. W . A . Kamps, D . M . Mehta, J.A. L e e u w and G . B . H u m p h r e y (Groningen). Intrathecal 'triple therapy' (IT-f) with methotrexate, hydrocortisone and cytosine arabinoside (15, 30 and 60 mg/m 2 resp.) followed by craniospinal irradiation (1 Gy) one week later was given once in 7 weeks to children with a primary isolated central nervous system (CNS) relapse of acute lymphocytic leukemia (ALL). Remission induction was achieved before by weekly ITT (x6). The protocol also included 4-drug systemic remduction and maintenance therapy. From June 1980 to November 1985 17 patients were entered; all had had 25 Gy 'prophylactic' cranial irradiation I> 6 months
earlier. They all attained a second complete remission at 6 weeks after CNS relapse. Four patients, who subsequently received an allogeneic bone marrow graft, were excluded. After a follow-up of 2-49 months (median 15) 7/13 patients are disease-free; 3/7 are off all therapy. The second remission ended in 5/13 patients by another CNS relapse and in 1/13 by a bone marrow relapse; 5/6 died. One patient refused further therapy while in second remission and subsequently died. The actuarial disease-free survival for these 13 patients is 68% at 15 months and 41% at 4 years; the median disease-free survival time is 21/z year. Three out of 7 survivors have a reduced cognitive ability. No overt encephalopathy or other 315
CNS toxicity was seen. Long term disease-free survival without major toxicity can be achieved by repetitive courses of radioand
chemotherapy in primary isolated CNS relapse of childhood ALL.
Some complications after chemo- and radiotherapy. J . H . van der H o e v e n and J . H . B e g e e r (Groningen). Different neurological problems associated with cancer therapy in children were described. Three examples of neurological complications with different therapeutic agents were presented. A patient with a cerebral infarct during L-asparaginase treatment in acute lymphoblastic leukemia. A temporary deficiency of the clotting factors fibrinogen and AT-III was detected.
A patient with a subacute encephalopathy associated with aphasia due to high dose methotrexate (MTX) intravenously for treatment of osteosarcoma without known metastasis. The symptoms disappeared within one week. The possible pathological mechanism was discussed (pulmonary micrometastasis?). A patient with necrotizing encephalopathy during combined MTX (intravenously and intrathecally) and radiotherapy. Radiotherapy after combined chemotherapy has proved to be less toxic for the nervous system than the reverse way.
Late effects of vincristine neuropathy in children. M.J. Plods van Amstel, M . M . van den Briel, and W . A . K a m p s (Groningen). We examined 31 patients, age 5 to 19 years (median 11), for the presence of residual clinical symptoms of vincristine neuropathy in the lower extremity. All patients had 2 to 3 years of chemotherapy for acute lymphoblastic leukemia and they were off-treatment for more than 9 months at the time of this study. We found a normal strength of the muscles around the knee. The patients did not show any loss of deep tendon refexes nor
insufficient touch and pain sensation. However, 6/31 patients had an abnormal gait with incomplete unrolling of the foot. Also a decrease of the motion of dorsiflexion and of plantar flexion at the talocrural joint was noticed in this group of patients. The incomplete unrolling of the foot during walking is probably due to this reduced dorsiflexion ability. Patients should be regularly seen by a physiotherapist during and after treatment with vincristine for prevention or early intervention of potential physical disabilities.
Cognitive functions and quality of life of children treated for a brain tumor - a prospective study. A. Kingma (Groningen). To investigate the effects of a brain tumor and its treatment (i.e. surgery and/or irradiation and/or chemotherapy) on higher cerebral functioning, our pediatric brain tumor patients are being followed in a prospective neuropsychological study. The results of 22 children (median age 9.6 years) could be evaluated with a 316
median follow-up of 1.7 years. The group comprised ten different tumor types, including eight patients with medulloblastoma. Cognitive functions (i.e. intelligence, memory, attention, cognitive speed, visual-motor integration, fine motor functioning and academic abilities) were evaluated by serial neuropsychological assessment. Physical and emotional status were also
evaluated. The results show an impairment in cognitive functions in 10/22 patients, a delay in emotional development in 7/22 patients and physical disabilities in 15/22 patients. Severe and multiple impairment with a seriously affected quality of life existed in 7/22 children. Adjustments in teaching were necessary for 50% of the children; however, a good setting for
cognitive and social rehabilitation is hard to find. Our conclusion is that the majority of children with a brain tumor will suffer at least some degree of cerebral dysfunctioning. We have to inform and support both patients and parents, regarding these potential adverse effects of a brain tumor and its treatment.
Scientific meeting of the Amsterdamsche Neurologenvereeniging held in Amsterdam, 1st May 1986.
The significance of Herpes Virus encephalitis animal models. A . C . B . Peters (Leiden). With respect to diagnosis, the most challenging viral infection of the human CNS is herpes simplex type 1 (HSV-1) encephalitis. Without treatment the disease has a high mortality and morbidity rate. A first message from antiviral drug trials is clear: for optimum effect specific therapy has to be started as early as possible. At present the only conclusive way to diagnose HSV encephalitis rapidly is by demonstrating the virus or its specific antigens in a brain biopsy specimen. Laboratory diagnosis of a viral infection requires the detection of: a) an immune response to the virus, or b) the virus itself, or c) components of the virus. The time interval from presentation of clinical symptoms to a demonstrable immune response (e.g. HSV IgM) takes too long to allow a diagnosis to be established within the first days of the disease. Attempts to isolate the herpes virus from the CSF have rarely
proved successful. Intracellular demonstration of HSV-antigen in CSF cells by an indirect immunofluorescence technique has given conflicting results. Lack of specificity and low sensitivity have been the major problems. Another approach to develop a reliable, rapid and noninvase method of diagnosis is to demonstrate viral components: structural proteins (VP 1757), virus induced enzymes (HSV specific kinases), or viral nucleic acids (HSV specific nucleic acids). Experimental study of herpes encephalitis in animals is a prerequisite to develop diagnostic tests as mentioned above in CSF. We compared the advantages and disadvantages of the rabbit, mouse and pig (Aujeszky's disease) herpes encephalitis model with respect to reproducibility of the infection, volume of CSF available, costs, etc. The CSF studies have been and will be focused on HSV-antigen detection in CSF cells and in situ hybridization techniques.
Aujeszky's disease in pigs; an animal model for herpes encephalitis. W. B o o g e r d , A . C . B . Peters, J. Pol*, J.T. van Oirschot* (Leiden, Lelystad*). The advantages of the pig model (intranasally infected with herpes virus suis), compared to rabbit and mice herpes models, are the clinical and histological similarities between pigs herpes encephalitis and human HSV encephalitis and
the amount of CSF that can be obtained without killing the animal, thus enabling a longitudinal study. A new procedure was developed for obtaining CSF by puncturing the cisterna magna. All 8 infected animals developed a severe meningo-encephalitis with a mortality rate of 60%. The histological changes and the distribu317