Agnete Mouritzen Dam

Epilepsy and Neuron Loss in the Hippocampus

Summary: Quantitation of hippocampal neurons was performed in 20 patients with generalized epilepsy. Twelve suffered from partial seizures. The neuronal numbers were compared with the control series of patients without epilepsy. It was established that there were fewer neurons in the hippocampi from patients with epilepsy than from those of controls. The neuron loss was particularly marked in the endfolium (field H3), the granule cells (fascia dentata), and particularly in the caudal (anterior) part of the structure. Frequent, generalized epileptic seizures and long duration of the epileptic disorder influenced the neuron loss. In some parts of the pyramidal band (field H,), the neuron loss appeared at a younger age, which leads one to suspect its particular involvement in the seizure mechanism. The neuron loss was not related to the different types of seizures investigated. The results support the hypothesis of neuron loss as an ongoing process in patients with epilepsy, whatever the type of epilepsy, when tonic‐clonic seizures, as is very common, are present.

Hippocampal Neuron Density and Seizures in the Mongolian Gerbil

Summary: Mongolian gerbils of the seizure‐sensitive strain exhibit epileptic seizures in relation to changes in the environment, a characteristic which has been increased to about 100% by inbreeding. The seizures vary from animal to animal but are rather stable in the individual animal, which makes it possible to study the neuron densities in the hippocampus of the gerbil in relation to seizure type and seizure intensity. Five groups of gerbils with seizures ranging from minor movements and motor arrest to intense generalized convulsions were investigated with a quantitative method including cell counting by light microscope and estimation of possible brain shrinkage, as well as determination of nucleoli and nuclei diameters. The cell densities were determined in different areas of the pyramidal cells of the hippocampus (H‐fields). The study discloses a reduction of cell densities in fields H2 and H3 in relation to intense generalized convulsions. It is suggested that the reduction in cell density in field H2 is a result of seizure activity, whereas the field H3 cell loss can be the result of both the hypoxia and the seizure activity.

Cognitive function and anticonvulsant therapy: effect of monotherapy in epilepsy.

Introduction– The effect of antiepileptic drugs (AED) on cognitive function was studied in 87 patients with epilepsy. Material and methods– Group A: (n = 52) started AED treatment (carbamazepine, oxcarbazepine, sodium‐valproate, phenobarbital or phenytoin). Group B: (n = 27) had AED monotherapy withdrawn (carbamazepine or sodium‐valproate). Group C: (n = 8) was switched from phenytoin to carbamazepine monotherapy. The patients were tested before and 4 months after change of the treatment. Results– In group A the test performances were in general unchanged. Patients who had their drug treatment withdrawn (group B) and the patients who were switched from phenytoin to carbamazepine (group C) improved in single tests. The predominant changes in performance seem to be due to practice effect. Conclusion– Cognitive functions are only minimally influenced by AEDs after short‐term treatment whereas there is a slight improvement after discontinuation of long‐term administration of carbamazepine and valproate. A lack of practice effect might be the first indicator of a negative effect of AED on cognitive function.

Does Seizure Activity Produce Purkinje Cell Loss

Summary: Eight Wistar rats were exposed to 140 electroconvulsive seizures over 50 days. Ten rats served as controls. The density of Purkinje cells in cerebellum ranged from 15.3 to 18.5/mm in the treated rats and from 15.2 to 19.1/mm in the controls. No Purkinje cell loss was disclosed in the rats subjected to electroconvulsive seizures. Twenty‐five Mongolian gerbils of the seizure‐susceptible strain were selected according to seizure score with five animals in each group. Five Mongolian gerbils of a seizure‐resistant strain served as controls. The density of the Purkinje cells ranged from 21.4 to 29.8/mm in the seizure‐susceptible animals and from 27.6 to 31.5/mm in the controls, with a lower density in the gerbils with seizures compared with the controls (p <0.05). There was no relation to type or number of seizures. Eight gerbils of the seizure‐susceptible strain were included as a supplementary group, to disclose any possible genetic trait as an explanation of the lower Purkinje cell density. The Purkinje cell density in these animals ranged from 24.8 to 30.9/mm and did not differ from the density in the seizure‐resistant gerbils. Thus the lower density of Purkinje cells in the seizure‐susceptible Mongolian gerbils is a result of seizure activity. The excessive epileptic input with stimulation of the glutamatergic innervation of the Purkinje cells resulting in a persistent elevated 7‐amino‐butyric acid (GABA) tone may explain the damage to the Purkinje cells in the gerbils and the loss of Purkinje cells found in patients with severe epilepsy.

SPASTIC PARAPLEGIA OF UNKNOWN ORIGIN: A Follow‐up of 32 Patients

Thirty‐two patients admitted to the University Clinic of Neurology, Copenhagen, in the years 1960‐67, had isolated spastic paraplegia of unknown etiology. Twenty‐four patients were followed up after five to twelve years of observation (mean observation time 8.9 years). The remaining eight patients had died. A diagnosis was reached in eight of the re‐examined patients and two of the deceased patients. Six patients had multiple sclerosis, and one had possible multiple sclerosis. One patient had spino‐cerebellar degeneration, one amyotrophic lateral sclerosis and one an intraspinal meningeoma. The undiagnosed patients at follow‐up still had an isolated spastic paraplegia, which in most cases had gradually progressed. The possibility that some of these patients might be suffering, from multiple sclerosis or hereditary spastic paraplegia is discussed. The necessary examinations are evaluated and it is concluded that air myelography should always be carried out in patients with spastic paraplegia of unknown origin.

Consequences of severe epilepsy: neuropathological aspects.

To determine whether pathology is a cause or a consequence is not always simple or possible. Alzheimer (1907) emphasized that developmental disturbances underly epilepsies. Hamarthomas, dystopic nerve cells and cortical dysplasia are some examples regarded as being of pre-epileptic origin. Meencke (1985) is the latest to support this theory with a quantitative study of cortical dysplasia in primary epilepsies. Two types of neurons are particular exposed to damage in patients with epilepsy. The pyramidal cells in hippocampus and the Purkinje cells in cerebellum. Sommer (1880) was the first person to describe selective neuron loss in one particular area of the pyramidal band in the hippocampus, which now bears his name, and corresponds approximately to field H1 (CA1). Loss of Purkinje cells was described also at that time. The first quantitative study of neuron loss in epilepsy was in fact performed on Purkinje cells (4). The purpose of that study was to disclose the relation between the Purkinje cells and phenytoin treatment. Phenytoin was claimed to be toxic to the Purkinje cells due to the fact that clinical signs of cerebellar dysfunction were often the result of high doses of the drug. In this first quantitative neuropathological study related to epilepsy it was demonstrated that Purkinje cell loss was related to many generalized convulsions. The probable role of increased inhibitory demand as the cause of the exhaustion and death of the Purkinje cells is not yet solved. The quantitative method is of great advantage in the neuropathological evaluation of damage to brains. Loss of neurons and receptors means loss of function, sooner or later. Quantitation allows various studies performed in different parts of the world to be compared giving the results more weight.

NEUROLOGICAL DISORDERS and DETRUSOR HYPERREFLEXIA

In 152 consecutively selected patients with detrusor hyperreflexia (DH) 96 (63 per cent) had neurological disorders. Thirty‐two patients did not show any primary neurological or urological cause for DH. This group was chosen to elucidate the evaluation of possible neurological symptoms in relation to the urological symptomatology. Nine had died and one failed to appear to the neurological examination. Twelve (63 per cent) of the 22 examined patients showed signs of lesions in different parts of the central nervous system, particularly cerebrovascular diseases and myeloneuropathy. Six had had neurological symptoms for years. In two the urological symptoms were first to appear. In the group with no neurological complaints the urological symptoms had existed for 2–30 years. No essential difference was found in the degree of voiding disturbance whether or not neurological signs were disclosed. It is concluded that the discovery of DH should be followed by a neurological examination to disclose further signs of lesions in CNS. Likewise, an extended urological examination with demonstration of DH might help in the evaluation of an obscure neurological disease.