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Late-Life Epilepsy
Late-Life Epilepsy EDWARD P. RICHARDSON, JR., M.D.*
WIIEN epilepsy, defined as recurrent convulsive seizures or equivalent paroxysmal disorders of cerebral function, is the result of abnormalities of the brain either genetically determined or acquired very early in life, it generally makes its appearance during childhood or adolescence, 01'more rarely-in early adulthood. Thus if an individual reaches the age of 50 without ever having had a seizure of any kind, his chances of having one of the congenital or early acquired cerebral disorders giving rise to epilepsy are small. Seizures occurring for the first time in the middle or later years of life, therefore, generally mean that a new disease process, not previously present in the brain, is making itself known. Consequently, the first problem confronting the clinician in the presence of a case of epilepsy of late onset is the recognition of the underlying disease state, so that the most effective treatment may be undertaken. What, then, are the disease processes which must be considered?
PATHOLOGIC-PHYSIOLOGIC CONSIDERATIONS
It would be most helpful to our understanding of the causative factors underlying seizures that begin in adult life if there had ever been a study of a large series of such cases in which the clinical findings had been supplemented with adequate postmortem neuropathologic examinations. However, no such study, as far as we know, has ever been made, doubtless because of the extreme difficulties attendant upon carrying it out. Nevertheless, there are readily available in the literature a number of clinical observations which give considerable insight into the kinds of disorders that may be encountered in older patients presenting seizures as a major complaint. ""fhe studies of Walker (1936),5 White, Bailey and Bickford (1953),8 and Smith, Robinson and I-Jennox (1954),4 are of particular value in this regard. These surveys clearly point out that cerebral neoplasms, perhaps contrary to commonly held beliefs, are not the major From the Department of Neuropathology-Neurology, Harvard Medical School, the Neuropathology Laboratory, Pathology Department, M assachusetts General Hospital, and the Neurology Service, Massachusetts General Hospital, Boston.
* Assistant Neurologist and Associate Neuropathologist, M assachusetts General H osp'ital; Associate in Neuropathology, H arvard M edical School. 349
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cause of late-life seizures, although admittedly they are a very important one-especially from the standpoint of treatment. The largest group of all is that in which some form of vascular disease of the brain is the significant underlying factor. In another well-recognized group of cases, the epileptic state follows upon cerebral trauma. Degenerative disease of the brain forms another group that may be distinguished. In all of these clinical series, there is a considerable group of cases in which the diagnosis remains unknown-and without pathologic studies of such a group, one can only speculate as to what the underlying abnormality may be. It is by now well established that almost any form of cerebral lesion, whether representing a reversible pathophysiologic state or an irreversible destruction of tissue, may under appropriate circumstances give rise to seizures. But seizures, representing the effect of abnormal discharges of nerve cell activity, must naturally depend upon the presence of nerve cells for their occurrence, so that a portion of brain tissue in which all the nerve cells have been destroyed by disease cannot of itself give rise to seizures. Incomplete lesions, on the other hand, which destroy some nerve cells and leave others intact, or in some way alter the physiologic properties of nerve cells in a diseased region, provide the circumstances which favor abnormal neuronal discharges; thus it is with partial or incomplete lesions of the brain, rather than with massive foci of destruction, that recurrent seizures, or epilepsy, may be expected to occur. Our own experience, based upon the regular examination of the brain in cases of all sorts coming to autopsy in a large general hospital, as well as upon more detailed studies of epilepsy with vascular lesions of the brain (about which more will be said below) leads us to believe that when epilepsy in any of its forms has been clinically recognized in patients of the older age group, involvement of the cerebral cortex by disease is to be expected. The location of the pertinent cortical lesions may be extremely varied, although lesions in or near the classic motor and sensory areas, and temporal lobes, are most frequently encountered. We have no certain knowledge as to what the actual mechanism of seizure production is in such cases, and such theories as have been offered to explain this phenomenon, though ingenious, remain largely speculative (cf. Penfield and Jasper, 1954).2 It is well recognized that the cerebral cortical scars produced by trauma are particularly likely to result in the epileptic state (inWatson's excellent studY,6 41.6 per cent of 286 patients with craniocerebral injuries incurred during World War 11 developed seizures within three years). However, we have found that the cortical scars arising from nontraumatic cerebral vascular lesions may be accompanied by seizures in a significantly high proportion of cases (26 per cent in a much smaller series)-so that we believe that it is not the type of lesion (i.e., whether traumatic, or vascular or produced by other means), but rather its location and extent, combined with other factors still unknown, that are of real in1portance in producing the epileptic state. We are still far from
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knowing why, with the same sorts of neuropathologic changes in both cases, one patient develops seizures and another does not, and it does not clarify thoughts on the subject to postulate a genetically based greater tendency to seizures in the one case as compared with the other, valid though such a supposition may be in some instances. With these few facts in mind, and with the realization that much basic work must yet be done before it is understood just how cerebral disease produces seizures, we may now proceed to a consideration of some of the conditions seen in clinical cases of late-life epilepsy. DISEASE STATES ASSOCIATED WITH LATE-LIFE EPILEPS Y
Neoplasllls of the Brain
Whenever a patient of middle or late adult life comes for medical advice because of the recent appearance of epileptic manifestations, whether focal or generalized, the clinician's thoughts generally turn first to the consideration of brain tumor. This is justifiable because some form of seizure may be an early prominent symptom of this condition. Obviously, however, the presence of seizures alone, however well documented and described, is insufficient in itself to lead to a diagnosis of brain tumor. One must have, in addition, evidence of a progressive course of symptoms and signs, and of an intracranial space-occupying mass, as shown by increased intracranial pressure. If the clinical findings, together with the results of radiographic, electroencephalographic and cerebrospinal fluid studies, do not suggest a process with these characteristics, then neoplasm does not have to be considered as a foremost possibility. Furthermore, cerebral tumor occurs as a basis for seizures in only a relatively minor proportion of patients developing epilepsy after the age of 50 (9 per cent of 107 cases in the series of White et aI., 8 two out of 13 patients 50 years old or older in Walker's study 5). Traulllatic Lesions of the Brain
Cerebral trauma must be considered an important etiologic factor in adult epilepsy; in fact, seizures may be the only significant or detectable residual symptom after otherwise satisfactory recovery from severe head injury. It is in these cases that one finds, on pathologic examination, small healed scars in the cerebral cortex, most commonly on the undersurfaces of the frontal lobes and at the tips of the temporal lobes, best understood as the result of impact of the brain against the hard, unyielding floor of the skull. It is fair to say that lesions of this kind do not result from the relatively minor bumps on the head which nearly everyone experiences at one time or another, and at most are accompanied by very brief, if any, loss of consciousness, but rather, they occur with more serious injuries such as are followed by coma for hours or days, with or without focal neurologic signs, but generally with some blood in the
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cerebrospinal fluid during the acute state. Usually an event of this kind is so dramatic that even if the seizures do not appear until several years after the injury (as not infrequently is the case), it stands out as a prominent landmark in the history. Of course, it must be realized that seizures occurring some time after a head injury need not necessarily be due to traumatic cerebral scars, but may be evidence of a more recently acquired disease state. Nevertheless, in view of the relative frequency of head injuries in this age of fast automobiles, and-as already pointed out -the frequency of epilepsy as a sequel to craniocerebr.al injury, a causeand-effect relationship between head injury and seizures can generally be safely assumed unless there is other convincing evidence to the contrary. Chronic subdural hematoma as a rule is not accompanied by seizures. However, they may occur in occasional cases, especially if there is an associated cerebral contusion; and if other suggestive evidence is present, such as persistent headaches and progressive intellectual deterioration, even in the absence of a history of head trauma, this possibility will have to be seriously entertained. Infections
Although seizures may be encountered as one of the clinical aspects in the acute stages of any of a number of infections involving the central nervous system-as in various forms of meningitis or diffuse encephalitis -the main problem is that of the severe underlying medical disorder, and this does not properly come within the scope of a discussion of late-life epilepsy as such. The physician may, however, be called to attend a patient in whom the first clear manifestation of a disorder of this kind is a convulsion or series of convulsions; in such a case, clinical and cerebrospinal fluid examination generally make the situation clear in relatively short order. One condition that may require serious consideration, however, when an adult of mature years suddenly develops seizures in the presence of otherwise generally good health, is neurosyphilis. This is a disease which nowadays tends rather to be overlooked, in view of its declining importance as a result of effective antispirochetal therapy with penicillin. Yet, it must be recalled that the symptoms of syphilitic involvement of the brain may not appear until many years after the acute infection-\vhich may have occurred before penicillin therapy was available, and may be overlooked, inapparent, or denied. rro be sure, other clinical signs, such as the Argyll-Robertson pupillary abnormality, mental changes, and tremors may indicate the true nature of the basic disorder, but they may be absent. However, the diagnosis can be readily made by examining the cerebrospinal fluid obtained on lumbar puncture for increase in cells and protein, and by appropriate serologic tests on blood and cerebrospinal fluid-examinations which should always be carried out in the adult epileptic. Brain abscess may have to be considered. 'fhe problem presented by
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acute brain abscess is that of a rapidly developing expanding intracranial lesion which can mimic neoplasm. The presence of a suppurative focus in the skull (middle ear, mastoid, or paranasal air sinuses) or in the lungs may lead to the diagnosis. Recurrent seizures may be a significant residual symptom after successful surgical treatment of a brain abscess; they are doubtless the result of cerebral cortical scarring. Although it is by no means a frequent problem in the United States, cerebral cysticercosis deserves particular mention as a cause of adult epilepsy. 'rhis condition is the result of direct infestation of the brain by the larvae (cysticerci) of the pork tapeworm, Taenia solium, which follows upon ingestion of the ova usually from eating fecally contaminated food. With increasing travel to and from undeveloped regions of the world, it is to be expected that cases will occasionally appear even in areas where the tapeworm does not ordinarily occur (cf. White, Richardson and Sweet, 1956 7). The parasite larvae become encysted in the brain tissue, where they apparently act as local irritants; convulsive seizures may be the only clinical evidence of their presence. With passage of time, the encysted larvae, which do not flourish in the human host, become calcified and then are readily demonstrated by x-ray films of the skull. They are generally present in the skeletal muscles as well, so that in a suspected case, even if skull films are negative, roentgenograms of the muscle may indicate the diagnosis. Surgery is of no value in the treatment of epilepsy due to cysticercosis, because of the large number of cysticerci generally present. Cerebral Vascular Disease
In our opinion-and this has been the experience of others as wellvascular lesions of the brain are of great importance in producing the epileptic state in the age group under discussion. In the Mayo Clinic series, reported by White, Bailey and Bickford (1953),8 vascular disease of the brain was held to be accountable for seizures in 46 per cent of their 107 cases of seizures beginning after the age of 50; in Walker's series (1936),4 it was considered to be the responsible factor in 10 out of 13 patients in a similar age group. Our own studies (Dodge, Richardson and Victor, 1954;1 Richardson and Dodge, 19543), based upon autopsy material, are of interest in reflecting to some extent the magnitude of the problem. In a series of 427 consecutive brains examined by us, representing cases of all sorts of medical and surgical disease in a general hospital population, we found easily recognizable cerebral vascular lesions in the form of infarction or hemorrhage, exclusive of lesions associated with congenital vascular malformations (angiomas, saccular aneurysms) in 113, or 27 per cent, with a mean age of 64. If we had included the minute lesions that are detectable only on microscopic examination, the incidence would have been higher. In this group of 113 cases, seizures were recorded as having
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occurred in 22, or 19.5 per cent. We furthermore discovered that there was direct involvement of the cerebral cortex in all of the patients who had seizures, whereas no seizures were observed in the cases of vascular lesions which did not involve the cortex. Further analysis of our material disclosed that there were 22 cases of old, healed vascular lesions of the cerebral cortex and that of these, recurrent seizures-i.e., epilepsy-occurred in six. In the remaining seizure cases, the condition could not be accurately termed "epilepsy," but instead consisted of one or more convulsions in the acute phase of a "stroke." These studies led us to emphasize the importance of vascular lesions of the cerebral cortex in the over-all problem of epilepsy in the older patient, particularly since seizures occurred in only one case* of a control series of 156 cases without old, healed cortical lesions including 79 cases of cerebral atherosclerosis (mean age 67) ,vithout grossly visible brain lesions. Although in most of our cases, the appearance of seizures was preceded either immediately, or by a latent interval of as long as 11 months, by an acute neurologic disorder with clinical signs (generally hemiparesis) that was readily identified as a "stroke," the patient could recover from this, leaving recurrent seizures, often generalized although typically with a focal onset of the attack, as the only residual neurologic disability. In two cases studied by us, chronic epilepsy was the only clinical sign of a cerebral cortical infarct. One would be led to suspect, on the basis of these observations, that when late-life epilepsy is the result of vascular lesions of the brain, it would be encountered in those cases in which there are cortical lesions of relatively small size that would be compatible with satisfactory neurologic recovery in other respects. This has proved, in our experience, to be the case. The massive cerebral infarct resulting from occlusion of a major cerebral artery which leaves the patient permanently hemiplegic if he survives is generally not accompanied by recurrent seizures. Furthermore, seizures are not a problem in the very frequent cases of advanced cerebral atherosclerosis combined with chronic hypertension, or diabetes mellitus, which may in the course of time reduce the patient to a mental and physical cripple with bilateral neurologic signs, but which characteristically produce lesions in deep structures in the brain (internal capsules, basal ganglia, central white matter, brain stem) rather than the cerebral cortex. In our material, the lesions favorable for the development of epilepsy were most frequently encountered with cerebral embolism, often arising from mural thrombi in the heart secondary to rheumatic heart disease (mitral stenosis, auricular fibrillation) or myocardial infarction-although a source cannot always be demonstrated. In such cases, a normal cerebral arterial system with good potentialities for collateral circulation, together with the tendency for emboli to travel
* A laboratory accident precluded thorough study of this case, in which no gross brain lesions were found.
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into distal arterial branches unless they are very large, can result in predominating, or exclusive, infarction of cerebral cortex, with lesions of relatively small size. Another form of cerebral vascular disease that is of importance in connection with late-life epilepsy is atherosclerosis and thrombosis of the common or internal carotid artery, on one or both sides. If the collateral circulation via the circle of Willis is adequate, there may be no sizeable infarction of the brain, although the regions most distally located from the source of blood supply may be rendered ischemic. One may then find small areas of cerebral infarction located in the cerebral cortex of the convexities of the brain, and convulsive seizures, typically with focal aspects, may be a prominent clinical· manifestation of their presence. Seizures of this kind, implying some form of involuntary motor activity, or positive manifestations (such as attacks of abnormal sensations on one side of the body), must be differentiated from "cerebral ischemic attacks," in which repeated episodes of a negative character (such as fleeting hemiparesis or fragments thereof, or attacks of monocular blindness, etc.) indicate a marginal or barely adequate blood supply to some part of the brain ,vhich results in focal impairment of cerebral function if the blood pressure falls belovv a critical level, or may even indicate impending thrombosis. In a given case, it may not be very easy to distinguish between a focal convulsive seizure resulting from a fixed or reversible vascular lesion of the cerebral cortex, and a "cerebral ischemic attack"-although careful questioning, and observation of the patient, may permit a decision as to the nature of the episode. Other forms of vascular disease involving the cerebral cortex, such as various inflammatory conditions (polyarteritis nodosa, granulomatous or giant cell arteritis), are rare causes of seizures in the older patient. Convulsions are, of course, a prominent manifestation of extremely severe degrees of hypertensive vascular disease ("malignant hypertension," "hypertensive encephalopathy") with or without uremia; the basis for them may well be disease of arterioles in the cerebral cortex. In such cases, the eyegrounds will show retinal arteriolar narrowing, with retinopathy. Special mention should be made of the Stokes-A dams syndrome, in \vhich episodic or persistent bradycardia may give rise to transitory cerebral ischemia with syncope, perhaps with a few irregular jerks of the limbs or, occasionally, generalized convulsive seizures, without there being any actual lesions in the brain whatsoever. The association of such episodes with a very slow heart rate serves to set them apart from other forms of convulsive disorders in the older age group. It should likewise be emphasized that elderly patients may at times be subject to other transient episodes of faintness, "dizziness," or unexplained falls, which cannot be regarded as genuine "seizures" such as characterize the true epileptic or convulsive state. In attacks of this sort, consciousness may not be lost at all, or only very briefly, and the involun-
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tary motor activity which usually accompanies the focal or diffuse neuronal discharge that is the essence of the epileptic state is absenteven though, during the unconscious period following such a fainting attack, a few muscular twitches may be observed. Episodes of this kind may be the result of orthostatic hypotension, which is revealed by blood pressure determinations in the standing posture as compared with those obtained when the patient is lying or sitting. Somewhat similar states, often entirely subjective, may be encountered as "anxiety attacks" in patients with agitated depressions, and may be brought on by hyperventilation. In taking the history from a patient, one may not be able at first to differentiate episodes of this general character from true seizures. Of great help in such cases is an eyewitness account of the attacks from another reliable informant. Furthermore, the physician may be able to reproduce an attack by having the patient undergo rapid changes of posture, or by getting the patient to hyperventilate. Where a hyperactive carotid sinus reflex results in changes in heart rate and blood pressure resulting in syncope, as occasionally happens, this can be brought out by gentle slight pressure on the carotid bifurcation in the neck on one or the other side. In all of the states under present consideration there are, of course, no irreversible cerebral changes, and treatment must be directed toward the underlying medical disorder. Degenerative Disease of the Brain
Slowly progressive degeneration and disappearance of nerve cells in the brain, chiefly in the cerebral cortex, in the absence of any obvious metabolic abnormality, may be a more important basis for generalized convulsive seizures in older patients than is generally supposed. This involutional process results in diffuse atrophy of the brain and is characteristically accompanied by the presence, microscopically, of scattered extracellular amorphous deposits principally in the cerebral cortex ("senile plaques") and intracellular skeinlike material of similar composition within nerve cells ("Alzheimer's neurofibrillary change"). This pathologic state is very common in advanced age, and is not invariably (in its milder degrees) attended by significant personality or mental changes, although it does form the typical patho-anatomical substratum of senile dementia. More rarely, it occurs in the presenile period, and then generally results in slowly progressive intellectual deterioration which can reach profound degrees before death ensues; the condition is then called Alzheimer' 8 disease. Clinically indistinguishable, but infinitely rarer in our experience, is the peculiar circumscribed severe atrophy of the frontal or temporal lobes, or both, known as Pick's disease. There is another very rare degenerative condition afflicting patients in late middle age, of which we have lately seen two examples, characterized clinically by rapidly progressive severe dementia, focal and diffuse myoclonic jerks, and generalized convulsions, with a total course from onset
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to death in less than a year. This condition, which is called J akob-Creutzfeldt disease, doubtless represents some form of as yet unidentified subacute toxic or metabolic encephalopathy. Although extremely uncommon, it forms such a distinct entity that it is worthy of mention. r-rhere are occasional cases of other forms of cerebral degenerative disease with seizures-particularly some strange varieties with principally white matter affection-but in none of these can the diagnosis be accurately made during life. Metabolic Disorders
A brief reminder is in order that convulsive seizures may result from episodes of hypoglycemia with islet cell adenoma of the pancreas, or with hypocalcemia resulting from parathyroid adenomas. Blood sugar and calcium and phosphorus determinations are thus clearly indicated in the investigation of late-life epilepsy. It should also be kept in mind that individuals habituated to the use of large amounts of alcohol or barbiturates over long periods of time may have one or a series of generalized convulsive seizures if the drug is rapidly withdrawn. Such patients are also prone to head injuries-so that, in such a case, if the physician sees focal convulsive activity in a seizure, or focal neurologic signs in the postconvulsive state, the possibility of cerebral trauma-perhaps with acute epidural or subdural hematoma-may require serious consideration. Late-Life Epilepsy of Undeterlllined Cause
This group probably includes the largest number of cases of late adult epilepsy actually met with in clinical practice. From the foregoing, it will be seen that we believe that some form of anatomically demonstrable brain lesion underlines the epileptic state in the majority of such cases. However, if the condition is not progressive and is unaccompanied by any clinical, electroencephalographic or other evidence of a focal disorder, its exact identity in the practical instance can be considered only of academic importance. DIFFERENTIAL DIAGNOSTIC AND THERAPEUTIC CONSIDERATIONS
In the preceding discussion of various disease states that may underlie convulsive seizures in older patients (particularly those beyond the fifth decade), some hints as to differential diagnosis have already been given. The importance of careful history (with an adequate description of attacks by another informant if possible) and thorough physical and neurological examinations cannot be overemphasized, and may well indicate whether one is dealing with a static or progressive process. In addition to the usual blood counts and urine examination and a blood serologic test for syphilis, further blood studies to rule out hypoglycemia or hypocalcemia may be indicated. Most patients should have roentgeno-
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grams of the skull and chest-the former may given valuable evidence as to increased intracranial pressure, calcified intracranial lesions, and so on; the latter, of course, give much needed information as to the state of the heart and lungs. Unless it is obvious that there is increased intracranial pressure, a lumbar puncture should be done in every case, with examination of the cerebrospinal fluid for pressure, cell count, total protein, sugar (if the fluid contains an increase of cells) and a serologic test for syphilis. Other determinations (qualitative or quantative globulin tests) can be done if available. If the findings are doubtful or equivocal, the lumbar puncture should be repeated within a reasonably short time. 'rhe electroencephalogram is a most valuable tool. Not only may it give valuable localizing evidence, but serial traci~gs in cases of doubt may settle the question as to whether a lesion is progressing before this is apparent by other means. In cases of epilepsy with diffuse degenerative disease of the brain, or in cases of ultimately undetermined cause, an interval electroencephalogram between episodes of seizures is likely to be normal-a fact which may be helpful in the assessment of a given case. In most of the cases seen in practice no further or specialized studies are indicated, and the patient should be treated medically, with standard anticonvulsant drugs alone or a combination according to generally accepted principles of the drug treatment of epilepsy, naturally assuming that underlying systemic disorders-infectious, metabolic or cardiachave been excluded. Difficulty is most likely to arise in cases in which focal aspects of the seizures, and past or present evidence of neurologic abnormalities on examination, may keep alive the suspicion of a turnor. If seizures are due to cerebral vascular lesions-an important possibility, as has already been pointed out-one would prefer to avoid such rigorous procedures as pneumo-encephalography or arteriography, since these patients as a group tolerate them poorly and may, because of the possibility of additional vascular lesions resulting from the procedure, be more seriously disabled than before. It may of course be better, where sufficient doubt exists, to take a calculated risk in order not to miss a surgically remediable lesion; however, sufficiently careful clinical observation, together with evidence from cerebrospinal fluid and electroencephalographic examinations, often make it possible to avoid these potentially dangerous procedures. In closing, it might be re-emphasized that in many instances, once obvious cerebral or systemic disease have been excluded, the clinician will not be able to reach a definite diagnosis in the late-life epileptic. He is likely to find, on the other hand, that he can arrive at satisfactory practical conclusions about the case with conservative, relatively simple diagnostic measures, and that with comparatively small amounts of standard anticonvulsant drugs, the seizure problem· is brought under control to everyone's satisfaction.
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REFERENCES 1. Dodge, P. R., Richardson, E. P., Jr. and Victor, M.: Recurrent Convulsive Seiz-
2. 3. 4. 5. 6. 7. 8.
ures as a Sequel to Cerebral Infarction: A Clinical and Pathological Study. Brain 77: 610, 1954. Penfield, W. and Jasper, H.: Epilepsy and the Functional Anatomy of the Human Brain. Boston, Little, Brown & Co., 1954. Richardson, E. P., Jr. and Dodge, P. R.: Epilepsy in Cerebral Vascular Disease. Epilepsia C3rd series) 3: 49, 1954. Smith, B., Robinson, G. E. and Lennox, W. G.: Acquired Epilepsy. A Study of 535 Cases. Neurology 4: 19, 1954. Walker, A. E.: Convulsive Seizures in Adult Life. Arch. Int. Med. 58: 250, 1936. Watson, C. W.: Incidence of Epilepsy Following Craniocerebral Injury. 11. ThreeYear Follow-up Study. A.M.A. Arch. Neural. & Psychiat. 68: 831,1952. White, J. C., Richardson, E. P., Jr. and Sweet, W. H.: Cysticercosis Cerebri. A Diagnostic and Therapeutic Problem of Increasing Importance. N. England J. Med. 256: 479, 1957. White, P. T., Bailey, A. A. and Bickford, R. G.: Epileptic Disorders in the Aged. Neurology 3: 674, 1953.
WIIEN epilepsy, defined as recurrent convulsive seizures or equivalent paroxysmal disorders of cerebral function, is the result of abnormalities of the brain either genetically determined or acquired very early in life, it generally makes its appearance during childhood or adolescence, 01'more rarely-in early adulthood. Thus if an individual reaches the age of 50 without ever having had a seizure of any kind, his chances of having one of the congenital or early acquired cerebral disorders giving rise to epilepsy are small. Seizures occurring for the first time in the middle or later years of life, therefore, generally mean that a new disease process, not previously present in the brain, is making itself known. Consequently, the first problem confronting the clinician in the presence of a case of epilepsy of late onset is the recognition of the underlying disease state, so that the most effective treatment may be undertaken. What, then, are the disease processes which must be considered?
PATHOLOGIC-PHYSIOLOGIC CONSIDERATIONS
It would be most helpful to our understanding of the causative factors underlying seizures that begin in adult life if there had ever been a study of a large series of such cases in which the clinical findings had been supplemented with adequate postmortem neuropathologic examinations. However, no such study, as far as we know, has ever been made, doubtless because of the extreme difficulties attendant upon carrying it out. Nevertheless, there are readily available in the literature a number of clinical observations which give considerable insight into the kinds of disorders that may be encountered in older patients presenting seizures as a major complaint. ""fhe studies of Walker (1936),5 White, Bailey and Bickford (1953),8 and Smith, Robinson and I-Jennox (1954),4 are of particular value in this regard. These surveys clearly point out that cerebral neoplasms, perhaps contrary to commonly held beliefs, are not the major From the Department of Neuropathology-Neurology, Harvard Medical School, the Neuropathology Laboratory, Pathology Department, M assachusetts General Hospital, and the Neurology Service, Massachusetts General Hospital, Boston.
* Assistant Neurologist and Associate Neuropathologist, M assachusetts General H osp'ital; Associate in Neuropathology, H arvard M edical School. 349
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cause of late-life seizures, although admittedly they are a very important one-especially from the standpoint of treatment. The largest group of all is that in which some form of vascular disease of the brain is the significant underlying factor. In another well-recognized group of cases, the epileptic state follows upon cerebral trauma. Degenerative disease of the brain forms another group that may be distinguished. In all of these clinical series, there is a considerable group of cases in which the diagnosis remains unknown-and without pathologic studies of such a group, one can only speculate as to what the underlying abnormality may be. It is by now well established that almost any form of cerebral lesion, whether representing a reversible pathophysiologic state or an irreversible destruction of tissue, may under appropriate circumstances give rise to seizures. But seizures, representing the effect of abnormal discharges of nerve cell activity, must naturally depend upon the presence of nerve cells for their occurrence, so that a portion of brain tissue in which all the nerve cells have been destroyed by disease cannot of itself give rise to seizures. Incomplete lesions, on the other hand, which destroy some nerve cells and leave others intact, or in some way alter the physiologic properties of nerve cells in a diseased region, provide the circumstances which favor abnormal neuronal discharges; thus it is with partial or incomplete lesions of the brain, rather than with massive foci of destruction, that recurrent seizures, or epilepsy, may be expected to occur. Our own experience, based upon the regular examination of the brain in cases of all sorts coming to autopsy in a large general hospital, as well as upon more detailed studies of epilepsy with vascular lesions of the brain (about which more will be said below) leads us to believe that when epilepsy in any of its forms has been clinically recognized in patients of the older age group, involvement of the cerebral cortex by disease is to be expected. The location of the pertinent cortical lesions may be extremely varied, although lesions in or near the classic motor and sensory areas, and temporal lobes, are most frequently encountered. We have no certain knowledge as to what the actual mechanism of seizure production is in such cases, and such theories as have been offered to explain this phenomenon, though ingenious, remain largely speculative (cf. Penfield and Jasper, 1954).2 It is well recognized that the cerebral cortical scars produced by trauma are particularly likely to result in the epileptic state (inWatson's excellent studY,6 41.6 per cent of 286 patients with craniocerebral injuries incurred during World War 11 developed seizures within three years). However, we have found that the cortical scars arising from nontraumatic cerebral vascular lesions may be accompanied by seizures in a significantly high proportion of cases (26 per cent in a much smaller series)-so that we believe that it is not the type of lesion (i.e., whether traumatic, or vascular or produced by other means), but rather its location and extent, combined with other factors still unknown, that are of real in1portance in producing the epileptic state. We are still far from
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knowing why, with the same sorts of neuropathologic changes in both cases, one patient develops seizures and another does not, and it does not clarify thoughts on the subject to postulate a genetically based greater tendency to seizures in the one case as compared with the other, valid though such a supposition may be in some instances. With these few facts in mind, and with the realization that much basic work must yet be done before it is understood just how cerebral disease produces seizures, we may now proceed to a consideration of some of the conditions seen in clinical cases of late-life epilepsy. DISEASE STATES ASSOCIATED WITH LATE-LIFE EPILEPS Y
Neoplasllls of the Brain
Whenever a patient of middle or late adult life comes for medical advice because of the recent appearance of epileptic manifestations, whether focal or generalized, the clinician's thoughts generally turn first to the consideration of brain tumor. This is justifiable because some form of seizure may be an early prominent symptom of this condition. Obviously, however, the presence of seizures alone, however well documented and described, is insufficient in itself to lead to a diagnosis of brain tumor. One must have, in addition, evidence of a progressive course of symptoms and signs, and of an intracranial space-occupying mass, as shown by increased intracranial pressure. If the clinical findings, together with the results of radiographic, electroencephalographic and cerebrospinal fluid studies, do not suggest a process with these characteristics, then neoplasm does not have to be considered as a foremost possibility. Furthermore, cerebral tumor occurs as a basis for seizures in only a relatively minor proportion of patients developing epilepsy after the age of 50 (9 per cent of 107 cases in the series of White et aI., 8 two out of 13 patients 50 years old or older in Walker's study 5). Traulllatic Lesions of the Brain
Cerebral trauma must be considered an important etiologic factor in adult epilepsy; in fact, seizures may be the only significant or detectable residual symptom after otherwise satisfactory recovery from severe head injury. It is in these cases that one finds, on pathologic examination, small healed scars in the cerebral cortex, most commonly on the undersurfaces of the frontal lobes and at the tips of the temporal lobes, best understood as the result of impact of the brain against the hard, unyielding floor of the skull. It is fair to say that lesions of this kind do not result from the relatively minor bumps on the head which nearly everyone experiences at one time or another, and at most are accompanied by very brief, if any, loss of consciousness, but rather, they occur with more serious injuries such as are followed by coma for hours or days, with or without focal neurologic signs, but generally with some blood in the
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cerebrospinal fluid during the acute state. Usually an event of this kind is so dramatic that even if the seizures do not appear until several years after the injury (as not infrequently is the case), it stands out as a prominent landmark in the history. Of course, it must be realized that seizures occurring some time after a head injury need not necessarily be due to traumatic cerebral scars, but may be evidence of a more recently acquired disease state. Nevertheless, in view of the relative frequency of head injuries in this age of fast automobiles, and-as already pointed out -the frequency of epilepsy as a sequel to craniocerebr.al injury, a causeand-effect relationship between head injury and seizures can generally be safely assumed unless there is other convincing evidence to the contrary. Chronic subdural hematoma as a rule is not accompanied by seizures. However, they may occur in occasional cases, especially if there is an associated cerebral contusion; and if other suggestive evidence is present, such as persistent headaches and progressive intellectual deterioration, even in the absence of a history of head trauma, this possibility will have to be seriously entertained. Infections
Although seizures may be encountered as one of the clinical aspects in the acute stages of any of a number of infections involving the central nervous system-as in various forms of meningitis or diffuse encephalitis -the main problem is that of the severe underlying medical disorder, and this does not properly come within the scope of a discussion of late-life epilepsy as such. The physician may, however, be called to attend a patient in whom the first clear manifestation of a disorder of this kind is a convulsion or series of convulsions; in such a case, clinical and cerebrospinal fluid examination generally make the situation clear in relatively short order. One condition that may require serious consideration, however, when an adult of mature years suddenly develops seizures in the presence of otherwise generally good health, is neurosyphilis. This is a disease which nowadays tends rather to be overlooked, in view of its declining importance as a result of effective antispirochetal therapy with penicillin. Yet, it must be recalled that the symptoms of syphilitic involvement of the brain may not appear until many years after the acute infection-\vhich may have occurred before penicillin therapy was available, and may be overlooked, inapparent, or denied. rro be sure, other clinical signs, such as the Argyll-Robertson pupillary abnormality, mental changes, and tremors may indicate the true nature of the basic disorder, but they may be absent. However, the diagnosis can be readily made by examining the cerebrospinal fluid obtained on lumbar puncture for increase in cells and protein, and by appropriate serologic tests on blood and cerebrospinal fluid-examinations which should always be carried out in the adult epileptic. Brain abscess may have to be considered. 'fhe problem presented by
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acute brain abscess is that of a rapidly developing expanding intracranial lesion which can mimic neoplasm. The presence of a suppurative focus in the skull (middle ear, mastoid, or paranasal air sinuses) or in the lungs may lead to the diagnosis. Recurrent seizures may be a significant residual symptom after successful surgical treatment of a brain abscess; they are doubtless the result of cerebral cortical scarring. Although it is by no means a frequent problem in the United States, cerebral cysticercosis deserves particular mention as a cause of adult epilepsy. 'rhis condition is the result of direct infestation of the brain by the larvae (cysticerci) of the pork tapeworm, Taenia solium, which follows upon ingestion of the ova usually from eating fecally contaminated food. With increasing travel to and from undeveloped regions of the world, it is to be expected that cases will occasionally appear even in areas where the tapeworm does not ordinarily occur (cf. White, Richardson and Sweet, 1956 7). The parasite larvae become encysted in the brain tissue, where they apparently act as local irritants; convulsive seizures may be the only clinical evidence of their presence. With passage of time, the encysted larvae, which do not flourish in the human host, become calcified and then are readily demonstrated by x-ray films of the skull. They are generally present in the skeletal muscles as well, so that in a suspected case, even if skull films are negative, roentgenograms of the muscle may indicate the diagnosis. Surgery is of no value in the treatment of epilepsy due to cysticercosis, because of the large number of cysticerci generally present. Cerebral Vascular Disease
In our opinion-and this has been the experience of others as wellvascular lesions of the brain are of great importance in producing the epileptic state in the age group under discussion. In the Mayo Clinic series, reported by White, Bailey and Bickford (1953),8 vascular disease of the brain was held to be accountable for seizures in 46 per cent of their 107 cases of seizures beginning after the age of 50; in Walker's series (1936),4 it was considered to be the responsible factor in 10 out of 13 patients in a similar age group. Our own studies (Dodge, Richardson and Victor, 1954;1 Richardson and Dodge, 19543), based upon autopsy material, are of interest in reflecting to some extent the magnitude of the problem. In a series of 427 consecutive brains examined by us, representing cases of all sorts of medical and surgical disease in a general hospital population, we found easily recognizable cerebral vascular lesions in the form of infarction or hemorrhage, exclusive of lesions associated with congenital vascular malformations (angiomas, saccular aneurysms) in 113, or 27 per cent, with a mean age of 64. If we had included the minute lesions that are detectable only on microscopic examination, the incidence would have been higher. In this group of 113 cases, seizures were recorded as having
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occurred in 22, or 19.5 per cent. We furthermore discovered that there was direct involvement of the cerebral cortex in all of the patients who had seizures, whereas no seizures were observed in the cases of vascular lesions which did not involve the cortex. Further analysis of our material disclosed that there were 22 cases of old, healed vascular lesions of the cerebral cortex and that of these, recurrent seizures-i.e., epilepsy-occurred in six. In the remaining seizure cases, the condition could not be accurately termed "epilepsy," but instead consisted of one or more convulsions in the acute phase of a "stroke." These studies led us to emphasize the importance of vascular lesions of the cerebral cortex in the over-all problem of epilepsy in the older patient, particularly since seizures occurred in only one case* of a control series of 156 cases without old, healed cortical lesions including 79 cases of cerebral atherosclerosis (mean age 67) ,vithout grossly visible brain lesions. Although in most of our cases, the appearance of seizures was preceded either immediately, or by a latent interval of as long as 11 months, by an acute neurologic disorder with clinical signs (generally hemiparesis) that was readily identified as a "stroke," the patient could recover from this, leaving recurrent seizures, often generalized although typically with a focal onset of the attack, as the only residual neurologic disability. In two cases studied by us, chronic epilepsy was the only clinical sign of a cerebral cortical infarct. One would be led to suspect, on the basis of these observations, that when late-life epilepsy is the result of vascular lesions of the brain, it would be encountered in those cases in which there are cortical lesions of relatively small size that would be compatible with satisfactory neurologic recovery in other respects. This has proved, in our experience, to be the case. The massive cerebral infarct resulting from occlusion of a major cerebral artery which leaves the patient permanently hemiplegic if he survives is generally not accompanied by recurrent seizures. Furthermore, seizures are not a problem in the very frequent cases of advanced cerebral atherosclerosis combined with chronic hypertension, or diabetes mellitus, which may in the course of time reduce the patient to a mental and physical cripple with bilateral neurologic signs, but which characteristically produce lesions in deep structures in the brain (internal capsules, basal ganglia, central white matter, brain stem) rather than the cerebral cortex. In our material, the lesions favorable for the development of epilepsy were most frequently encountered with cerebral embolism, often arising from mural thrombi in the heart secondary to rheumatic heart disease (mitral stenosis, auricular fibrillation) or myocardial infarction-although a source cannot always be demonstrated. In such cases, a normal cerebral arterial system with good potentialities for collateral circulation, together with the tendency for emboli to travel
* A laboratory accident precluded thorough study of this case, in which no gross brain lesions were found.
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into distal arterial branches unless they are very large, can result in predominating, or exclusive, infarction of cerebral cortex, with lesions of relatively small size. Another form of cerebral vascular disease that is of importance in connection with late-life epilepsy is atherosclerosis and thrombosis of the common or internal carotid artery, on one or both sides. If the collateral circulation via the circle of Willis is adequate, there may be no sizeable infarction of the brain, although the regions most distally located from the source of blood supply may be rendered ischemic. One may then find small areas of cerebral infarction located in the cerebral cortex of the convexities of the brain, and convulsive seizures, typically with focal aspects, may be a prominent clinical· manifestation of their presence. Seizures of this kind, implying some form of involuntary motor activity, or positive manifestations (such as attacks of abnormal sensations on one side of the body), must be differentiated from "cerebral ischemic attacks," in which repeated episodes of a negative character (such as fleeting hemiparesis or fragments thereof, or attacks of monocular blindness, etc.) indicate a marginal or barely adequate blood supply to some part of the brain ,vhich results in focal impairment of cerebral function if the blood pressure falls belovv a critical level, or may even indicate impending thrombosis. In a given case, it may not be very easy to distinguish between a focal convulsive seizure resulting from a fixed or reversible vascular lesion of the cerebral cortex, and a "cerebral ischemic attack"-although careful questioning, and observation of the patient, may permit a decision as to the nature of the episode. Other forms of vascular disease involving the cerebral cortex, such as various inflammatory conditions (polyarteritis nodosa, granulomatous or giant cell arteritis), are rare causes of seizures in the older patient. Convulsions are, of course, a prominent manifestation of extremely severe degrees of hypertensive vascular disease ("malignant hypertension," "hypertensive encephalopathy") with or without uremia; the basis for them may well be disease of arterioles in the cerebral cortex. In such cases, the eyegrounds will show retinal arteriolar narrowing, with retinopathy. Special mention should be made of the Stokes-A dams syndrome, in \vhich episodic or persistent bradycardia may give rise to transitory cerebral ischemia with syncope, perhaps with a few irregular jerks of the limbs or, occasionally, generalized convulsive seizures, without there being any actual lesions in the brain whatsoever. The association of such episodes with a very slow heart rate serves to set them apart from other forms of convulsive disorders in the older age group. It should likewise be emphasized that elderly patients may at times be subject to other transient episodes of faintness, "dizziness," or unexplained falls, which cannot be regarded as genuine "seizures" such as characterize the true epileptic or convulsive state. In attacks of this sort, consciousness may not be lost at all, or only very briefly, and the involun-
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tary motor activity which usually accompanies the focal or diffuse neuronal discharge that is the essence of the epileptic state is absenteven though, during the unconscious period following such a fainting attack, a few muscular twitches may be observed. Episodes of this kind may be the result of orthostatic hypotension, which is revealed by blood pressure determinations in the standing posture as compared with those obtained when the patient is lying or sitting. Somewhat similar states, often entirely subjective, may be encountered as "anxiety attacks" in patients with agitated depressions, and may be brought on by hyperventilation. In taking the history from a patient, one may not be able at first to differentiate episodes of this general character from true seizures. Of great help in such cases is an eyewitness account of the attacks from another reliable informant. Furthermore, the physician may be able to reproduce an attack by having the patient undergo rapid changes of posture, or by getting the patient to hyperventilate. Where a hyperactive carotid sinus reflex results in changes in heart rate and blood pressure resulting in syncope, as occasionally happens, this can be brought out by gentle slight pressure on the carotid bifurcation in the neck on one or the other side. In all of the states under present consideration there are, of course, no irreversible cerebral changes, and treatment must be directed toward the underlying medical disorder. Degenerative Disease of the Brain
Slowly progressive degeneration and disappearance of nerve cells in the brain, chiefly in the cerebral cortex, in the absence of any obvious metabolic abnormality, may be a more important basis for generalized convulsive seizures in older patients than is generally supposed. This involutional process results in diffuse atrophy of the brain and is characteristically accompanied by the presence, microscopically, of scattered extracellular amorphous deposits principally in the cerebral cortex ("senile plaques") and intracellular skeinlike material of similar composition within nerve cells ("Alzheimer's neurofibrillary change"). This pathologic state is very common in advanced age, and is not invariably (in its milder degrees) attended by significant personality or mental changes, although it does form the typical patho-anatomical substratum of senile dementia. More rarely, it occurs in the presenile period, and then generally results in slowly progressive intellectual deterioration which can reach profound degrees before death ensues; the condition is then called Alzheimer' 8 disease. Clinically indistinguishable, but infinitely rarer in our experience, is the peculiar circumscribed severe atrophy of the frontal or temporal lobes, or both, known as Pick's disease. There is another very rare degenerative condition afflicting patients in late middle age, of which we have lately seen two examples, characterized clinically by rapidly progressive severe dementia, focal and diffuse myoclonic jerks, and generalized convulsions, with a total course from onset
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to death in less than a year. This condition, which is called J akob-Creutzfeldt disease, doubtless represents some form of as yet unidentified subacute toxic or metabolic encephalopathy. Although extremely uncommon, it forms such a distinct entity that it is worthy of mention. r-rhere are occasional cases of other forms of cerebral degenerative disease with seizures-particularly some strange varieties with principally white matter affection-but in none of these can the diagnosis be accurately made during life. Metabolic Disorders
A brief reminder is in order that convulsive seizures may result from episodes of hypoglycemia with islet cell adenoma of the pancreas, or with hypocalcemia resulting from parathyroid adenomas. Blood sugar and calcium and phosphorus determinations are thus clearly indicated in the investigation of late-life epilepsy. It should also be kept in mind that individuals habituated to the use of large amounts of alcohol or barbiturates over long periods of time may have one or a series of generalized convulsive seizures if the drug is rapidly withdrawn. Such patients are also prone to head injuries-so that, in such a case, if the physician sees focal convulsive activity in a seizure, or focal neurologic signs in the postconvulsive state, the possibility of cerebral trauma-perhaps with acute epidural or subdural hematoma-may require serious consideration. Late-Life Epilepsy of Undeterlllined Cause
This group probably includes the largest number of cases of late adult epilepsy actually met with in clinical practice. From the foregoing, it will be seen that we believe that some form of anatomically demonstrable brain lesion underlines the epileptic state in the majority of such cases. However, if the condition is not progressive and is unaccompanied by any clinical, electroencephalographic or other evidence of a focal disorder, its exact identity in the practical instance can be considered only of academic importance. DIFFERENTIAL DIAGNOSTIC AND THERAPEUTIC CONSIDERATIONS
In the preceding discussion of various disease states that may underlie convulsive seizures in older patients (particularly those beyond the fifth decade), some hints as to differential diagnosis have already been given. The importance of careful history (with an adequate description of attacks by another informant if possible) and thorough physical and neurological examinations cannot be overemphasized, and may well indicate whether one is dealing with a static or progressive process. In addition to the usual blood counts and urine examination and a blood serologic test for syphilis, further blood studies to rule out hypoglycemia or hypocalcemia may be indicated. Most patients should have roentgeno-
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grams of the skull and chest-the former may given valuable evidence as to increased intracranial pressure, calcified intracranial lesions, and so on; the latter, of course, give much needed information as to the state of the heart and lungs. Unless it is obvious that there is increased intracranial pressure, a lumbar puncture should be done in every case, with examination of the cerebrospinal fluid for pressure, cell count, total protein, sugar (if the fluid contains an increase of cells) and a serologic test for syphilis. Other determinations (qualitative or quantative globulin tests) can be done if available. If the findings are doubtful or equivocal, the lumbar puncture should be repeated within a reasonably short time. 'rhe electroencephalogram is a most valuable tool. Not only may it give valuable localizing evidence, but serial traci~gs in cases of doubt may settle the question as to whether a lesion is progressing before this is apparent by other means. In cases of epilepsy with diffuse degenerative disease of the brain, or in cases of ultimately undetermined cause, an interval electroencephalogram between episodes of seizures is likely to be normal-a fact which may be helpful in the assessment of a given case. In most of the cases seen in practice no further or specialized studies are indicated, and the patient should be treated medically, with standard anticonvulsant drugs alone or a combination according to generally accepted principles of the drug treatment of epilepsy, naturally assuming that underlying systemic disorders-infectious, metabolic or cardiachave been excluded. Difficulty is most likely to arise in cases in which focal aspects of the seizures, and past or present evidence of neurologic abnormalities on examination, may keep alive the suspicion of a turnor. If seizures are due to cerebral vascular lesions-an important possibility, as has already been pointed out-one would prefer to avoid such rigorous procedures as pneumo-encephalography or arteriography, since these patients as a group tolerate them poorly and may, because of the possibility of additional vascular lesions resulting from the procedure, be more seriously disabled than before. It may of course be better, where sufficient doubt exists, to take a calculated risk in order not to miss a surgically remediable lesion; however, sufficiently careful clinical observation, together with evidence from cerebrospinal fluid and electroencephalographic examinations, often make it possible to avoid these potentially dangerous procedures. In closing, it might be re-emphasized that in many instances, once obvious cerebral or systemic disease have been excluded, the clinician will not be able to reach a definite diagnosis in the late-life epileptic. He is likely to find, on the other hand, that he can arrive at satisfactory practical conclusions about the case with conservative, relatively simple diagnostic measures, and that with comparatively small amounts of standard anticonvulsant drugs, the seizure problem· is brought under control to everyone's satisfaction.
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REFERENCES 1. Dodge, P. R., Richardson, E. P., Jr. and Victor, M.: Recurrent Convulsive Seiz-
2. 3. 4. 5. 6. 7. 8.
ures as a Sequel to Cerebral Infarction: A Clinical and Pathological Study. Brain 77: 610, 1954. Penfield, W. and Jasper, H.: Epilepsy and the Functional Anatomy of the Human Brain. Boston, Little, Brown & Co., 1954. Richardson, E. P., Jr. and Dodge, P. R.: Epilepsy in Cerebral Vascular Disease. Epilepsia C3rd series) 3: 49, 1954. Smith, B., Robinson, G. E. and Lennox, W. G.: Acquired Epilepsy. A Study of 535 Cases. Neurology 4: 19, 1954. Walker, A. E.: Convulsive Seizures in Adult Life. Arch. Int. Med. 58: 250, 1936. Watson, C. W.: Incidence of Epilepsy Following Craniocerebral Injury. 11. ThreeYear Follow-up Study. A.M.A. Arch. Neural. & Psychiat. 68: 831,1952. White, J. C., Richardson, E. P., Jr. and Sweet, W. H.: Cysticercosis Cerebri. A Diagnostic and Therapeutic Problem of Increasing Importance. N. England J. Med. 256: 479, 1957. White, P. T., Bailey, A. A. and Bickford, R. G.: Epileptic Disorders in the Aged. Neurology 3: 674, 1953.