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The Differential Diagnosis of Convulsions
The Differential Diagnosis of Convulsions H. HOUSTON MERRITT, M.D.* SIDNEY CARTER, M.D. **
CONVULSIVE seizures are one of the more common symptoms encountered in patients with disease or functional disturbances of the central nervous system. 'rhey may occur as an isolated episode in association with febrile illnesses in children, in which case they are of relatively little significance, or they may recur at intervals as an indication of serious organic disease. It has been estimated that approximately 0.5 per cent of the population or over three-quarters of a million people in the United States are subject to seizures. For diagnostic purposes it is customary to divide patients with convulsive seizures into two groups.; symptomatic and idiopathic, according to the presence or absence of organic factors v/hich may be of importance in the occurrence of the attacks. Utilizing such a classification the differential diagnosis is mainly concerned with the question as to whether there is a strueturallesion in the brain or a metabolic defect which may be the underlying cause of the seizures or whether the convulsions are of undetermined origin (e~:sential, idiopathic). The answer to this question is of great importance in planning the therapy. In addition, convulsive seizures must be distinguished from other paroxysmal disorders (migraine, Meniere's syndrome, syncope and narcolepsy) and from such conditions as carotid sinus irritability, oculogyric crises, anxiety attacks and hysterical attacks. 'rhe differentiation of the various conditions with which convulsions are associated and exclusion of the disorders which may simulate seizures
From the Department of Neurology, College of Physic'ians and Surgeons, Columbia University and the Neurological Institute of the Presbyterian Hospital of N ew York.
* Professor of Neurology, College of Physicians and Surgeons, Columbia University; Director of Service of Neurology , Neurological Institute, Presbyterian Hospital. ** Assistant Professor of Neurology, College of Physicians and Surgeons, Columbia University; Attending Neurologist, N eurologicallnstitute, Presbyterian Hospital. 693
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can usually be made in most cases by a thorough study of the patient which includes a complete history, general physical and neurological examination, x-rays of the skull and chest, determination of the glucose, nonprotein nitrogen and calcium content of the blood, examination of cerebrospinal fluid, electrocardiography, electroencephalography and, when indicated, pneumoencephalography or cerebral angiography. ETIOLOGY OF CONVULSIONS
Although a great number of biochemical and physiological studies have been made on patients with convulsive seizures, the pathophysiology of convulsive seizures is still unknown. The high incidence of seizures in patients with organic lesions in the brain makes it seem probable that the presence of damage to cerebral tissue is of great importance in the occurrence of seizures. Evidence of gross damage to the brain is absent, however, in the majority of patients with seizures. It must, therefore, be concluded that factors other than organic damage to the brain playa role in the precipitation of the seizures. It is obvious that brain damage, when present, is not the sole cause of the seizure. This abnormality is always present, but the seizures occur only at irregular intervals. Similarly it can not be presumed that inert tissue is the site of origin of a convulsive seizure, and it is more probable that this is in the more nearly normal but slightly damaged tissue adjacent to the injury. An undue degree of irritability of the relatively normal tissue in the neighborhood of destroyed or damaged nervous tissue to various exogenous or endogenous stimuli or metabolic disturbances would explain the high incidence of seizures in patients with organic lesions in the nervous system. The nature of the metabolic disturbance which produces an increased irritability of cortical neurones is unknown. Conditions Accolllpanied by Seizures
From the foregoing it is obvious that seizures are much more apt to occur in patients with organic lesions in the brain than in patients with a normal central nervous system. There are, however, certain diseases of the brain which have a relatively high incidence of seizures and others in which the incidence is only slightly greater than that of the general population. The list of diseases and conditions which are frequently accompanied by seizures is extensive and includes developmental and congenital defects, cerebral aplasias, birth injuries, acute infectious diseases of childhood, meningitis, encephalitis, cerebral trauma, tumors, abscesses, granulomas, parasitic cysts, degenerative diseases of the nervous system, metabolic disturbances or intoxications such as uremia, water and alcoholic intoxication, cerebral edema, polycythemia, asphyxia, carbon
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monoxide poisoning, protein shock, anaphylaxis, Raynaud's disease, Stokes-Adams' syndrome, carotid sinus sensitivity, tetany, insulin shock, hyperventilation, and the ingestion of convulsant drugs. Conversely, there are several diseases or morbid states of the brain in which the incidence of convulsive seizures is relatively low despite the presence of large or multiple small areas of brain damage. Examples of this nature are encephalomalacia, and multiple sclerosis. SIGNIFICANCE OF THE VARIOUS MANIFESTATIONS WHICH MAY OCCUR IN PATIENTS WITH CONVULSIVE SEIZURES
Since convulsive seizures may manifest themselves in a variety of forms, an accurate description of the patient's attacks by a competent observer is of great value in the differential diagnosis. The clinical manifestations of convulsive seizures are quite diverse, but in most patients the seizures can be classified in one of four groups. These four groups are: grand mal or generalized seizures; petit mal or minor attacks; psychomotor attacks and epileptic equivalents; and focal seizures, i.e., Jacksonian or generalized seizures with a focal onset.
Grand Mal Attacks Approximately 85 per cent of patients with convulsions suffer with seizures of the grand mal type, either alone or in combination with other types of attacks. Grand mal seizures are initiated by an aura in about half of the cases. The seizures are characterized by a sudden loss of consciousness, followed by tonic and clonic spasms of the musculature with or without tongue biting, urinary or fecal incontinence, and excessive salivation. Consciousness may return within a few minutes or the patient may lapse into a heavy sleep to awaken several hours later. On regaining consciousness, the patient may complain of headache, nausea, stiffness of the muscles and general fatigue or he may be dazed, drowsy and confused. 'When grand mal seizures are present, there are usually no features of the attack itself to indicate whether it is of symptomatic or unknown origin. Such attacks have no specific diagnostic significance and can occur in association with a focal lesion in any portion of the cerebral cortex, with diffuse disease of the brain or in the absence of a demonstrable lesion. Although a brief aura may be present in 50 per cent of the patients with grand mal seizures, it is often of a nonspecific nature and gives little or no information in regard to the site of origin within the brain of the attack. For the most part in grand mal or generalized convulsions the spread of the convulsive discharge is so rapid that consciousness is lost before any evidence of the source of the original discharge can be detected.
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Petit Mal Attacks
If the number of affected individuals is considered, petit mal attacks rank second to grand mal in order of frequency. According to Lennox, the petit mal syndrome consists of a triad of symptoms, myoclonic jerks, akinetic seizures and the characteristic petit mal attacks-transient absences or loss of contact with the environment. r:rhese three symptoms are classified together by Lennox on account of the similarity of the electroencephalographic changes and also because they are all refractory to the drugs which are effective in the control of grand mal seizures. Myoclonus consists of sudden involuntary contraction of the muscles of the trunk or extremities without apparent loss of consciousness. Myoclonic jerks may occur in patients with petit mal seizures, but they are equally as frequent in patients whose seizures are of the grand mal type. The myoclonic jerks may occur at any time but tend to be more frequent in the early hours of the day and may be the only manifestations of a convulsive disorder for a period of months to years. Occasionally, myoclonic jerks may occur with great frequency and culminate in a grand mal seizure. Myoclonus is also a symptom of an organic disease of the cerebellum, brain stem and cerebral cortex known as myoclonus epilepsy. Akinetic seizures are characterized by a sudden loss of tone in all of the muscles of the body of such severity that the patient falls to the ground. The fall is sometimes so violent that the patient may seriously injure himself. More usually, however, he is able to get up immediately and continue with his activities. Akinetic seizures, similar to the myoclonus jerks, may occur in patients who have typical petit mal attacks, but they also occur in patients whose clinical seizures are of the grand mal type. rrhe classical petit mal attack is manifested by a transient clouding of consciousness lasting about 5 to 30 seconds with or without minor movements of the head, eyes and extremities and loss of muscular tone. Sucli attacks tend to recur several to many times daily. After an attack the patient is immediately alert and able to carryon with previous activities. Petit mal attacks can be precipitated by causing the patient to hyperventilate for a period of one to three minutes. Petit mal seizures are characteristically a manifestation of the convulsive disorders in childhood and rarely, if ever, have their onset after the age of 20. They may occur in patients with birth injuries or developmental defects or may develop following acute febrile illnesses in childhood, but they are most commonly seen in children with no organic lesion in the nervous system and practically never appear for the first time in adult patients with cerebral tumors, abscesses or following cerebral trauma. It is thought by some that the focus of the abnormal
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discharge which precipitates a petit mal attack is subcortical, possibly in the thalamic nuclei. psychomotor Attacks
Psychomotor seizures are the third most common type of attack and constitute a much less clear clinical entity than either grand mal or petit mal. They are characterized by a period of loss of contact with the environment usually lasting for 1 to 2 minutes. During an attack the patients behave in a stereotyped manner and do not understand what is said to them. There may be twisting or writhing movements of the extremities or trunk, smacking movements of the lips, incoherent speech, the involuntary performance of apparently purposeful activities, or resistance to any attempt to aid them during the attack. Electroencephalographic recordings, particularly those made during sleep, indicate that the focus for the abnormal discharge which precipitates a characteristic psychomotor attack is usually in the anterior portion of one temporal lobe. Because of this finding many authorities consider psychomotor seizures to be of symptomatic origin, secondary to a structural lesion (tumor or scar) in one or both temporal lobes. Jacksonian and Focal Seizures
These attacks are less common than the other forms of seizures. They will be found to be more common than generally supposed, however, if the onset of supposedly generalized attacks is carefully analyzed. r-rhe focal seizures described by Jackson are associated with lesions in the motor cortex. l'he seizure starts with convulsive twitchings of one portion of the body, usually the distal part of one extremity. If the seizure starts in the fingers it spreads to the wrist, the forearm, the face and then to the homolateral leg. The power of speech may be impaired or lost when the convulsive movements involve th.e dominant side of the body. Consciousness is retained unless the movements spread to the opposite half of the body. If this occurs consciousness is lost and the further manifestations are similar to those of a grand mal seizure. Lesions in other portions of the cerebral cortex may be accompanied by focal seizures, but with the exception of the focal sensory seizures which are characterized by a sensation of numbness or tingling in one extremity or one-half of the body, they do not have the specific localizing value of the Jacksonian seizure. They do, however, localize the lesion to one hemisphere and sometimes to a restricted portion of the hemisphere. Jacksonian and focal seizures occur almost exclusively in patients with an organic lesion in the cortex. This lesion may be of macroscopic or microscopic size. It is commonly thought that the occurrence of
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Jacksonian or focal convulsive seizures is pathognomonic of tumors of the brain, but in more than 50 per cent of the cases these attacks are associated with lesions due to other causes (birth injury, trauma or infection). In addition to the above, there are other types of attacks which are less clearly defined but which are frequently classified under the convulsive disorders because of their paroxysmal nature and because they may occur in patients who also have the more typical type of seizures or who have electroencephalographic evidence of a convulsive disorder. Pain in the abdomen may occur as an aura in patients with seizures, and it is claimed by some authors that paroxysmal attacks of abdominal pain may be the only manifestation of the convulsive seizures. These cases have been described as a clinical entity, occurring primarily in children, under the term "abdominal epilepsy." The evidence in support of the claim that the abdominal pain is a convulsive manifestation consists of the finding of an abnormal electroencephalogram, favorable results of treatment with anticonvulsant drugs and the development of recurrent convulsive seizures in later years. AGE AT ONSET
The age at the time of onset of seizures may have considerable differential diagnostic significance. Convulsive seizures of unknown cause usually have their onset early in life. In the vast majority seizures start before the age of 25, but from this age to senility there is a small but fairly constant percentage for each decade in which seizures of unknown origin occur for the first time. As a rule, however, the later the onset of seizures the greater the probability that they are associated with some organic lesion of the brain. There are two peaks in the curve for the onset of seizures of unknown cause. The first peak is in the first two years of life and the second is at the age of puberty. Convulsive seizures associated with organic disease of the brain may have their onset at any age of life. The distribution of the curve of the age of incidence is more even in these cases than in the cases of unknown cause, but like the latter, there are two peaks. The first is in the early years of life and the second after the third decade of life. The first peak is related to the fact that the developing brain of the infant or young child is much more apt to react with convulsive seizures when it is injured by trauma, by infections of the nervous system or by simple febrile illnesses. The second peak is related to severe head injuries and the neurological diseases of adult life. Convulsions in Childhood
Convulsive seizures occur more frequently during infancy and childhood than they do in any other period of life and it is in this period
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that the differentiation of the various conditions associated with seizures may be most difficult. Peterman's! invaluable study of 2500 children with convulsions has contributed statistical data of considerable significance. In his series the convulsions were associated with acute infections in one-third of the cases, were of undetermined origin (idiopathic) in one-fourth of the cases and were related to cerebral birth injuries in 14 per cent of the patients (Table 1). Under infections, Peterman included the cases with febrile convulsions and those with acute infectious diseases in which there was an invasion of the central nervous system by bacteria or viruses. Idiopathic epilepsy was found to be the most common cause of recurring convulsions in childhood. In his evaluation of convulsions in childhood, Peterman classified the various causes of seizures at different age levels. He found that birth trauma and infections were the major causes of seizures in infants under the age of 6 months; infections, epilepsy and tetany were the major Table I CA USES OF CONVULSIONS IN CHILDHOOD CAUSE
(2500
CASES) PER CENT
Acute infection. ". . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Idiopathic epilepsy Cerebral birth injury or residue ; Miscellaneous causes. . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . .. Infantile tetany...... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Causes not established. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
33.4 26.3 14.2 13.1 7.4 5.6
(From Peterman, M. G., A.M.A. Am. J. Dis. Child., October 1946.)
causes of seizures in infants between the ages of 6 months and 3 years; idiopathic epilepsy and infections were the most commonly associated conditions with convulsions in patients between the ages of 3 and 10; and idiopathic epilepsy accounted for approximately 75 per cent of the cases between the ages of 10 and 16. When a child who has been previously normal develops convulsive seizures and regresses mentally or develops focal neurological signs, one should consider such possibilities as an intracranial tumor, subdural hematoma, cerebral vascular malformation, degenerative cerebral disease or lead poisoning. Because brain tumors in children tend to be situated in the cerebellum and brain stem rather than in the cerebral hemispheres, they are not as frequently associated with convulsive seizures as they are in adults. However, children with supratentorial tumors will have as high an incidence of seizures as do adults. 2 It is difficult to assess the significance of febrile convulsions in infants and young children, particularly in regard to their relationship to epilepsy. According to Lennox,s seizures occur in about 5 per cent of all children under the age of 5. In approximately one-half of these patients
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the seizures are related to some febrile illness. It is generally agreed that the occurrence of seizures in young children with febrile illness does not necessarily presage the later development of epilepsy but the likelihood of this eventuality is great if the seizures recur with every febrile illness, if there are multiple seizures, or if there are paroxysmal abnormalities in the electroencephalogram in the seizure-free interval. Convulsions in Adults
Convulsive seizures occurring for the first time in adults are much more likely to imply an underlying organic lesion than they do in children. While there are many disorders which are associated with convulsions in adult life, the more common conditions are the intracranial space-occupying lesions, cerebral trauma and vascular malformations. Intracranial neoplasms are the most frequent cause of the onset of convulsive manifestations in patients between the ages of 35 and 55. 4 A third of the patients with brain tumors and 50 per cent of those with brain abscesses have convulsive seizures. The incidence is considerably less for subdural hematomas where the figures in different reported series varied from "rare" to 25 per cent. In those cases where seizures occur they frequently may be the first manifestation and in some instances the only clinical sign of the tumor. Hoefer, Schlesinger and Pennes 5 noted that seizures were the initial symptom in 68 per cent of their cases of astrocytoma, in 60 per cent of their cases of meningioma and in 51 per cent of their cases of glioblastoma. The laity are prone to relate convulsive seizures to head trauma and, actually, it is sometimes very difficult to assess the significance of head trauma in the production of seizures. Over 40 per cent of the men who sustained penetrating wounds of the skull, dura and brain in World Wars I and II developed post-traumatic seizures, regardless of the site of injury. 6 , 7 The relationship of closed head injuries to the development of seizures is much less definite. They undoubtedly play some part, particularly if the injury has been a severe one and if the seizures begin within a two year period after the injury. Vascular lesions, particularly those which involve the venous system, can give rise to convulsions at any time of life. Vascular anomalies (hemangiomas) are also commonly accompanied by convulsive seizures. Even though they are rare, adenomas of the pancreas (hyperinsulinism) and hypoparathyroidism should always be considered in the differentiation of the various conditions associated with convulsions because they are amenable to specific therapy. Mter all the above conditions have been excluded there remains a small but fairly constant percentage of patients who have their first seizures after the age of 25 for no apparent reason that can be determined by the present available methods. When one considers patients
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of all ages the great majority are those whose seizures are of unknown origin (Table 2). PHYSICAL FINDINGS
There are usually no abnormal physical findings in patients whose seizures are of the idiopathic variety. Some of these patients may, however, have scars on the tongue or lips that have resulted from lacerations occurring during attacks. The physical examination may be equally nonrevealing in patients with seizures of symptomatic origin but when abnormalities are demonstrated they may have considerable diagnostic significance. The finding of an elevated blood pressure may point to cardiovascular renal disease as a possible cause of the convulsions. The demonstration of a mass lesion in the breast, thyroid or prostate may indicate that the convulsions are secondary to cerebral metastases. Table 2 THE RELA'l'IVE FHEQUENCY OF THE VARIOUS CAUSES OF RECURRENT CONVULSIVE SEIZURES IN 2000 N ONINS'l'ITUTIONAL CASES Oli' EPILEPSY AT ALL AGES (AFTER LENNOX) PER CENT PRESUMED CAUSE OF SEIZURES
OF CASES
None demonstrated 77.6 Cerebral trauma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 5.7 Birth inj ury or congenital defect. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 5.6 Brain infection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 4.2 Brain tumor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2.6 Cerebral circulatory defect 1.9 Extracerebral causes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 0.9
When cutaneous lesions are evident in patients with seizures they may suggest such possibilities as tuberous sclerosis or the Sturge-Weber syndrome. Tuberous sclerosis is characterized by convulsions, adenoma sebaceum (fibromata of the sebaceous glands situated on the cheeks and side of the nose-butterfly distribution) and mental retardation. The Sturge-Weber syndrome is manifested by convulsions, angiomata of the face and scalp, frequently in the distribution of one or more divisions of the trigeminal nerve, and intracranial calcifications. Abnormal neurological findings may be present in the patients in whom the convulsive seizures accompany organic lesions or disease of the nervous system. These abnormal findings are characteristic of the underlying pathology and are exactly the same as those which occur in patients having similar lesions without convulsive seizures. Abnormal neurological findings may be found in patients with convulsions of unknown origin; (1) during an attack, (2) as a result of injuries sustained during seizures, and (3) as the result of untoward side reactions of anticonvulsant medicines. Extensor plantar responses and loss of pupillary reflexes are the most common abnormal findings during a seizure.
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With the exception of the electroencephalogram, laboratory findings are within normal limits 'in the majority of patients with seizures of unknown cause. When the seizures are associated with some metabolic disturbance such as hyperinsulinism or hypoparathyroidism there will be a low sugar or calcium content in the blood. When seizures are associated with brain tumor, brain abscess or other organic diseases of the nervous system, the laboratory findings will be those which are characteristic of the underlying disease process. Electroencephalograms. Electroencephalography is one of the most important of all the ancillary procedures utilized in the diagnosis of the convulsive disorders. Electroencephalographic records taken during a clinical seizure show abnormalities that are characteristic for each of the three types of clinical seizures. The electroencephalogram, however, is not only of value in recording the changes that occur coincident with the attack, but also in registering abnormal activity in the interval between attacks. During a seizure the abnormalities in the electroencephalogram involve all portions of the cortex. In the interval between seizures, focal abnormalities are present in a high percentage of the patients with a local lesion in the cortex and are of value in establishing the diagnosis of cortical injury resulting from trauma, infections or tumors. According to the Gibbses,8 focal abnormalities in the temporal lobes are relatively common in the records of patients with seizures of the psychomotor type if the records are taken during sleep. It must be remembered that approximately 15 per eent of patients with seizures will have a normal record if only one traeing is taken in the seizure-free interval. On the other hand, the presence of abnormalities in the electroencephalogram is not in itself diagnostic of a convulsive disorder, because abnormalities are found in 10 per cent of the normal population. The two additional procedures of value in the study of patients with convulsive seizures are pneumoencephalography and cerebral angiography. These tests are not done routinely and are utilized only when there are indications in the history or in the neurologic examination that the patient has seizures secondary to some progressing or expanding lesion. They are particularly indicated when there is a suspicion of an expanding mass or a vascular abnormality. SUMMARY
A great variety of conditions can be associated with convulsive seizures. The differential diagnosis in patients with seizures is mainly concerned with the question as to whether there is a focal lesion in the brain or a metabolic defect which is amenable to treatment.
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The diagnostic procedures usually advisable for the study of a patient who has had one or more convulsive seizures are somewhat dependent upon the age of onset, the type of seizure and the frequency of the seizures, but as a rule the following examinations should be carried out: A. 1. Complete history and physical examination. 2. Neurological examination. 3. Urinalyses and blood examinations including serum calcium, glucose tolerance test and the serologic test for syphilis. 4. X-rays of the skull. 5. Electrocardiography. 6. Spinal fluid examination. 7. Electroencephalography. B. A pneumoencephalogram, ventriculogram or cerebral angiogram should be performed: 1. If there are indications from the description of an attack that the seizure is of a focal nature. 2. If there are findings on neurological examination which indicate a focal lesion, which cannot be explained adequately, or if there is choking of the disks. 3. If there is an increase in intracranial pressure as measured by the lumbar puncture of if the cerebrospinal fluid protein content is greater than 75 mg. in the absence of syphilis or other infections of the meninges. 4. If there are persistent focal abnormalities in the electroencephalogram. Pneumoencephalography is contraindicated and ventriculography or angiography is preferred whenever there is (1) choked disk, or (2) high cerebrospinal fluid pressure. Angiography is contraindicated whenever there is (1) sensitivity to the dye, or (2) moderate or advanced arteriosclerosis. It must be remembered that neither a normal angiogram nor a normal pneumoencephalogram excludes the diagnosis of a small tumor, scar or other fixed lesions. A small tumor, for example may be the focus of convulsive seizures and not be demonstrated by any of our diagnostic methods. Continued observation over a period of several or many years may be needed before a definite diagnosis is established.
REFERENCES 1. Peterman, M. G.: Convulsions in Childhood. Twenty Year Study of 2500 Cases. Am. J. Dis. Child. 72: 399, 1946. 2. Miller, R. H., Craig, W. MeR. and Kernohan, J. W.: Supratentorial Tumors among Children. Arch. Neurol. & Psychiat. 68: 797, 1952. 3. Lennox, M. A.: Febrile Convulsions in Childhood. Proc. A. Research Nerv. & Ment. Dis. 26: 342, 1947. 4. Penfield, W. and Erickson, T. C.: Epilepsy and Cerebral Localization. Springfield, Ill., C. C Thomas, 1941, 623 pp.
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5. Hoefer, P. F. A., Schlesinger, E. B. and Pennes, H. H.: Seizures in Patients with Brain Tumors. Proc. A. Research Nerv. & Ment. Dis. 26: 50,1947. 6. Ascroft, P. B.: Traumatic Epilepsy after Gunshot Wounds of the Head. Brit. M. J. 1: 739, 1941. 7. Watson, C. W.: Incidence of Epilepsy Following Craniocerebral Injury. Arch. N eurol. & Psychiat. 68: 831, 1952. 8. Gibbs, E. L., Gibbs, F. A. and Fuster, B.: Psychomotor Epilepsy. Arch. Neurol. & Psychiat. 60: 331, 1948. 710 West 167th Street New York 32
CONVULSIVE seizures are one of the more common symptoms encountered in patients with disease or functional disturbances of the central nervous system. 'rhey may occur as an isolated episode in association with febrile illnesses in children, in which case they are of relatively little significance, or they may recur at intervals as an indication of serious organic disease. It has been estimated that approximately 0.5 per cent of the population or over three-quarters of a million people in the United States are subject to seizures. For diagnostic purposes it is customary to divide patients with convulsive seizures into two groups.; symptomatic and idiopathic, according to the presence or absence of organic factors v/hich may be of importance in the occurrence of the attacks. Utilizing such a classification the differential diagnosis is mainly concerned with the question as to whether there is a strueturallesion in the brain or a metabolic defect which may be the underlying cause of the seizures or whether the convulsions are of undetermined origin (e~:sential, idiopathic). The answer to this question is of great importance in planning the therapy. In addition, convulsive seizures must be distinguished from other paroxysmal disorders (migraine, Meniere's syndrome, syncope and narcolepsy) and from such conditions as carotid sinus irritability, oculogyric crises, anxiety attacks and hysterical attacks. 'rhe differentiation of the various conditions with which convulsions are associated and exclusion of the disorders which may simulate seizures
From the Department of Neurology, College of Physic'ians and Surgeons, Columbia University and the Neurological Institute of the Presbyterian Hospital of N ew York.
* Professor of Neurology, College of Physicians and Surgeons, Columbia University; Director of Service of Neurology , Neurological Institute, Presbyterian Hospital. ** Assistant Professor of Neurology, College of Physicians and Surgeons, Columbia University; Attending Neurologist, N eurologicallnstitute, Presbyterian Hospital. 693
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can usually be made in most cases by a thorough study of the patient which includes a complete history, general physical and neurological examination, x-rays of the skull and chest, determination of the glucose, nonprotein nitrogen and calcium content of the blood, examination of cerebrospinal fluid, electrocardiography, electroencephalography and, when indicated, pneumoencephalography or cerebral angiography. ETIOLOGY OF CONVULSIONS
Although a great number of biochemical and physiological studies have been made on patients with convulsive seizures, the pathophysiology of convulsive seizures is still unknown. The high incidence of seizures in patients with organic lesions in the brain makes it seem probable that the presence of damage to cerebral tissue is of great importance in the occurrence of seizures. Evidence of gross damage to the brain is absent, however, in the majority of patients with seizures. It must, therefore, be concluded that factors other than organic damage to the brain playa role in the precipitation of the seizures. It is obvious that brain damage, when present, is not the sole cause of the seizure. This abnormality is always present, but the seizures occur only at irregular intervals. Similarly it can not be presumed that inert tissue is the site of origin of a convulsive seizure, and it is more probable that this is in the more nearly normal but slightly damaged tissue adjacent to the injury. An undue degree of irritability of the relatively normal tissue in the neighborhood of destroyed or damaged nervous tissue to various exogenous or endogenous stimuli or metabolic disturbances would explain the high incidence of seizures in patients with organic lesions in the nervous system. The nature of the metabolic disturbance which produces an increased irritability of cortical neurones is unknown. Conditions Accolllpanied by Seizures
From the foregoing it is obvious that seizures are much more apt to occur in patients with organic lesions in the brain than in patients with a normal central nervous system. There are, however, certain diseases of the brain which have a relatively high incidence of seizures and others in which the incidence is only slightly greater than that of the general population. The list of diseases and conditions which are frequently accompanied by seizures is extensive and includes developmental and congenital defects, cerebral aplasias, birth injuries, acute infectious diseases of childhood, meningitis, encephalitis, cerebral trauma, tumors, abscesses, granulomas, parasitic cysts, degenerative diseases of the nervous system, metabolic disturbances or intoxications such as uremia, water and alcoholic intoxication, cerebral edema, polycythemia, asphyxia, carbon
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monoxide poisoning, protein shock, anaphylaxis, Raynaud's disease, Stokes-Adams' syndrome, carotid sinus sensitivity, tetany, insulin shock, hyperventilation, and the ingestion of convulsant drugs. Conversely, there are several diseases or morbid states of the brain in which the incidence of convulsive seizures is relatively low despite the presence of large or multiple small areas of brain damage. Examples of this nature are encephalomalacia, and multiple sclerosis. SIGNIFICANCE OF THE VARIOUS MANIFESTATIONS WHICH MAY OCCUR IN PATIENTS WITH CONVULSIVE SEIZURES
Since convulsive seizures may manifest themselves in a variety of forms, an accurate description of the patient's attacks by a competent observer is of great value in the differential diagnosis. The clinical manifestations of convulsive seizures are quite diverse, but in most patients the seizures can be classified in one of four groups. These four groups are: grand mal or generalized seizures; petit mal or minor attacks; psychomotor attacks and epileptic equivalents; and focal seizures, i.e., Jacksonian or generalized seizures with a focal onset.
Grand Mal Attacks Approximately 85 per cent of patients with convulsions suffer with seizures of the grand mal type, either alone or in combination with other types of attacks. Grand mal seizures are initiated by an aura in about half of the cases. The seizures are characterized by a sudden loss of consciousness, followed by tonic and clonic spasms of the musculature with or without tongue biting, urinary or fecal incontinence, and excessive salivation. Consciousness may return within a few minutes or the patient may lapse into a heavy sleep to awaken several hours later. On regaining consciousness, the patient may complain of headache, nausea, stiffness of the muscles and general fatigue or he may be dazed, drowsy and confused. 'When grand mal seizures are present, there are usually no features of the attack itself to indicate whether it is of symptomatic or unknown origin. Such attacks have no specific diagnostic significance and can occur in association with a focal lesion in any portion of the cerebral cortex, with diffuse disease of the brain or in the absence of a demonstrable lesion. Although a brief aura may be present in 50 per cent of the patients with grand mal seizures, it is often of a nonspecific nature and gives little or no information in regard to the site of origin within the brain of the attack. For the most part in grand mal or generalized convulsions the spread of the convulsive discharge is so rapid that consciousness is lost before any evidence of the source of the original discharge can be detected.
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Petit Mal Attacks
If the number of affected individuals is considered, petit mal attacks rank second to grand mal in order of frequency. According to Lennox, the petit mal syndrome consists of a triad of symptoms, myoclonic jerks, akinetic seizures and the characteristic petit mal attacks-transient absences or loss of contact with the environment. r:rhese three symptoms are classified together by Lennox on account of the similarity of the electroencephalographic changes and also because they are all refractory to the drugs which are effective in the control of grand mal seizures. Myoclonus consists of sudden involuntary contraction of the muscles of the trunk or extremities without apparent loss of consciousness. Myoclonic jerks may occur in patients with petit mal seizures, but they are equally as frequent in patients whose seizures are of the grand mal type. The myoclonic jerks may occur at any time but tend to be more frequent in the early hours of the day and may be the only manifestations of a convulsive disorder for a period of months to years. Occasionally, myoclonic jerks may occur with great frequency and culminate in a grand mal seizure. Myoclonus is also a symptom of an organic disease of the cerebellum, brain stem and cerebral cortex known as myoclonus epilepsy. Akinetic seizures are characterized by a sudden loss of tone in all of the muscles of the body of such severity that the patient falls to the ground. The fall is sometimes so violent that the patient may seriously injure himself. More usually, however, he is able to get up immediately and continue with his activities. Akinetic seizures, similar to the myoclonus jerks, may occur in patients who have typical petit mal attacks, but they also occur in patients whose clinical seizures are of the grand mal type. rrhe classical petit mal attack is manifested by a transient clouding of consciousness lasting about 5 to 30 seconds with or without minor movements of the head, eyes and extremities and loss of muscular tone. Sucli attacks tend to recur several to many times daily. After an attack the patient is immediately alert and able to carryon with previous activities. Petit mal attacks can be precipitated by causing the patient to hyperventilate for a period of one to three minutes. Petit mal seizures are characteristically a manifestation of the convulsive disorders in childhood and rarely, if ever, have their onset after the age of 20. They may occur in patients with birth injuries or developmental defects or may develop following acute febrile illnesses in childhood, but they are most commonly seen in children with no organic lesion in the nervous system and practically never appear for the first time in adult patients with cerebral tumors, abscesses or following cerebral trauma. It is thought by some that the focus of the abnormal
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discharge which precipitates a petit mal attack is subcortical, possibly in the thalamic nuclei. psychomotor Attacks
Psychomotor seizures are the third most common type of attack and constitute a much less clear clinical entity than either grand mal or petit mal. They are characterized by a period of loss of contact with the environment usually lasting for 1 to 2 minutes. During an attack the patients behave in a stereotyped manner and do not understand what is said to them. There may be twisting or writhing movements of the extremities or trunk, smacking movements of the lips, incoherent speech, the involuntary performance of apparently purposeful activities, or resistance to any attempt to aid them during the attack. Electroencephalographic recordings, particularly those made during sleep, indicate that the focus for the abnormal discharge which precipitates a characteristic psychomotor attack is usually in the anterior portion of one temporal lobe. Because of this finding many authorities consider psychomotor seizures to be of symptomatic origin, secondary to a structural lesion (tumor or scar) in one or both temporal lobes. Jacksonian and Focal Seizures
These attacks are less common than the other forms of seizures. They will be found to be more common than generally supposed, however, if the onset of supposedly generalized attacks is carefully analyzed. r-rhe focal seizures described by Jackson are associated with lesions in the motor cortex. l'he seizure starts with convulsive twitchings of one portion of the body, usually the distal part of one extremity. If the seizure starts in the fingers it spreads to the wrist, the forearm, the face and then to the homolateral leg. The power of speech may be impaired or lost when the convulsive movements involve th.e dominant side of the body. Consciousness is retained unless the movements spread to the opposite half of the body. If this occurs consciousness is lost and the further manifestations are similar to those of a grand mal seizure. Lesions in other portions of the cerebral cortex may be accompanied by focal seizures, but with the exception of the focal sensory seizures which are characterized by a sensation of numbness or tingling in one extremity or one-half of the body, they do not have the specific localizing value of the Jacksonian seizure. They do, however, localize the lesion to one hemisphere and sometimes to a restricted portion of the hemisphere. Jacksonian and focal seizures occur almost exclusively in patients with an organic lesion in the cortex. This lesion may be of macroscopic or microscopic size. It is commonly thought that the occurrence of
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Jacksonian or focal convulsive seizures is pathognomonic of tumors of the brain, but in more than 50 per cent of the cases these attacks are associated with lesions due to other causes (birth injury, trauma or infection). In addition to the above, there are other types of attacks which are less clearly defined but which are frequently classified under the convulsive disorders because of their paroxysmal nature and because they may occur in patients who also have the more typical type of seizures or who have electroencephalographic evidence of a convulsive disorder. Pain in the abdomen may occur as an aura in patients with seizures, and it is claimed by some authors that paroxysmal attacks of abdominal pain may be the only manifestation of the convulsive seizures. These cases have been described as a clinical entity, occurring primarily in children, under the term "abdominal epilepsy." The evidence in support of the claim that the abdominal pain is a convulsive manifestation consists of the finding of an abnormal electroencephalogram, favorable results of treatment with anticonvulsant drugs and the development of recurrent convulsive seizures in later years. AGE AT ONSET
The age at the time of onset of seizures may have considerable differential diagnostic significance. Convulsive seizures of unknown cause usually have their onset early in life. In the vast majority seizures start before the age of 25, but from this age to senility there is a small but fairly constant percentage for each decade in which seizures of unknown origin occur for the first time. As a rule, however, the later the onset of seizures the greater the probability that they are associated with some organic lesion of the brain. There are two peaks in the curve for the onset of seizures of unknown cause. The first peak is in the first two years of life and the second is at the age of puberty. Convulsive seizures associated with organic disease of the brain may have their onset at any age of life. The distribution of the curve of the age of incidence is more even in these cases than in the cases of unknown cause, but like the latter, there are two peaks. The first is in the early years of life and the second after the third decade of life. The first peak is related to the fact that the developing brain of the infant or young child is much more apt to react with convulsive seizures when it is injured by trauma, by infections of the nervous system or by simple febrile illnesses. The second peak is related to severe head injuries and the neurological diseases of adult life. Convulsions in Childhood
Convulsive seizures occur more frequently during infancy and childhood than they do in any other period of life and it is in this period
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Differential Diagnosis of Convulsions
that the differentiation of the various conditions associated with seizures may be most difficult. Peterman's! invaluable study of 2500 children with convulsions has contributed statistical data of considerable significance. In his series the convulsions were associated with acute infections in one-third of the cases, were of undetermined origin (idiopathic) in one-fourth of the cases and were related to cerebral birth injuries in 14 per cent of the patients (Table 1). Under infections, Peterman included the cases with febrile convulsions and those with acute infectious diseases in which there was an invasion of the central nervous system by bacteria or viruses. Idiopathic epilepsy was found to be the most common cause of recurring convulsions in childhood. In his evaluation of convulsions in childhood, Peterman classified the various causes of seizures at different age levels. He found that birth trauma and infections were the major causes of seizures in infants under the age of 6 months; infections, epilepsy and tetany were the major Table I CA USES OF CONVULSIONS IN CHILDHOOD CAUSE
(2500
CASES) PER CENT
Acute infection. ". . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Idiopathic epilepsy Cerebral birth injury or residue ; Miscellaneous causes. . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . .. Infantile tetany...... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Causes not established. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
33.4 26.3 14.2 13.1 7.4 5.6
(From Peterman, M. G., A.M.A. Am. J. Dis. Child., October 1946.)
causes of seizures in infants between the ages of 6 months and 3 years; idiopathic epilepsy and infections were the most commonly associated conditions with convulsions in patients between the ages of 3 and 10; and idiopathic epilepsy accounted for approximately 75 per cent of the cases between the ages of 10 and 16. When a child who has been previously normal develops convulsive seizures and regresses mentally or develops focal neurological signs, one should consider such possibilities as an intracranial tumor, subdural hematoma, cerebral vascular malformation, degenerative cerebral disease or lead poisoning. Because brain tumors in children tend to be situated in the cerebellum and brain stem rather than in the cerebral hemispheres, they are not as frequently associated with convulsive seizures as they are in adults. However, children with supratentorial tumors will have as high an incidence of seizures as do adults. 2 It is difficult to assess the significance of febrile convulsions in infants and young children, particularly in regard to their relationship to epilepsy. According to Lennox,s seizures occur in about 5 per cent of all children under the age of 5. In approximately one-half of these patients
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the seizures are related to some febrile illness. It is generally agreed that the occurrence of seizures in young children with febrile illness does not necessarily presage the later development of epilepsy but the likelihood of this eventuality is great if the seizures recur with every febrile illness, if there are multiple seizures, or if there are paroxysmal abnormalities in the electroencephalogram in the seizure-free interval. Convulsions in Adults
Convulsive seizures occurring for the first time in adults are much more likely to imply an underlying organic lesion than they do in children. While there are many disorders which are associated with convulsions in adult life, the more common conditions are the intracranial space-occupying lesions, cerebral trauma and vascular malformations. Intracranial neoplasms are the most frequent cause of the onset of convulsive manifestations in patients between the ages of 35 and 55. 4 A third of the patients with brain tumors and 50 per cent of those with brain abscesses have convulsive seizures. The incidence is considerably less for subdural hematomas where the figures in different reported series varied from "rare" to 25 per cent. In those cases where seizures occur they frequently may be the first manifestation and in some instances the only clinical sign of the tumor. Hoefer, Schlesinger and Pennes 5 noted that seizures were the initial symptom in 68 per cent of their cases of astrocytoma, in 60 per cent of their cases of meningioma and in 51 per cent of their cases of glioblastoma. The laity are prone to relate convulsive seizures to head trauma and, actually, it is sometimes very difficult to assess the significance of head trauma in the production of seizures. Over 40 per cent of the men who sustained penetrating wounds of the skull, dura and brain in World Wars I and II developed post-traumatic seizures, regardless of the site of injury. 6 , 7 The relationship of closed head injuries to the development of seizures is much less definite. They undoubtedly play some part, particularly if the injury has been a severe one and if the seizures begin within a two year period after the injury. Vascular lesions, particularly those which involve the venous system, can give rise to convulsions at any time of life. Vascular anomalies (hemangiomas) are also commonly accompanied by convulsive seizures. Even though they are rare, adenomas of the pancreas (hyperinsulinism) and hypoparathyroidism should always be considered in the differentiation of the various conditions associated with convulsions because they are amenable to specific therapy. Mter all the above conditions have been excluded there remains a small but fairly constant percentage of patients who have their first seizures after the age of 25 for no apparent reason that can be determined by the present available methods. When one considers patients
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of all ages the great majority are those whose seizures are of unknown origin (Table 2). PHYSICAL FINDINGS
There are usually no abnormal physical findings in patients whose seizures are of the idiopathic variety. Some of these patients may, however, have scars on the tongue or lips that have resulted from lacerations occurring during attacks. The physical examination may be equally nonrevealing in patients with seizures of symptomatic origin but when abnormalities are demonstrated they may have considerable diagnostic significance. The finding of an elevated blood pressure may point to cardiovascular renal disease as a possible cause of the convulsions. The demonstration of a mass lesion in the breast, thyroid or prostate may indicate that the convulsions are secondary to cerebral metastases. Table 2 THE RELA'l'IVE FHEQUENCY OF THE VARIOUS CAUSES OF RECURRENT CONVULSIVE SEIZURES IN 2000 N ONINS'l'ITUTIONAL CASES Oli' EPILEPSY AT ALL AGES (AFTER LENNOX) PER CENT PRESUMED CAUSE OF SEIZURES
OF CASES
None demonstrated 77.6 Cerebral trauma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 5.7 Birth inj ury or congenital defect. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 5.6 Brain infection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 4.2 Brain tumor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2.6 Cerebral circulatory defect 1.9 Extracerebral causes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 0.9
When cutaneous lesions are evident in patients with seizures they may suggest such possibilities as tuberous sclerosis or the Sturge-Weber syndrome. Tuberous sclerosis is characterized by convulsions, adenoma sebaceum (fibromata of the sebaceous glands situated on the cheeks and side of the nose-butterfly distribution) and mental retardation. The Sturge-Weber syndrome is manifested by convulsions, angiomata of the face and scalp, frequently in the distribution of one or more divisions of the trigeminal nerve, and intracranial calcifications. Abnormal neurological findings may be present in the patients in whom the convulsive seizures accompany organic lesions or disease of the nervous system. These abnormal findings are characteristic of the underlying pathology and are exactly the same as those which occur in patients having similar lesions without convulsive seizures. Abnormal neurological findings may be found in patients with convulsions of unknown origin; (1) during an attack, (2) as a result of injuries sustained during seizures, and (3) as the result of untoward side reactions of anticonvulsant medicines. Extensor plantar responses and loss of pupillary reflexes are the most common abnormal findings during a seizure.
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H. Houston Merritt, Sidney Carter LABORATORY DATA AND ANCILLARY PROCEDURES
With the exception of the electroencephalogram, laboratory findings are within normal limits 'in the majority of patients with seizures of unknown cause. When the seizures are associated with some metabolic disturbance such as hyperinsulinism or hypoparathyroidism there will be a low sugar or calcium content in the blood. When seizures are associated with brain tumor, brain abscess or other organic diseases of the nervous system, the laboratory findings will be those which are characteristic of the underlying disease process. Electroencephalograms. Electroencephalography is one of the most important of all the ancillary procedures utilized in the diagnosis of the convulsive disorders. Electroencephalographic records taken during a clinical seizure show abnormalities that are characteristic for each of the three types of clinical seizures. The electroencephalogram, however, is not only of value in recording the changes that occur coincident with the attack, but also in registering abnormal activity in the interval between attacks. During a seizure the abnormalities in the electroencephalogram involve all portions of the cortex. In the interval between seizures, focal abnormalities are present in a high percentage of the patients with a local lesion in the cortex and are of value in establishing the diagnosis of cortical injury resulting from trauma, infections or tumors. According to the Gibbses,8 focal abnormalities in the temporal lobes are relatively common in the records of patients with seizures of the psychomotor type if the records are taken during sleep. It must be remembered that approximately 15 per eent of patients with seizures will have a normal record if only one traeing is taken in the seizure-free interval. On the other hand, the presence of abnormalities in the electroencephalogram is not in itself diagnostic of a convulsive disorder, because abnormalities are found in 10 per cent of the normal population. The two additional procedures of value in the study of patients with convulsive seizures are pneumoencephalography and cerebral angiography. These tests are not done routinely and are utilized only when there are indications in the history or in the neurologic examination that the patient has seizures secondary to some progressing or expanding lesion. They are particularly indicated when there is a suspicion of an expanding mass or a vascular abnormality. SUMMARY
A great variety of conditions can be associated with convulsive seizures. The differential diagnosis in patients with seizures is mainly concerned with the question as to whether there is a focal lesion in the brain or a metabolic defect which is amenable to treatment.
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The diagnostic procedures usually advisable for the study of a patient who has had one or more convulsive seizures are somewhat dependent upon the age of onset, the type of seizure and the frequency of the seizures, but as a rule the following examinations should be carried out: A. 1. Complete history and physical examination. 2. Neurological examination. 3. Urinalyses and blood examinations including serum calcium, glucose tolerance test and the serologic test for syphilis. 4. X-rays of the skull. 5. Electrocardiography. 6. Spinal fluid examination. 7. Electroencephalography. B. A pneumoencephalogram, ventriculogram or cerebral angiogram should be performed: 1. If there are indications from the description of an attack that the seizure is of a focal nature. 2. If there are findings on neurological examination which indicate a focal lesion, which cannot be explained adequately, or if there is choking of the disks. 3. If there is an increase in intracranial pressure as measured by the lumbar puncture of if the cerebrospinal fluid protein content is greater than 75 mg. in the absence of syphilis or other infections of the meninges. 4. If there are persistent focal abnormalities in the electroencephalogram. Pneumoencephalography is contraindicated and ventriculography or angiography is preferred whenever there is (1) choked disk, or (2) high cerebrospinal fluid pressure. Angiography is contraindicated whenever there is (1) sensitivity to the dye, or (2) moderate or advanced arteriosclerosis. It must be remembered that neither a normal angiogram nor a normal pneumoencephalogram excludes the diagnosis of a small tumor, scar or other fixed lesions. A small tumor, for example may be the focus of convulsive seizures and not be demonstrated by any of our diagnostic methods. Continued observation over a period of several or many years may be needed before a definite diagnosis is established.
REFERENCES 1. Peterman, M. G.: Convulsions in Childhood. Twenty Year Study of 2500 Cases. Am. J. Dis. Child. 72: 399, 1946. 2. Miller, R. H., Craig, W. MeR. and Kernohan, J. W.: Supratentorial Tumors among Children. Arch. Neurol. & Psychiat. 68: 797, 1952. 3. Lennox, M. A.: Febrile Convulsions in Childhood. Proc. A. Research Nerv. & Ment. Dis. 26: 342, 1947. 4. Penfield, W. and Erickson, T. C.: Epilepsy and Cerebral Localization. Springfield, Ill., C. C Thomas, 1941, 623 pp.
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5. Hoefer, P. F. A., Schlesinger, E. B. and Pennes, H. H.: Seizures in Patients with Brain Tumors. Proc. A. Research Nerv. & Ment. Dis. 26: 50,1947. 6. Ascroft, P. B.: Traumatic Epilepsy after Gunshot Wounds of the Head. Brit. M. J. 1: 739, 1941. 7. Watson, C. W.: Incidence of Epilepsy Following Craniocerebral Injury. Arch. N eurol. & Psychiat. 68: 831, 1952. 8. Gibbs, E. L., Gibbs, F. A. and Fuster, B.: Psychomotor Epilepsy. Arch. Neurol. & Psychiat. 60: 331, 1948. 710 West 167th Street New York 32