Emergencies of Cerebral Origin

EMERGENCIES OF CEREBRAL ORIGIN iUCHJ\IOND S. PAINE, M.D.

This discussion of emergencies of cerebral origin in children will con sider principally head injuries, nontraumatic cerebrovascular accidents, infections of the brain, and brain tumors. Convulsions and unconsciousness are considered in other clinics in this volume, as arc emergencies of cardiac or pulmonary origin, shock, poisonings, and others which affect the central nervous system profoundly and may give rise to symptoms emanating from it. The discussion will concern chiefly the management of these conditions during the initial emergency stage, although it is hoped that sufficient references have been provided for readers wishing to seek more details. HEAD INJURIES GENERAL MANAGEMENT

Whether the physician sees a child on the scene of the head injury, or whether the child is brought to him subsequently, his initial approach to the problem should be in the following order of priorities unless there is sound reason for deviating from it: l. Maintenance of an airway. If there is evidence of respiratory obstruction, priority should be given to oropharyngeal suction and to direct laryngoscopy with suction or intubation if necessary, Rarely, an emergency tracheotomy might be required. 2. Treatment of shock (see p. 17). 3. Control of external bleeding. 4. Rapid physical examination with particular attention to the state of conscious· ness or degree of coma or stupor, the ability to speak, the cranial nerves and pupils

From the Department of Pediatrics, Harvard Medical School, and the Department of Medicine, The Children's Hospital Medical Center, Boston. Supported in part by a grant (no. B-2400) from the National Institute of Neurological Diseases and Blindness, National Institutes of Health, United States Public Health Service.

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EMERGENCIES OF CEREBRAL ORIGIN

spontaneous movement of the limbs, muscle tone and reflexes, and response to painful or other stimuli. The possibility of injuries to other areas than the head should not be overlooked. Examination of the eyegrounds is desirable, especially if time has elapserl since the injury, but mydriatic drops should never be used to facilitate this, since the size of the pupils and their reaction to light are invaluable physical signs. 5. Control of convulsions if present (seep. 101). Dilantin and small doses of barbiturates may be used, but the possible depressant effect of barbiturates on respiration should be considered. Paraldehyde is usually preferable. 6. A more detailed history of the accident, to supplement the briefer descriptioJl which will have been given initially. 7. Supportive measures such as rest, aspirin or alcohol sponges if the temperature is elevated, and regular recording of the pulse, respiration and vital signs at hourly intervals, or more frequently if they are abnormal or if the patient's condition appears critical. Initially, the patient should be kept warm, but hypothermia may be desirable later on if there is cerebral edema or respiratory depression. Intravenous fluids shoul~ be supplied if oral intake is impossible, but the quantity of these should be such as to keep the patient a little "on the dry side." Restlessness is usually best controlled with rectal paraldehyde, or with small doses of barbiturates if respirations are satisfactory. 1\lorphine should ordinarily not be used. 8. Further diagnostic measures. Immediate x-ray films of the skull arc rarely indicated, since decision for immediate surgery depends mainly on clinical signs. A lumbar puncture is also of little value unless the neck is stiff or the temperature is elevated so as to suggest subarachnoid hemorrhage. In the latter instance it may be of some therapeutic value as well.

For further elaboration of the principle of management of head injuries the reader is referred to one of the standard textbooks on neurosurgery such as that of Ingraham and Matson. 39 The general practitioner or pediatrician is wise to obtain initial neurosurgical consultation for any severe head injury, or for a seemingly minor one presenting signs or symptoms of the complications to be described below. Subsequently the cardinal indications for neurosurgical help are deterioration in the general condition of the patient, progression of abnormal neurologic signs, or evidence of increasing intracranial pressure (slowing pulse and respirations, rising blood pressure, and cranial nerve paralyses, especially of the third, sixth and seventh nerves). FRACTURES

Depressed fractures are usually obvious on inspection, but if doubtful should be considered indications for early x-ray study of the skull. Prompt elevation of depressed fractures is desirable, and patients with these should be referred to a neurosurgeon. Compound fractures also warrant early neurosurgical referral. General surgeons not experienced in this type of work and other physicians should generally not attempt local debridement, since the intracranial extensions of these injuries are often much more extensive than appears at first glance. Supportive measures should be continued, including treatment of shock and antibiotics in hope of preventing infection, until transfer can be arranged

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and the patient is able to travel to a center where facilities for definitive intracranial surgery arc available. CONCUSSION

Concussion can be defined as a temporary, reversible, acute traumatic encephalopathy, supposedly without anatomic change, but accompanied by at least transient loss of consciousness. It must be distinguished from cerebral contusion and intracranial hemorrhage, but the differentiation may be difficult on clinical grounds in severe cases of concussion. After a brief or sometimes a longer period of unconsciousness the child cries vigorously, is pale, desires to be left alone, or else clings to its mother, and frequently vomits or sleeps. Even patients presenting this full-blown picture usually run a benign course, and the decision whether or not to hospitalize the child for observation depends a great deal on judgment as to the severity of the insult and also as to the reliability and stability of the patient's mother. The duration of pretraumatic and especially of post-traumatic amnesia is an indication of the probable severity of the injury, but it is frequently impossible to obtain this information from the child at the time. If it is decided to keep the patient at home, his mother should be instructed to check his condition every hour or two until she goes to bed, and two or three times more during the night. If the mother is not unduly panicky or lacking in intelligence, one can usually explain how to check the pulse and respirations, the symmetry of movement or "feel" of the limbs, the state of the pupils, and whether the child can be roused from sleep to some extent by stimulation (as opposed to his being unconscious). In most cases another examination by the physician on the following morning is desirable, for all cases of head injury must be thoughtfully considered for any suggestion of intracranial hemorrhage. INTRACRANIAL HEMORRHAGE

Epidural Hemorrhage

This is less common in children than in adults, but Ingraham and Matson 3 u report 30 examples among 13 30 hospitalized patients. The condition usually results from a fracture involving the middle meningeal artery, but in infants it can be associated with a diastasis of the lambdoid or squamosal sutures. There is usually a short, lucid interval of an hour or more, but lack of a lucid interval does not rule out the diagnosis.

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EMERGENCIES OF CEREBRAL ORIGIN

Particularly in children, epidural hemorrhage may develop without any initial unconsciousness at the time of the injury, but blood loss may be evidenced by a feeble pulse or by pallor of the skin. The physical signs are those of rapidly increasing intracranial pressure, inequality of the pupils or the failure of one or both to react to light, and neurologic signs such as hemiparesis or convulsions which are often unilateral. X-ray films of the skull are an important diagnostic aid, but one should not delay for these if the patient's condition is critical, since this is a neurosurgical emergency in which immediate operation is required to save life. In infants with open sutures an epidural puncture may be performed much as one would do a subdural tap. This may help with diagnosis in doubtful cases, but is of limited and only temporary therapeutic value, since bleeding will continue, and any symptoms referable to blood loss will be aggravated. Subdural Hemorrhage

This is far commoner than epidural hemorrhage in children. The course is usually less acute and the lucid interval often longer. The physical signs are similar to those of epidural hemorrhage, but of slower evolution. Hemiparesis is perhaps commoner, and retinal hemorrhages are frequently seen. The source of the bleeding may be from the middle meningeal artery or from dural sinuses or bridging veins. An electroencephalogram may help in diagnosis by showing localized slowing, bnt is frequently not reliable. Normal x-ray films of the skull and normal cerebrospinal fluid do not rule ont the possibility of acute snbdura 1 hemorrhage. Subarachnoid Hemorrhage

This presents more variable physical signs, but these usually include severe headache, vomiting, stiff neck, and frequently loss of consciousness (see also p. 73). Occasionally pulmonary edema may occur as a complication. Children with subarachnoid hemorrhage rarely have aneurysms of the intracranial arteries, but bleeding sometimes occurs from arteriovenous malformations (or less commonly from angiomas). Thus, especially if a severe hemorrhage followed relatively slight head injury, one should consider arteriography, particularly if a bruit is heard on auscultation of the head. An appreciable number of arteriovenous malformations are operable, and this may prevent the progressively increasing shunting of blood through the malformation which is the usual future course of such lesions. Arteriography is not urgent in the acute stage of subarachnoid hemorrhage, however. Symptoms may be relieved by repeated lumbar puncture, or by ventricular puncture in

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young infants with whom it soon becomes impossible to obtain fluid by lumbar tap (serial measurements of the head circumference should be recorded with infants). There is conflicting evidence of lessening of brain damage through relief of pressure by repeated tapping. 34 Intracerebral Hemorrhage

This may be the result of a severe cerebral contusion or may be deep in the cerebral substance, possibly as the result of some mechanism such as that by which interior bubbles may be produced by suddenly jarring a closed bottle filled with water. The hemorrhage may be on the side of the injury or more frequently opposite to it by the contrecoup phenomenon in which the skull is displaced more rapidly than the brain, which is then thrown against the opposite side. The differential diagnosis from diffuse or multiple small intracerebral bleeding and from cerebral edema is not easy, although a large intracerebral hemorrhage is usually accompanied by the presence of red blood cells in the cerebrospinal fluid. Neurosurgery usually has little to offer unless there are clear signs of a single massive intracerebral clot which could be evacuated. MANAGEMENT OF CEREBRAL EDEMA

Cerebral edema is common in head injuries of greater than moderate severity, and its management will be discussed at this point. Many of the same principles are applicable to cerebral edema associated with infarction, meningitis, encephalitis, lead poisoning, pulmonary emphysema 14 and other conditions. The diagnosis is usually not difficult, the patient having headache, vomiting, depressed consciousness, slow pulse and respirations, and a rising blood pressure. The eyegrounds show papilledema, usually within a day or two, and congestion and tortuosity of the retinal vessels can often be seen earlier. Progressive increase in intracranial pressure leads to tentorial herniation, one or both pupils becoming dilated and unreactive to light. Hemiplegia or tetraplegia may be present, and predominantly unilateral cerebral edema may produce paradoxical ipsilateral hemiplegia by forcing the opposite cerebral peduncle against the edge of the tentorium. X-ray films of the skull may show separated sutures in young children. The electroencephalogram is slowed, but may be asymmetric. Lumbar puncture will reveal the cerebrospinal fluid to be under increased pressure, but should be considered only if the diagnosis is in doubt and one wishes to obtain cerebrospinal fluid for bacteriologic, microscopic or chemical examination. The dangers of lumbar puncture in the presence of increased intracranial pressure have

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long been regarded with respect, but the procedure is less dangerous if there is not a space-occupying lesion in the posterior fossa, and its dangers may be overrated. Spencer78 reports lumbar punctures on 56 of 87 patients with papilledema, whose initial spinal fluid pressures were 200 to 560 mm. of water, and whose symptoms had durations ranging from 2 days to 3 years. None of the patients were reportedly any the worse for the procedure, whether or not they had retinal hemorrhages as well as papilledema. Nevertheless a cautious lumbar puncture is one thing, and incautious removal of fluid another. In any doubtful case one should have at hand a sterile three-way stopcock connected to a manometer filled with sterile saline solution. This is connected to the hub of the lumbar puncture needle immediately when the puncture is accomplished, and the pressure measured. If the pressure is elevated, the handle of the stopcock should be turned to permit slow collection of the minimum quantity of fluid essential for examination, preferably not more than 1 cc. The needle is then withdrawn without the stopcock's having been disconnected. Letting larger quantities escape rapidly carries grave danger of sudden death. The most valuable weapon in the treatment of cerebral edema at present is hypertonic urea solution, 84 given in 30 per cent solution in 10 per cent invert sugar. One to 1.5 gm. per kilogram of body weight is given intravenously, normally in 30 minutes' time, but can safely be given in as little as 15 minutes. Dramatic clinical improvement is often observed within 15 or 20 minutes and may last for 4 to 8 hours. It is usually safe to repeat the urea up to 3 times in 24 hours. Caution must be observed if there is any cardiac condition in which an increase in circulatory volume would be hazardous. The level of blood urea nitrogen may reach 500 mg. at the end of the infusion.84 There appear to be no serious side effects from this, although the use of intravenous administration of urea is unlikely to be of benefit and may be risky in the presence of severe renal disease. Hypertonic glucose solutions in concentrations up to 50 per cent can also be used, but are less effective than urea. Intravenous acetazolamide (Diamox) may be of some use, but is perhaps more effective if cerebral edema results from general water intoxication.85 Hyperventilation may be a useful temporary expedient and could be accomplished by the patient himself if cooperative, or with the various types of respirators. Increasing the minute volume to the range of 7 to 20 liters per minute in adults has been reported to cause up to 47 per cent decrease in intracranial pressure with improvement in clinical status, doubtless through cerebral vasoconstriction produced by hypocapnia.47 Subtemporal or other neurosurgical decompression remains a last resort in desperate cases of cerebral edema.

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NONTRAUMATIC CEREBROVASCULAR ACCIDENTS SPONTANEOUS SUBARACHNOID HEMORRHAGE

So-called spontaneous subarachnoid hemorrhage in children, in contrast to that in adults, is rarely due to rupture of an arterial aneurysm. It may, however, occur from an arteriovenous malformation after minimal or unrecognized trauma. A substantial number of cases in children are of undiscoverable origin, but the physician should always think of the various causes of abnormal bleeding tendencies. Subarachnoid hemorrhage is relatively common as a complication of leukemia and frequently occurs even in patients whose peripheral blood and bone marrow are supposed to be in remission. Distinction must be made, however, from intracerebral or multiple small hemorrhages as well as from meningeal leukemia and leukemic infiltration of the brain substance. A diagnostic lumbar puncture is thus indicated because the latter two conditions may be amenable for a time to x-radiation or intrathecal medication with Methotrexate or other drugs. The symptoms of spontaneous subarachnoid hemorrhage are similar to those of subarachnoid hemorrhage following head injury except that the onset is usually sudden and dramatic with no antecedent injury. The picture may resemble a stroke or an epileptic fit if the patient suddenly screams, falls to the ground, possibly convulses or vomits and then loses consciousness (see also p. 70). A stiff neck is usually present within a few hours. Differential diagnosis must be made from meningitis or from a ruptured brain abscess, so that a diagnostic lumbar puncture is essential. A traumatic tap may be difficult to distinguish from subarachnoid hemorrhage, but the best guide is the impression of the physician performing the puncture as to whether his tap was traumatic. Failure of the fluid to clear partially in tubes subsequent to the first is suggestive of hemorrhage pre-existing the tap. If the hemorrhage is several days old, the supernatant fluid may be xanthochromic, but crenation of the red blood cells is a rather unreliable clue. Once subarachnoid hemorrhage is discovered, there is usually little except supportive treatment available. Immediate arteriography in the hope of discovering a bleeding point which can be approached by operation or by ligation of a carotid or vertebral artery in the neck is perhaps to be considered in desperate cases. Arteriography is dangerous in itself in such patients, even if the patient tolerates carotid compression, which should invariably be tested first. In a series of 261 adults the results of immediate angiography followed by early surgery were no better than with patients treated expectantly. 55 The induction of hypotension with reserpine or other drugs has been suggested, 81 but is certainly an experimental approach at present. It might depress

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renal function or produce further cerebral ischemia, even though the danger of ischemia is less in children than in arteriosclerotic adults. CEREBRAL EMBOLI

A small embolus may produce minor and transient symptoms, depending on the collateral circulation, or else no immediate symptoms, only to be followed by later development of an abscess. Larger emboli, however, produce sudden, severe dyspnea, cyanosis, convulsions, and frequently hemiplegia or coma. The commonest causes in children are subacute bacterial endocarditis or congenital heart disease with a constant or intermittent right-to-left shunt. Rarer causes include any other condition in which thrombi are present or may form in the left side of the heart, aorta, or carotid or vertebral arteries. Vascular malformations in the lungs are also potential sources of emboli, 94 and it has heen suggested that hyaline emboli may reach the brain from the lung in nonsuppurative pneumonias. 64 The emboli most commonly lodge in the middle cerebral artery and its branches, 87 where the sudden onset serves to distinguish it from a thrombotic process if an accurate history is available. Less well defined episodes of loss of consciousness and convulsions are also common among children with cyanotic congenital heart disease. 88 These often follow episodes of paroxysmal dyspnea and are probably not based on cerebral emboli, although the presence of small infarcts cannot be excluded. If the diagnosis of embolus can be made promptly and its location defined by arteriography, early surgical embolectomy may prove of value in some cases in the future. Mention should be made in passing of the possibility of fat emboli complicating fractures or operations on the long bones. Air emboli may occur during open cardiac surgery or more occasionally may follow fractures of the long bones. Neither fat nor air emboli appear susceptible of direct treatment at present. CEREBRAL THROMBOSIS Arterial Thrombosis

This may occur in the presence of septicemia or sickle cell anemia, but is most common in patients with cyanotic congenital heart disease, particularly if there is an episode of dehydration due to some intercurrent illness or to inadequate fluid intake during hot weather. It has been suggested that at least in the case of tetralogy of Fallot, cerebrovascular accidents are correlated with a relative hypochromic microcytic anemia (proportionately high red blood cell count with relatively lower hemoglobin, mean corpuscular hemoglobin, mean cor-

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puscular volume and mean corpuscular hemoglobin concentration) more than with the height of the hematocrit. 51 Major or minor episodes of occlusion must be common, for Banker5 found occlusive vascular disease in over 10 per cent of patients with congenital heart disease coming to autopsy. Administration of iron to selected patients may possibly be of some value in reducing the danger of cerebral vascular accidents. Cerebral thrombosis may also occur in children with severe dehydration due to diarrhea or any other cause, but arterial thrombosis is less common under these circumstances than is venous thrombosis. Hyperosmolarity of the blood may in itself produce acute neurologic symptoms and signs distinguishable from thrombosis only by the future course of events, and it is important to correct such imbalances of electrolytes by conventional methods. 12 • 83 Conversely, thrombosis of the anterior cerebral artery may be associated with changes in the concentration of electrolytes in the blood, as may occasionally intracranial tumors or basal skull fractures.U· 28 A rare cause of arterial thrombosis, almost always multiple, is thrombotic thrombocytopenic purpura. 65 Patients with neurologic manifestations of this disease almost always die in coma, although adrenal hormones and splenectomy have been suggested as possible therapeutic approaches. There are in addition a considerable number of cases in children of arterial thrombosis of entirely mysterious origin. Many of these are examples of the syndrome called "acute infantile hemiplegia," the manifestations and evolution of which are comparable to hemiplegia in adults, although of course varying widely from case to case. The hemiplegia may come on suddenly with or without a convulsion ( unilateral or generalized), it may develop insidiously over a period of days or weeks, or it may follow a series of convulsions. The explanation of most of these cases remains obscure, although occlusion of the middle cerebral artery can often be demonstrated by arteriography. In some there is probably a background of congenital defect of one cerebral hemisphere or of its vascular supply which has remained relatively silent until stress is thrown on it by a febrile illness, dehydration, or especially by a convulsion, although this hypothesis is at present impossible to prove. In other cases there is a series of unilateral convulsions which may or may not be febrile and which may or may not be associated with postictal hemiplegia. If the last mentioned occurs, it clears within a few hours or a few days on a number of occasions, but may subsequently prove permanent after a severe convulsion. A series of vascular or infectious insults may be involved in such histories. 25 There is little to do about this sequence by way of emergency measures aside from the control of convulsions, but I have seen a sufficient number of instances in which subsequent permanent hemiplegia

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resulted, together with mental deficiency and epilepsy, to believe that children with recurring unilateral "simple febrile convulsions" should be placed on continuous prophylactic anticonvulsants. Arteriographic investigations of such patients would be of great interest, but a little hard to justify. Wise management of such patients would seem to depend on a better understanding of the respective roles of neuronal exhaustion, vasospasm, and thrombosis with early recanalization or establishment of collateral circulation as bases of postictal hemiplegia. 58 Finally, it should be mentioned that trauma to the neck and head has been stated to be a factor in occlusion of cerebral arteries, but remission of symptoms under such circumstances is generally poor. 23 Venous Thrombosis

Venous thrombosis or thrombosis of the dural sinuses may occur with septicemia, cerebral thrombophlebitis (as a complication of otitis media or otherwise), dehydration, and particularly in patients with cyanotic congenital heart disease. Cardiac patients under two years of age are particularly subject to thrombosis and rarely to abscess, but abscess is much commoner among children over two. Thrombosis of venous sinuses is now uncommon with modern intravenous fluid therapy, and it will probably not again be possible to assemble a series such as Byers and Hass 9 reported in 193 3. The symptoms vary widely according to the location of the thrombosis. Signs may be minimal if the occipital and posterolateral parietal and temporal veins are involved. Thrombosis of the middle cerebral vein or of the anastomotic vein of Labbe is associated with coma, hemiplegia and focal or generalized seizures. Occlusion of the internal cerebral vein or of the great vein of Galen is rare and usually produces early death in decerebrate rigidity. Signs of thrombosis of the straight sinus or left lateral sinus may be similar, but are usually chiefly of increased intracranial pressure unless the blood is able to return via the right lateral sinus (occlusion here produces infarction of the convexities of the hemisphere). The sagittal sinus is perhaps the one most commonly thrombosed in infants and produces sudden coma, convulsions and paraplegia. The picture of proptosis, papilledema, conjunctival and retinal hemorrhages, and paresis of the third, fourth and sixth cranial nerves due to thrombosis of the cavernous sinus is well known. Aside from these variations with location, there are general signs which are common to most cases of sinus thrombosis. Intracranial pressure is likely to be increased, but may be concealed, and the fontanel may be depressed if the infant is dehydrated. The cerebrospinal fluid is frequently bloody. Infants frequently show distention of the

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superficial veins of the scalp, especially if the sagittal sinus is involved. Venous (as opposed to sinus) thrombosis is less often productive of increased intracranial pressure, but focal signs and focal seizures are commoner. MANAGEMENT OF CEREBRAL INFARCTION

If thrombosis of the sagittal or of a lateral sinus is documented, neurosurgical thrombectomy might be considered, although risks are considerable, especially in sagittal sinus thrombosis. Thrombectomy could also be considered for arterial occlusion. The presence of a Horner syndrome may be of localizing value in the consideration of carotid thrombosis. 67 It has been claimed that internal carotid occlusion can be detected by palpation through the pharynx. 17 (I have found this unreliable and have been bitten by several children while trying it.) Arteriography seems clearly required before consideration of thrombectomy, but it is noteworthy that in a series of cases of infantile hemiplegia it gave rather inconsistent findings not well correlated with the mode of onset. 45 There are available, however, a considerable number of nonsurgical methods of treatment. Hypothermia appears of value in many cases and is reasonably simple to achieve by the use of an ice mattress, a room airconditioner, and minimal clothing, although chlorpromazine may have to be given to abolish shivering. Intravenous hypertonic urea solution (see p. 72) is indicated if there is cerebral edema with increased intracranial pressure. Inhalation of 5 per cent carbon dioxide may produce cerebral vasodilatation and improve collateral circulation and has been shown to reduce slowing of the electroencephalogram, 89 but l 00 per cent oxygen is ineffective, at least in regard to the electroencephalogram.72 If the thrombosis is venous, attention should be directed to correction of fluid and electrolyte imbalance, and antibiotics should be given prophylactically. Many publications are currently appearing on the use of anticoagulants (heparin or Dicumarol) for treatment of cerebrovascular accidents. In general, the encouraging reports have concerned particularly adults with a series of small strokes or a slowly progressing stepwise occlusion and have been much less impressive in regard to acute strokes. 50 Particularly in children, cerebrovascular syndromes of slower onset are possibly venous. Under such circumstances the infarction is likely to be hemorrhagic, and the use of anticoagulants would be extremely hazardous. It would seem that in our present state of knowledge they should be used only for carefully selected instances of documented arterial occlusions.

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CEREBRAL INFECTIONS MENINGITIS Purulent Meningitis

Purulent meningitis has as its first emergency aspect the making of the diagnosis. This is easy if the case is typical: within a few days the child becomes obviously acutely ill with high fever and more or less clouding of the sensorium, he may convulse, and on examination shows signs of meningeal irritation ( Kernig, Brudzinski, and so on), and usually little or no other obvious basis for the fever. The diagnosis is less obvious if antibiotics have previously been given for some other illness, and one must bear in mind that meningitis is a fairly frequent complication of otitis media and of the various states associated with bacteremia. In infancy a stiff neck and other signs of meningeal irritation are less reliable, and tension of the fontanel is more suggestive. At all ages one must have a high degree of suspicion for atypical cases. This is particularly true for infants who appear acutely ill without adequate explanation on physical examination, even though fever may be low or absent. Lumbar puncture is essential for the diagnosis and should be performed in any case which is even slightly suspect of meningitis. It is also indicated for every child who has had his first febrile convulsion, but may not be required on every future occasion if the fever can be adequately explained, although again a high index of suspicion IS important. The cerebrospinal fluid is usually frankly purulent, presenting a cloudy appearance to the naked eye. White blood cells are usually present in numbers ranging from several hundred to 15,000 or more per cubic millimeter, and polymorphonuclear cells constitute the majority in early stages. Occasionally, in very early cases, cells will be absent from the fluid, and the physician will be surprised to receive a report of a positive culture. Thus cultures should always be taken on two chocolate agar slants, one of which should be incubated anaerobically and the other in air. A few cubic centimeters of the fluid should also be centrifuged and the sediment examined for bacteria after staining by the Gram method. The choice of antibiotics depends on the organism, and this decision is of such importance that the physician in charge should personally examine the slide unless a highly qualified bacteriologist is available. Meningococci are not difficult to see in most cases, and pneumococci are usually present in profusion (in some cases they are so numerous as to account in themselves for the cloudy appearance of the fluid, which may contain only a few hundred leukocytes). Hemophilus infiuenzae is less easy to find and is statistically the likeliest bet if no organisms are seen. Even if found, it

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cannot be distinguished by appearance alone from other gram-negative rods. In any doubtful case, or if appearances are in any way atypical, treatment should be given as described below for an unidentified organism until a definitive report of the culture is available. If the organism is identifiable by culture or if one feels sufficiently confident after examination of the stained smear (as is often possible in the case of the first three listed), the drugs of choice are probably as follows (details of dosage are given in Table 5) : 1. Meningococcus: Sulfadiazine and penicillin, although sulfadiazine alone is po~ sibly sufficient. 2. Pneumococcus: Penicillin. Intrathecal therapy is unnecessary if sufficiently high doses of intravenous or intramuscular penicillin are given. It is true that penicillin does not enter the cerebrospinal fluid in appreciable quantities in normal patients, but permeability is altered in the presence of meningitis. 3. Hemophilus Influenzae: Chloramphenicol, probably supplemented by streptomycin for the first five days. 4. Escherichia Coli: Kanamycin2o or kanamycin plus polymyxin B. 5. Streptococcus: Penicillin. 6. Staphylococcus: At present this must be assumed to be penicillin-resistant unless proved otherwise. Staphcillin is probably the drug of choice now that it has become available. Previously one used chloramphenicol and erythromycin until sensitivity tests were available. Other possible choices (all less desirable than Staphcillin at present) include vancomycin, streptomycin, kanamycin or novobiocin (but resistance develops . quickly to novobiocin93) . 7. Proteus Vulgaris, Pseudomonas Aeruginosa, Aerobacter Aerogenes and Klebsiella Pneumoniae: Kanamycin is perhaps the best choice and is less toxic than neomycin, to which it is somewhat similar, and with which cross resistance of organisms is encountered.20 Polymyxin B may also be used_ These four organisms are difficult to treat, especially Proteus, of which different strains vary considerably in sensitivities (novobiocin is another possibility for this organism) . Kanamycin, polymyxin and neomycin all have pqtential toxicity for the acoustic and vestibular nerves as well as for the kidneys. The urine should be examined daily for albumin and the level of nonprotein nitrogen in the bJood checked every two or three days. In general, one can "get away with" one of these antibiotics for 10 or 12 days. Longer therapy is frequently required, but one can then switch to another drug. Sensitivity tests in vitro are of value in selection, but do not always parallel response in vivo. Treatment of meningitis due to the four organisms mentioned is difficult and prolonged, and the mortality rate is high under the best of circumstances, particularly with Proteus. Intrathecal medication is often necessary for these organisms,! although probably not for others. The only case of Proteus meningitis with which I haye personally obtained a cure was treated alternately for over a month with polymyxin and neomycin, switching from one to another whenever the nonprotein nitrogen level rose above 45 mg. per 100 ml. 8. Salmonella: Chloramphenicol or kanamycin, or both. 9. Other organisms: The drugs of choice are changing constantly, especially for the rarer types of meningitis in the newborn, 27 • 36 and the current literature should be consulted. · 10. Unidentified organisms are best treated with chloramphenicol, sulfadiazine and penicillin until definitive cultures are available. Cultures are frequently sterile if previous antibiotics have been given, and under such circumstances all three drugs mentioned must be continued throughout the period of therapy, or modified if clinical response is not satisfactory.

Special features of drug dosage and precautions to be observed are listed in footnotes to Table 5. The dosage of many drugs needs to be

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TABLE

5. Drug Dosage Table for Meningitis (1

DOSE IN MG./KG./24 HOURS (USUALLY DIVIDED INTO

Intravenous

4

Intramuscular

Chloramphenicol. .... 100 1 Chlortetracycline ..... 50 (NR) Erythromycin ........ 50 1 • 2 Kanamycin .•........ 153, 4 Neomycin .•......... NA Novobiocin .......... 25 1 • 2 Oxytetracycline ...... 50 (NR) Penicillin G-Potassium ....... 12,000,000 u. 5 • 6 Polymyxin B ........ NA Staphcillin .......... 100-150 Streptomycin ........ NA Sulfadiazine ......... See Notes 1 • 8 Tetracycline ......... 50 (NR) Vancomycin ......... 40-50 3· 4

INJECTION/DAY;

DOSES)

Oral

Intrathecal

100 1 NA 50-75 1 • 2 15-25 3 • 4 10-15 1 • 3 • 4 NR 100 (NR)

100-200 1 100 (NR) 75 1 • 2 NAbs NAbs 50 1 • 2 100 (NR)

NR NR NR NA 5 NR NR

12,000,000 u. 5 • 6 3-6'· 3, 4 100-150 100 4 • 7 100 (s.c.) 1 • 8 100 (NR) NA

NR NAbs NA NAbs 125-1501 • 8 100 (NR) NA

10,000 u. (NR) 2.5 5 (NR) NR NR NR

NOTES NR = Not recommended. NAbs = not absorbed in appreciable quantity. NA = Not available. 1. Reduced dosage should be used_for..,newborns,_especiallyJor_ chloramphenico (25-50 mg./kg./24 hours). 2. Should not be used alone. Early resistance may develop. 3. Possible renal toxic effects. Follow urinalysis and NPN q. 2-3 days. 4. Possible acoustic or vestibular nerve damage. 5. Recommend 1,000,000 u. I.V. q. 2 h. to start, and if possible continue this I.V. because of severe local reactions to I.M. injections, until switch is made to procaine penicillin ( 1,200,000 u./day) after not less than 5 days. 6. Contains 1.4 mEq. K+ /1,000,000 u. which might be at least a theoretical hazard for small infants, for whom 6,000,000 units or less would be therapeutically sufficient (or penicillin G-sodium may be used instead). 7. Cut dosage to 50 mg./kg./day after 4-5 days. Normally, not over 1.0 gm./24 hours maximum dose. 8. Initial dose should be equal to 24 hours' maintenance dose. Recommend giving initial dose ~ I.V. and % s.c. Levels of sulfadiazine in blood should be followed daily (or q. 2 days after 4-5 days) and dosage adjusted to maintain a blood level of 12-15 mg. per 100 ml.

reduced for newborns, and especially for premature infants, most importantly in the case of chloramphenicol.90 Suggestions have been made from time to time that the use of combinations of antibiotics results in one interfering with the action of the other, but a recent controlled studya 2 showed no evidence of either synergy or antagonism, and I personally favor the use of the combinations mentioned above. Successful results have been reported with tetracyclines,4 4 but I believe that they are distinctly inferior to the other preparations listed in subparagraphs 1 through 8 above. The stakes are high in treatment of meningitis. One frequently cannot be sure of the identity of the organism from examination of stained

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smears or even from cultures, and certainly not from physical examination (the presence of petechiae, for example, is not confined to meningococcemia, but can occur with meningitis due to Pneumococcus, Streptococcus, Hemophilus influenzae, aseptic meningitis24 and even on children who have been struggling during lumbar punctures or have been vomiting vigorously, although chiefly on the head and neck in the last two instances). If the responsible organism is in any doubt, it is desirable to overtreat rather than undertreat, and there is little if anything to lose by using the combined ("shotgun") regimen of chloramphenicol, sulfadiazine and penicillin. There may be some rationale for the use of hydrocortisone (4 mg. per kilogram a day intravenously) to prevent the formation of adhesions and loculations of infection, particularly with pneumococcal meningitis, although a study of alternate patients has not shown any improvement in results. 46 Almost every child with meningitis will initially be too ill to take oral medication, and even if he is not, the likelihood of vomiting and delayed absorption is so great that parenteral administration of antibiotics is always indicated. Absorption of even intramuscular or subcutaneous injections may be considerably delayed if shock is present, and antibiotics should preferably be started intravenously if possible. It is almost always necessary to supply fluids intravenously in the early days. An adequate quantity should be suppliedas calculated from the patient's weight or surface area, but overhydration may lead to cerebral edema and should be avoided. Acceptable is 2400 cc. per square meter per 24 hours, supplying approximately one third of this as normal saline solution and two thirds as 5 per cent glucose and water. This rough scheme may need modifying if the serum electrolytes are abnormal in concentration. Potassium should generally not be given until adequate renal function is established. Initial and possibly subsequent blood transfusions are of value if the patient is anemic or in shock. In the case of shock, plasma is to be preferred if there is extreme hemoconcentration. Repeated lumbar punctures at intervals of 24 hours or more may be of some value in relieving pressure and meningeal irritation, making the patient more comfortable. Early and frequent retapping carries some risk of brain stem herniation. Also, re-examination of the cerebrospinal fluid after two or three days of treatment may be desirable in order to evaluate adequately the efficacy of therapy. The earliest response is usually the return of sugar in the fluid, from which it has been initially absent or nearly absent. This is followed by a shift from polymorphonuclear leukocytes in favor of a larger number of lymphocytes and a gradual decline in the total number of leukocytes in the fluid. The level of total protein is the last abnormality to subside and may

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actually rise in early stages. Unsatisfactory response, clinically or in the cerebrospinal fluid, should make one wonder whether another antibiotic should be used or whether there may be loculated or walled-off infection associated with meningeal adhesions. Intravenous hydrocortisone is probably of more value in preventing adhesions than in getting rid of them, and its value is controversial, as already stated.46 Intrathecal streptokinase and streptodornase may be considered, but produce considerable systemic reactions and are seldom indicated if adequate doses of appropriate antibiotics are given. Sedation may be indicated for extreme restlessness, and efforts should be made to control convulsions if present, although it is not necessary to give anticonvulsants routinely in every case. Phenobarbital is satisfactory if one is not concerned about respiratory depression and may be supplemented by intramuscular (or later, oral) Dilantin for convulsions. For rapid action and for safety, rectal paraldehyde is probably the best preparation available, although rectal irritation and expulsion of the drug occur after a few doses even if mixed with equal parts of mineral or olive oil. Paraldehyde may also be given by deep intramuscular injection, but there is appreciable danger of a slough, especially if local circulation is inadequate. Cerebral edema not infrequently complicates bacterial meningitis. The use of hypothermia and intravenous urea as described on pages 77 and 72 is extremely valuable under these circumstances. If an initially satisfactory response is followed by a rise in temperature, return of vomiting or deterioration of clinical state, or if the cerebrospinal fluid begins to show a rise in leukocyte counts or protein content after several days, one should think of subdural effusion as a complication. Subdural effusions, whether associated with meningitis or with the irritant effect of blood in the subdural space, are most probably due to effusion of serum proteins through meningeal vessels whose permeability is altered. 26 • 73 Subdural taps may reveal the situation and be of some therapeutic value. There is reason for debate, however, as to how much fluid should be removed and how frequently the taps should be repeated, and it has been suggested that multiple tapping with removal of more than diagnostic quantities may prolong the effusion and increase the likelihood of need for neurosurgical intervention to remove a membrane. 92 Certainly it is possible that removal of 10 cc. or more may alter dynamics enough to cause rupture of small bridging veins. In some cases persistent subdural effusions will be associated with membrane formation and require neurosurgical intervention for removal of the membrane (although the mechanism of formation of membranes remains obscure). In children with closed sutures investigation of possible subdural effusion requires surgical burr holes and thus

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should be postponed for clearer indications than are required for subdural tapping of infants. X-ray films of the skull are of little value unless there is persistent or increasing separation of the sutures, but an electroencephalogram may have localizing value once cerebral edema has subsided. An infected subdural effusion or subdural empyema may occur as a complication of meningitis (as well as with otitis media, sinusitis, pneumonia or skull fractures) . A nonspecific but usually rather severe exacerbation of symptoms occurs, but the diagnosis is often difficult, and the death rate is high if the condition remains undetected. The condition can be treated by aspiration and instillation of appropriate antibiotics, but neurosurgical consultation should be obtained if response is not prompt and satisfactory. Waterhouse-Friderichsen Syndrome

This is an acute state of shock in fulminating meningococcemia. There are usually profuse petechiae in the skin (although these are far from pathognomonic24 ), and the patient is desperately ill with prostration, rapid, feeble pulse, and falling blood pressure. The eosinophile count in the peripheral blood is likely to be elevated in contrast to the absence of the eosinophils in the initial stage of cases which do well, 33 but is probably a less reliable guide than the clinical situation. Hydrocortisone, 2.5 to 7.5 mg. per kilogram per 24 hours intravenously, has been an accepted therapeutic measure, although doubts have been raised about it recently by May 54 among others, who points out that the shock is probably due to pooling of blood in the liver and mesenteric vessels and that the level of corticoids in the circulating blood is already elevated. The basis of the areas of necrosis which often occur in the skin (and may require subsequent grafting) is similar to the Shwartzman phenomenon. Fatal cases may show renal glomerular or intertubular capillary thrombi or renal cortical necrosis similar to findings in the generalized Shwartzman phenomenon in animals. 49 Another argument along these lines is that the Shwartzman phenomenon can be produced by a single injection of meningococcal endotoxin in animals if cortisone is given in addition, although two separated injections are required otherwise, but admittedly there is no comparable human evidence.54 Margaretten and McAdams 49 report a higher death rate in patients not initially in shock who were given hydrocortisone, but this was not a blind controlled study, and one could argue that the more desperately ill cases were more likely to be treated. My personal opinion would be to use hydrocortisone (or subsequently, intramuscular cortisone) if the patient were in shock, but not otherwise for meningococcemia in general.

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Norepinephrine may be given by constant intravenous drip in a solution containing l mg. per liter to control blood pressure30 and is probably preferable to levarterenol, which may also be used. The rate of infusion must be carefully titrated to the patient's actual blood pressure, and close observation is essential, since both are potentially dangerous. May 54 believes that the use of norepinephrine is also highly debatable, since both it and epinephrine can produce shock and local necrosis in animals if the reactivity of the terminal blood vessels is altered by meningococcal endotoxin. May favors a single initial transfusion of 10 per cent of the patient's estimated blood volume. This is a measure to combat shock and might be followed by plasma if there is hemoconcentration. If such measures do not produce prompt recovery of adequate blood pressure, the probability of an early fatal outcome would seem to warrant the use of norepinephrine. The usual supportive measures and particularly good nursing care are important in managing the Waterhouse-Friderichsen syndrome. Oxygen should be given if the patient is cyanotic. Intravenous fluids should be given as for other cases of meningitis, but it is desirable not to include any potasium until shock is controlled, circulation adequate, and urine being secreted normally. Tuberculous Meningitis

Tuberculous meningitis usually presents a more gradual onset than other types of bacterial meningitis. There may be a fairly acute onset in fulminating miliary tuberculosis, but it is more usual for the victim to become gradually but progressively ill over a period of one to three weeks with malaise, irritability, headache, vomiting and, finally, increasing lethargy. The neck may be less stiff and signs of meningeal irritation less evident than with other meningitides. Lumbar puncture produces fluid containing small or moderate numbers of leukocytes (rarely more than a few hundred) which are usually a mixture of polymorphonuclears and lymphocytes. In very early cases the number of cells may be borderline (or even normal if a routine tap is done on a patient with miliary tuberculosis). Elevation of protein may not be striking initially, but the concentration of sugar is usually depressed. The depression is not so great as in other bacterial meningitides, however, and simultaneous determination should be made of the level of sugar in the blood. It has long been claimed that the chlorides in the cerebral spinal fluid are specifically depressed in tuberculosis meningitis. This is frequently true, but is probably related to the amount of vomiting which has taken place rather than to the organisms specifically. Acid-fast organisms may be seen in stained smears of centrifuged sediment of the cerebrospinal fluid, but cannot

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be detected in a high percentage. Cultures and guinea pig inoculation may help in retrospective diagnosis later on, but not as to the immediate decision, which must be made as to diagnosis and plan of treatment. The tuberculin skin test is usually positive, but may be negative in early fulminating cases. If a 1:10,000 intradermal test with Old Tuberculin is negative after 24 hours, one should proceed directly to a 1:100 injection, since the risk of a slough is unimportant compared with the probability of irreparable brain damage if the diagnosis is delayed. X-ray films of the chest will usually show evidence of tuberculosis, but may be negative in early miliary cases. The features mentioned will usually distinguish tuberculous meningitis from that due to Cryptococcus, Histoplasma or Toxoplasma, as well as from viral or aseptic forms. In doubtful cases examination of the eyegrounds for choroidal tubercles is valuable. These are present only in a minority of cases, but are pathognomonic if seen. The child must be sedated for adequate examination, and the pupils dilated. In order to be successful, one must have some experience in the use of an ophthalmoscope and devote sufficient time to the examination, since the tubercles are commonest in the peripheral retina, through which they are seen as small, yellowish projections of diameter of one third to half that of the optic disk. A family or household contact with tuberculosis can usually be established at least in retrospect, and of course should be investigated as a public health measure, but is frequently of no assistance with the immediate diagnosis. Isoniazid (10 to 20 mg. per kilogram per day orally) has greatly changed the prognosis of tuberculous meningitis; the death rate is now small, and the likelihood of death or brain damage should be less in children than in older people. 91 It is possible that isoniazid alone is sufficient (5 patients taken off other medication because of complications have been reported to do well 74), but it is preferable to supplement it with para-aminosalicylic acid, 200 to 400 mg. per kilogram per day orally if tolerated without excessive anorexia or vomiting, and with streptomycin, of which 100 mg. per kilogram daily intramuscularly should be given for the first few days. Intrathecal streptomycin was essential for cure before the introduction of isoniazid, but is no longer needed in most cases. 91 Isoniazid is continued at 10 to 20 mg. per kilogram daily for 6 weeks and then at 7 mg. per day for a year. Paraaminosalicylic acid is also continued for 12 months. Streptomycin should be reduced to 50 mg. per kilogram daily after the first week or so and continued at that level for 6 weeks. The same dose is then given twice weekly for six months. It may well be that shorter periods of treatment will be adequate, 41 but the program mentioned is a conservative and successful one at present.

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Viomycin ( 10 to 20 mg. per kilogram daily) may be given in cases not responding successfully, but this is rarely necessary if diagnosis is made in time, now that isoniazid is available. Poor response usually results from delayed diagnosis and therapy or less often from meningeal adhesions and loculation of infection. Intrathecal streptokinase and streptodornase, or intrathecal tuberculin, can be considered under such circumstances, but have been associated with violent reactions and a high mortality rate and are seldom indicated with the other drugs now available. Streptomycin, of course, carries the risk of damage to the acoustic and vestibular nerves. This risk is lessened if the dose is reduced to 50 mg. per kilogram daily after 5 to 7 days, but although present, must be accepted because of the gravity of the meningitis itself, unless it can be shown that isoniazid and para-aminosalicylic acid are sufficient. It has been claimed that pantothenic acid (50 mg. orally 2 or 3 times a day for adults) will abolish vertigo and halt or reverse hearing loss. 71 Isoniazid has a host of possible side effects, including peripheral neuritis most commonly, but also psychosis, hyperreflexia or convulsions, hepatitis, skin rash, tinnitus, ataxia, purpura, agranulocytosis, hemolytic anemia and states resembling pellagra. Most of these occur after two or three weeks' treatment, but may subside spontaneously even though the drug is continued. Pyridoxine hydrochloride, 10 mg. per 100 mg. of isoniazid, has been said to prevent or reverse side effects from isoniazid, particularly polyneuritis.6 • 48 Acute isoniazid poisoning can cause convulsions or other complications in children, 38 but it is not clear whether normal dosage produces pyridoxine deficiency in children or not. 61 Nonbacterial Infectious Meningitis

This may be due to a variety of organisms which present subacute clinical pictures resembling tuberculous meningitis. Meningitis is far commoner and more successfully treated and should always be ruled out first. The more important other possibilities are Cryptococcus, Histoplasma and Toxoplasma. Cryptococcus meningitis (torulosis) usually presents with a subacute onset much in the manner of tuberculous meningitis, but may run a slower course. The cerebrospinal fluid contains 50 to 1000 leukocytes per cubic millimeter, chiefly lymphocytes. Cryptococcus organisms are often visible in the fluid and are more easily demonstrable if a small amount of India ink is added to the fluid before microscopic examination. In preparations without India ink they strongly resemble red blood cells except that many are budded. The condition was always fatal in the past, but recent results with amphotericin B are promis-

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ing. 21 • 35, 75 The drug is given daily, l.O mg. per kilogram by intravenous infusion over an 8-hour period, but the length of therapy required is uncertain at present. Histoplasma meningitis is usually of insidious onset with evidence of generalized histoplasmosis by weight loss, anorexia, pallor, cough, fever, lymphadenopathy, possible enlargement of the spleen, and changes in the lungs, at least by x-rays. Signs of central nervous system involvement are gradual with lethargy, irritability, and ultimately convulsions or cranial nerve or other paralyses. Diagnosis may be made from the finding of Histoplasma organisms in the sputum or by a skin test, although in many areas of the country a high percentage of the normal population are reactors to histoplasmin. The cerebrospinal fluid contains moderate numbers of white blood cells, largely or entirely lymphocytes. Most cases of Histoplasma meningitis occur in infants, 79 and the condition has been considered inevitably fatal, although a cure has been recently reported with amphotericin B, 1 mg. per kilogram daily, with 62 doses over a 4-month period.63 Toxoplasmosis is known chiefly as an intrauterine or neonatal infection causing hydrocephalus or microcephaly, intracranial calcification and chorioretinitis. Less commonly, the organism can be the cause of pulmonary infections in adults and of meningitis in children and young adults. The clinical picture is of a subacute meningitis of gradual onset, and the spinal fluid contains a moderate number of lymphocytes. Many patients probably recover spontaneously, but some are left with residual damage. Kaser40 has reported successful treatment of both neonatal and later meningitic cases with pyrimethamine (Daraprim R), 6 to 25 mg. daily or on alternate days, in combination with sulfamethazine. (Sulfadiazine could probably also be used.) Aseptic Meningitis

Aseptic meningitis may be due to a variety of viruses, but even the most careful viral studies of stools, cerebrospinal fluid and antibody titers in the blood do not always lead to an etiologic diagnosis, and such methods are sometimes confused by the frequent recoverability of viruses from the stools of asymptomatic persons in certain seasons. A recent report59 identified viruses in 26 of 31 patients. Sixteen were poliovirus type 1, seven were ECHO 9, one was Coxsackie B3, and two were mumps. Similar distributions have been reported by others. Less common types of aseptic meningitis include herpes simplex, lymphocytic choriomeningitis, infectious mononucleosis, 80 cat-scratch fever 70• 84 and Behc;et's syndrome. 69 Except for excluding other treatable conditions, the management of aseptic meningitis is symptomatic, and spontaneous recovery is the rule.

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Coxsackie B virus, however, may produce increased intracranial pressure96 and a highly fatal encephalohepatomyocarditis in the newborn. 43 Herpes simplex invasion also has a grave outlook in newborn infants. ENCEPHALITIS Encephalitides of Viruses Invading the Brain Directly

The most important varieties in the United States are the Eastern and Western equine and the St. Louis types. Herpes simplex and Coxsackie viruses may also cause meningoencephalitis and in infants are often extremely serious, with a high death rate. In neonates the Coxsackie virus most often produces a combination of meningoencephalitis with myocarditis, and sometimes with hepatitis as welJ.3 7 • 43 Cerebral poliomyelitis with convulsions has also been described in young infants. 82 The mumps virus most often produces an aseptic meningitis with severe headache and signs of meningeal irritation, but may involve the brain itself occasionally with residual damage. 68 Rabies should be mentioned in passing. All the encephalitides mentioned are accompanied by the presence of white blood cells in the cerebrospinal fluid, ranging from small numbers up to a thousand or more. Considerable numbers of polymorphonuclears, or even a majority, may be present. But in the Royal Free Hospital encephalitis epidemic in London the cerebrospinal fluid was usually normal. 57 Some encephalitides are associated with leukocytosis in the blood, especially Japanese B and the equine types. Diagnosis depends on excluding other possible explanations, and on retrospective virus isolation or serologic tests, although knowledge of what is current in the neighborhood will often lead to a good hunch. Treatment is, at present, entirely symptomatic, including control of elevated temperature, dehydration, convulsions if present, and cerebral edema (see p. 71). Para-infectious Encephalitides

These occur in association with the common childhood infectious diseases and also with influenza and many other types of respiratory infections. The associated primary infection may be minor in itself, even with a fulminating encephalitis. A number of different forms have been described. "Acute toxic encephalitis" is the earliest of onset and the most grave. It may follow the respiratory infection or the exanthem by a few days or may even precede the appearance of the rash, and presents as acute cerebral edema with prostration, coma, convulsions, papilledema, and

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the like. The cerebrospinal fluid is under increased pressure, but is otherwise normal. Cases coming to autopsy usually show only a large, swollen brain with minimal round cell infiltration and no demyelination. The death rate is high, and residual damage frequent among survivors. Treatment is symptomatic, but attention should be especially directed at cerebral edema, since this will soon lead to herniation of the brain stem and a fatal outcome if left alone. The measures outlined on page 72 will sometimes result in dramatic relief of symptoms, and the use of intravenous urea is the principal recent development. Hyperventilation may also have something to offer by reducing carbon dioxide tension in the blood. 47 Hypothermia is of considerable use. The classic postinfectious encephalitis or encephalomyelitis has as its histologic basis multiple small areas of perivenous demyelination and round cell infiltration. The picture is similar to the experimental allergic encephalitis or myelitis which can be produced in animals by injection of brain or spinal cord tissue with the Freundt adjuvants. Symptoms usually begin 3 to 10 days after the rash of the childhood exanthems (measles, German measles and chickenpox are the most important in this connection) or after smallpox vaccination. The clinical picture varies enormously according to the loci of greatest involvement. The principal variations are described in standard textbooks and elsewhere, 60 and it is sufficient to say here that alterations of consciousness, coma, convulsions, hemiplegia, and so on, dominate measles encephalitis, which is often severe and is frequently followed by death or by residual neurologic damage. The encephalitis associated with German measles may also be fulminating, but is much less frequent in proportion to the number of cases of the exanthem. Encephalitis with chickenpox usually (but not always) gives predominant cerebellar signs with ataxia and vomiting; a few patients die during the acute stage, but recovery is a rule otherwise. Mumps, as already mentioned, usually produces a benign meningitic picture, although the patient may be quite ill at the time. Less frequently there may be coma, convulsions or hemiplegia, but it is uncertain whether to classify such cases here or as a direct cerebral invasion. 68 Postvaccinal encephalitis is usually associated with myelitis. The incidence has been estimated at anywhere from one in a few thousand vaccinations to one in 100,000, according to the age at which initial vaccination is done. The risk is higher in older children or in young adults vaccinated for the first time. Diagnosis is usually not difficult because of the history, although, as mentioned, the presenting physical signs are extremely variable. It is well known that convulsions frequently complicate roseola infantum. Permanent brain damage is by no means unknown,8 but it is not clear on what pathologic basis; high fever and

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severe convulsions may be chiefly responsible. The encephalopathy sometimes associated with whooping cough, especially in infants, is mainly anoxic and hemorrhagic. In para-infectious encephalitides the cerebral spinal fluid usually contains small numbers to several hundred leukocytes, but there are doubtless authentic cases in which the number of cells is not elevated. (The usual picture, however, is in contrast to that of acute toxic encephalitis, in which the pressure of the fluid is extremely high, but in which no abnormal number of cells is seen.) Treatment is principally supportive and symptomatic. Cerebral edema is not rare with measles and German measles encephalitis and may be treated as already described. Adrenal steroids are a debatable form of therapy, and their evaluation is extremely difficult because of the variability of the conditions under discussion and the frequency of sudden dramatic improvement even without any specific treatment. Allen 3 reports recovery in all of 10 severe cases of measles encephalitis given hydrocortisone hemisuccinate, 100 units intravenously at once and again over the first 24 hours. He also gave 300 mg. of cortisone acetate intramuscularly on the first day, 150 on the second, and 75 on the third. Intravenous ACTH was given, 40 units on the first day, and followed by 40 intramuscular units the first day and 20 units on the second and third days. Gamma globulin has been advocated in the treatment of measles encephalitis, 66 but is probably of no value, 2 and it is generally acknowledged that encephalitis may complicate measles modified by previous gamma globulin. The use of adrenal steroids is credible for other cases of postinfectious encephalomyelitis as well as for measles. Acute hemorrhagic leukoencephalitis is a reasonably well defined histologic picture which may complicate infectious diseases. The clinical picture overlaps the later acute disseminated encephalomyelitis (with perivenous demyelination), to which it is nosologically at least closely related, 77 but the course is more fulminant and the prognosis graver. Treatment, again, is symptomatic, including control of cerebral edema if present. Adrenal steroids are probably of no value unless shock accompanies. BRAIN ABSCESS

Brain abscess may result from direct bacterial invasion in connection with skull fractures, osteomyelitis of the skull, congenital dermoid sinuses, or sinusitis or otitis media. It may also occur hematogenously, although most bacteremias are confined to the venous circulation because of the filtering action of the normal lung. Congenital heart disease with a constant or potential right-to-left shunt is the commonest

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mechanism for hematogenous brain abscess, although it has been reported with hemangiomas or arteriovenous aneurysms of the lungs. 56 • 94 Groff31 attempted to produce experimental brain abscesses by introduction of bacteria intracranially, but these failed to cause abscesses unless there was some pre-existing brain damage. Nevertheless small areas of encephalomalacia are common in routine autopsies of patients with congenital disease, 5 • 13 and the necessary fertile ground for seeding of bacteria would seem to be present. The clinical picture is variable, and the diagnosis sometimes difficult. If there is rapid spread of the abscess without encapsulation, there is lethargy, delirium, convulsions and headache with variable and frequently absent focal neurologic signs. If the abscess becomes encapsulated, the principal signs are headache and increased intracranial pressure, but there may also be convulsions, paralyses or focal signs, depending on the location of the abscess. These signs are likely to be few if the abscess is in the temporal or inferior parietal lobe, which is its common location if associated with otitis media. Cerebellar abscesses with corresponding symptoms also occur, but are much less common than supratentorial abscessesP A number of clinical studies of patients with brain abscesses have been presented, 12 • 29 • 53 • 6 2 and study of these will emphasize the variability of the symptoms. Most abscesses are single. 29 • 62 Of l3 patients reviewed by Matson and Salam,53 all had increased intracranial pressure, and 11 had papilledema. Eight of the l3 had convulsions, and 10 had hemiparesis or lateralizing cranial nerve signs. Nine of the 13 had a history of infection within 2 months of the onset; the infection was otitis media in three. Thus it would seem that brain abscess most typically presents as a space-occupying intracranial mass lesion, associated with a history of recent infection, especially in the ears, unless the opportunity of direct invasion of the brain through the skull exists (fracture, dermoid, osteomyelitis). The presence of cyanotic congenital heart disease should heighten one's suspicions, and Newton 62 estimated the incidence of abscess at 4 to 6 per cent, even if subacute bacterial endocarditis is not present (none of the 72 cases he reviewed had this). Less typical cases with abscess in "silent" areas of the brain may be difficult of diagnosis if there are no localizing signs and if evidence of increased intracranial pressure is equivocal. The majority of cases have leukocytosis in the peripheral blood, but the white blood cell count may be normal. \Vhite blood cells are often, but by no means always, present in the cerebrospinal fluid. Their number may be as high as several hundred. Lymphocytes usually predominate, but the proportion and the number of cells probably depend on how near the abscess is to the surface of the brain. The spinal fluid protein is usually mildly elevated, but only 3 of Matson's cases 53

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had a level of over 50 mg. per 100 mi. Culture of an organism from the cerebrospinal fluid is rarely possible, 12 and even direct culture of the abscess may frequently be sterile, 62 particularly if antibiotics have been given. The electroencephalogram is one of the most useful diagnostic measures and has a high localizing value. 85 Contrast x-ray studies are usually required for demonstration of the abscess, but doubtful cases often merit a period of observation before one can decide whether these are warranted. The use of antibiotics during the observation period may slow the evolution of the picture, but this effect must be balanced against arguments to the contrary. If the hematocrit level of the blood is high, a ventriculogram or pneumoencephalogram may be safer than an arteriogram.5 3 Actually, brain abscess is an emergency principally in terms of making the diagnosis and referring the patient to a neurosurgeon. Successful treatment is now possible for the majority either by repeated aspiration with instillation of antibiotics or by excision of the entire encapsulated abscess if possible. Abscesses may present an emergency in terms of acute increased intracranial pressure with signs of tentorial herniation. Neurosurgical referral is the best means of handling this, since accompanying cerebral edema is not great and intravenous urea therefore of less benefit than in other circumstances. Hypothermia may be of value as a holding measure. Rupture of an abscess into one of the cerebral ventricles sometimes occurs, resulting in sudden prostration, rapid elevation of temperature, a stiff neck and other signs of spreading meningitis. Immediate management is largely as for ordinary bacterial meningitis, but such cases are usually fatal. BRAIN TUMORS DIAGNOSIS

From the point of view of the pediatrician or general practitioner, the principal emergency about brain tumors in children is that of making the diagnosis or of having a proper degree of suspicion as to which cases should be referred for further investigations. The presenting symptoms vary widely according to the location of the tumor, as would be expected. Among children the majority of tumors are infratentorial and present with symptoms emanating from the cerebellum and brain stem. Except for infiltrating gliomas of the pons, most cause early obstructive hydrocephalus. Headache is frequent and should be taken seriously, since genuine migraine is relatively uncommon in children even if psychogenic headaches are not excessively rare. The posterior fossa of the head may be tender to pressure. Vomiting is of even greater importance as an alerting sign when it persists over a period of weeks and cannot be otherwise explained. In

•

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the classic history the child wakes in the morning and vomits, or even is waked from a sound sleep to vomit. The vomiting is forceful or projectile and is preceded by little or no nausea. The act of vomiting must in some way temporarily diminish the intracranial pressure, for the child then feels better and goes and eats his breakfast with little complaint. In other instances the history may be less typical, and a high degree of suspicion is always indicated. In infants vomiting is also important as a presenting sign, but to some extent the increased pressure can be relieved by separation of the sutures. This may be felt with the examining finger, and the fontanel may bulge. The head circumference may increase more rapidly than normal. Under these circumstances papilledema may be absent. Crying and excessive irritability or, contrariwise, lethargy are also common modes of presentation, and a slowing of development may raise suspicion of mental retardation or some degenerative encephalopathy. Other presenting symptoms depend largely on the location of the tumor and will be described below. The most important physical sign is papilledema, which develops early in most cases of tumor in the posterior fossa. Supratentorial tumors may produce papilledema relatively late, however, particularly if of the infiltrating type. Other localizing signs may also be long delayed if the growth is in a silent area. X-ray films of the skull are of great diagnostic value, primarily for possible evidence of increased intracranial pressure, chiefly by separation of the sutures. The standard of normal varies with age, and misdiagnoses are occasionally made even by qualified radiologists, who work largely with adults and seldom have occasion to interpret children's skull films. The "beaten silver" appearance of the skull is of limited value as a diagnostic criteron and may be misleading. In older children erosion of the dorsum sellae may occur from long-standing, gradual increase of intracranial pressure. Calcification is of particular value if seen, but is more likely to be absent. Local thinning of the tables of the skull is occasionally · seen, but the thickening which is common with meningiomas in adults is scarcely to be sought, for these tumors are rare in childhood. The pineal is not calcified in children, and one is thus deprived of a valuable sign in looking for tumors of the hemispheres, since its shift cannot be detected. Other specific aspects of the presenting history, physical signs and x-ray findings depend on the location of the neoplasm. Cerebellum

Roughly, half of cerebellar tumors in children are medulloblastomas. These are frequently midline in the vermis and produce a picture of truncal ataxia in which the child falls backward. The neck is often

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stiff, and the posterior fossa tender to pressure. In tumors of the cerebellar hemispheres there is also ataxia of station, gait and hand function which is likely to be greater on or toward the side of the lesion. There is frequently head tilting or rotation (the patient "looks toward the lesion"). Nystagmus is often present and is maximal on looking toward the side of the lesion. Past-pointing may be detected, again toward the affected side. Other possible signs include hypotonia, drift, pendulous knee jerks, dysdiadochokinesis. The cerebellar manifestations must be distinguished from idiopathic cerebellar ataxia, Friedreich's ataxia, and other states, but one should remember that these conditions are usually symmetric. Strongly lateralized cerebellar signs should be considered evidence of a tumor until proved otherwise. One can make some guess as to the approximately equal statistical chance of medulloblastoma or astrocytoma by history and signs, but with many errors. It is thus probable that all cases warrant the making of ventriculograms. The majority of neurosurgeons will explore the posterior fossa if these are diagnostic of a mass lesion, since, again, one cannot distinguish a potentially curable astrocytoma from a medulloblastoma by x-ray study alone. If a medulloblastoma is found, the patient must be consigned to radiation therapy with no prospect of a permanent cure, but operable astrocytomas will be missed if definitive investigation is not carried out. Pons and Medulla

Surprisingly, the infiltrating gliomas of the brain stem produce obstructive hydrocephalus only rather late. The classic physical signs are single or multiple cranial nerve palsies plus crossed long-tract signs such as hemiparesis (e.g. a right-sided facial nerve palsy plus a left hemiparesis, in which instance the right sixth nerve would also likely be paretic). Tumors of the cerebellopontine angle give a combination of hearing loss, vestibular signs and symptoms and tinnitus (although children infrequently give a history of this), combined with signs and symptoms referable to the cerebellum and to the lower cranial nerves. Acoustic neuromas rarely occur in children except in association with neurofibromatosis, in which disease they are likely to be bilateral. Gliomas of the cerebellopontine angle do occur in childhood, however. The corneal reflex is usually absent on the affected side, owing to mvolvement of the spinal tract of the trigeminal nerve. Midbrain

The cerebral peduncles may be involved in combinations such as hemiparesis with crossed oculomotor palsy. If the lesion is posterior, one may see paresis of conjugate upward gaze, optic atrophy and

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relatively early obstructive hydrocephalus. Pineal tumors may be associated with precocious puberty, chiefly in males. Hypothalamic signs may also be present. Hypothalamus

The commonest symptoms are obesity, diabetes insipidus, sexual variations, glycosuria and disturbances of sleep. Less frequently there may be hyperpyrexia, gastrointestinal disorders and emotional disturbances. 42 Diencephalon

Recently described cases of diencephalic tumors have been reported to present a striking syndrome of emaciation and wasting in the presence of adequate caloric intake, accompanied by an extremely bright, expressive, alert appearance of the face and eyes. 7 • 15 • 76 Unfortunately, such lesions are not operable. Optic Chiasm

Diminished vision or altered visual fields are the principal signs. Hypothalamic symptoms may accompany, or there may be evidence of pituitary insufficiency such as dwarfism or cachexia. Calcification by skull x-ray can be found in almost all craniopharyngiomas in children, although this is not true in later life. Basal Ganglia

Signs may be minimal for a long time, but are most likely to include unilateral tremor of gradual development or other disorders of movement such as choreoathetosis and dystonia. Involvement of the adjacent internal capsule may produce hemiparesis, and there may be a quadrantic homonymous visual field defect if the lesion extends into the temporal lobe. Cerebral Hemispheres

The signs are often few until late. It is difficult to examine young children for signs of parietal lobe involvement which are so spectacular in adults with tumors in this region. Personality changes are a frequent mode of presentation in children. Ingraham and Matson 39 report that one third of their cases of hemisphere tumor in children had convulsions, and a tumor should be considered a possibility in all cases of focal or jacksonian seizures. Contrariwise however, jacksonian or other seizures in children are statistically unlikely to be due to neoplasms,

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and the small meningiomas which frequently produce this picture in adults are rare in childhood. Obstruction of the ventricular system occurs late or not at all, and the lesion may reach enormous size without producing evidence of increased pressure if it grows by replacement and infiltration. MANAGEMENT OF SUSPECTED CASES

The presenting signs and symptoms are variable. The principal need of the pediatrician or general practitioner is a reasonable degree of suspicion. Diagnosis is often difficult except in classic examples, and it is usually wisest to refer doubtful cases for neurologic or neurosurgical consultation. X-ray studies of the skull are important, as already mentioned. Electroencephalography may furnish evidence by localized slowing, which is frequently seen in the occipital leads in the presence of posterior fossa tumors (produced by pressure through the tentorium). Lumbar puncture is of limited value, although the protein content of the cerebral spinal fluid is often elevated (but far from always). A cautious lumbar puncture to measure pressure and obtain a minimal amount of fluid for examination without withdrawal of larger amounts is less dangerous than is often believed,78 but should not be attempted by the inexperienced. It is particularly dangerous in the presence of posterior fossa mass lesions, and brain stem herniation and immediate death may follow. Differential diagnosis must be made from other causes of increased intracranial pressure such as encephalitis, lead poisoning, brain abscess, "otitic hydrocephalus" and other forms of benign intracranial hypertension, 22 • 86 as well as from other varieties of hydrocephalus, and rarer causes of increased intracranial pressure. 16 • 96 Emergency management is fortunately not often required except for acute obstructive hydrocephalus or impending brain stem herniation. Prompt neurosurgical referral is the best management in such cases, although efforts to shrink the brain as for cerebral edema (p. 72) may help as temporary measures. If the cause of increased pressure is obstructive, ventricular puncture through the coronal suture in infants or through a burr hole may help if qualified assistance is available, pending arrangements for neurosurgical help. ACKNOWLEDGMENT

Dr. Donald Matson kindly reviewed parts of this article concerned with neurosurgery. REFERENCES 1. Alexander, H. E.: Guides to Optimal Therapy in Bacterial Meningitis. J.A.M.A.,

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