Vascular diseases of the brain and tics, twitches and habit spasms

VASCULAR DISEASES OF THE BRAIN and TICS, TWITCHES AND HABIT SPASMS GERALD S. GOLDEN, M.D.

0045-9380/78/0004-0001505.00 9 1978 Year Book Medical Publishers, Inc.

TABLE OF CONTENTS V A S C U L A R D I S E A S E S OF T H E

INCIDENCE

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FACTORS S P E C I F I C TO C H I L D R E N PATHOLOGY .

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PRIMARY VASCULAR DISEASE

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BRAIN

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CEREBROVASCULAR ACCIDENTS ASSOCIATED W I T H

SYSTEMIC DISEASE

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INTRACRANIAL BLEEDING IN THE NEONATE DIAGNOSTIC APPROACH THERAPY

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PREVENTION

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Tics,

TWITCHES AND

MOVEMENT DISORDERS TIC DISORDERS

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H A B I T SPASMS

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SIMPLE TICS AND MULTIPLE CHRONIC Tics T O U R E T T E SYNDROME SPECULATION .

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is Professor of pediatrics and neurology and Director, Child Development Division, University of Texas Medical Branch, Galveston. He received his M.D. from Columbia University College of Physicians and Surgeons and completed an internship and residency in pediatrics at the University of Minnesota Hospitals. Dr. Golden's major interest is in chronic handicapping conditions in children, particularly movement disorders.

Vascular Diseases of the Brain VASCULAR DISEASES OF T H E BRAIN in children are uncommon, especially when compared to the high level of morbidity produced by these conditions in older adults. Strokes do occur in children, however, are often severe, and m ay lead to a long life of chronic incapacity or death. All age groups are affected although the causative factors are quite varied and highly agespecific. The prognosis varies with the age, and to some e x t e n t independently, with the pathogenetic events.

INCIDENCE The g r eat variation in causative factors with age m akes an overall estimate of incidence difficult to det erm i ne and clinically of very little value. 1 The use of different age groups by various authors also does not allow for comparability of data. In one study incidence ranged from 3 per million population in 5- to 9-year-old children to 6 per million in those both older and younger. A n o t h e r study gave an overall incidence of 2 per 100,000 per y e a r for individuals u n der 35 years of age. Prevalence rates in the range of 1 1 .7 - 2 3 .9 per 100,000 have been reported from two c o m m u n i t y surveys. The age dependence of etiology is clearly shown in the fact t h a t 53% of all vascular diseases of the brai n in children occur in those less t h a n 2 years of age. If neonatal subarachnoid and i n t r a v e n t r i c u l a r h e m o r r h a g e are excluded, this group accounts for only 36% of all cases. When strokes do occur in children, t he y are often severe. In one series of autopsies, cerebrovascular disease accounted for d e a t h in 8.7%, a disproportionately high figure. 2 A survey of a population of children with cerebral palsy indicated t h a t 4% of cases were due to serious postnatal vascular disease. 3

FACTORS SPECIFIC TO CHILDREN The serious morbidity and high mortality of cerebrovascular disease in children is partially due to the need for an extremely high proportion of total cardiac output to traverse the intracranial circulation to meet the large energy demands of the brain. The subependymal neuronal layers in the p r e m a t u r e infant are highly dependent on the maintenance of adequate blood flow and oxygenation. Failure to maintain the metabolic needs of this area leads to cell necrosis, the first step toward intraventricular hemorrhage. The major difference in comparing cerebrovascular disease in children and adults lies in the widely disparate etiologic factors. 3 Atheromatous disease, the overwhelmingly common cause in adult strokes, is so rare in children that only a limited number of case reports exist. The ability to define clearly the pathogenetic mechanism in children is often lacking, although congenital anomalies, t r a u m a and birth anoxia play prominent roles. Another problem specific to the pediatric age group is the phenomenon of growth arrest involving hemiparetic limbs, usually more pronounced if the cerebral lesion is in the parietal area. A detailed explanation is not available, b u t it appears to be more complex than j u s t poor growth secondary to disuse. This unequal growth can lead to progressive difficulties, an important one being the development of postural scoliosis as a result of a short leg. The child with an acute cerebrovascular accident has an advantage over the adult in one respect, that of increased potential for recovery resulting from functional and perhaps anatomical plasticity. This phenomenon is most apparent in language functions. In the great majority of children younger than 4 years of age, an insult to the left cerebral hemisphere causes no permanent deficit in language ability. There m a y be temporary aphasia, but language is rapidly regained and the child often follows the same developmental pattern as with initial language acquisition, b u t with an abbreviated time scale. Between ages 4 and 8 years return of language will be slower and will more closely resemble the adult pattern of recovery from aphasia. The time course will be more rapid, however, and the recovery more complete. In the age range of 8 - 1 2 years there m a y be some residual deficit, and older children generally follow the same recovery course as adults. There is less clinical evidence for functional plasticity in reference to motor, sensory or visual field return.

PATHOLOGY CENTRAL NERVOUS SYSTEM

The basic pathologic changes in the central nervous system are identical to those seen in adults, and vary according to whether the underlying cause was arterial thrombosis, embolism or venous occlusion. In thrombotic lesions, acute tissue necrosis is followed by some pericapillary hemorrhage and then an influx of polymorphonuclear leukocytes. There is always some brain edema; the amount depends on the extent of the infarction. The acute inflammatory reaction soon subsides and the necrotic tissue is gradually removed by macrophages, leaving an area of cystic encephalomalacia. Embolic lesions may produce an identical picture or m a y differ in one respect. Soon after the infarction is produced the embolus m a y break up and move further upstream. This restores blood flow to the necrotic area. Because of breakdown in the integrity of the walls of local blood vessels there is bleeding into the area with production of a hemorrhagic infarction. Venous thromboses differ in an important way. Arterial supply to the infarcted brain is maintained, giving rise to a severely hemorrhagic infarction. This accentuates the surrounding area of brain edema. Venous obstruction also causes interference with the absorption of cerebrospinal fluid, further increasing intracranial pressure. Finally, the thrombosis tends to propagate and involve other veins and the dural sinuses. This leads to more widespread infarction and is yet another factor in producing intracranial hypertension. PATHOLOGIC CHANGES SPECIFIC TO CHILDREN

Vascular occlusions occurring prenatally or very early in life may produce lesions that are somewhat different from the adult type infarction. 4 Bilateral carotid occlusions with necrosis of the greater portion of both cerebral hemispheres in utero produces one type of hydranencephaly. More scattered vascular lesions can give rise to a brain showing multiple areas of cystic encephalomalacia. The encephaloclastic type of porencephalic cyst also most probably is residual to an early infarction. Subarachnoid hemorrhage can lead to progressive hydrocephalus. Less severe vascular compromise in utero m a y be the causative agent in certain structural anomalies classified as developmental malformations. These include ulegyria (atrophic sclerosis ofgyri) and focal subcortical cystic lesions. Subependymal hemorrhage, intraventricular hemorrhage, and periventricular leukomalacia have a common pathogenesis in vascular insufficiency and local anoxia. The highly cellular subependymal germinal layer is de5

pendent on the maintenance of adequate blood flow and oxygenation. Problems during delivery causing fetal hypoxia or blood loss, and postnatal factors such as respiratory distress or failure, may lead to circulatory collapse. Venous thrombosis ensues followed by hemorrhagic infarction of this layer. This m a y remain as a localized subependymal hematoma, or rupture into the ventricular system and produce intraventricular hemorrhage. A similar mechanism without hemorrhage leads to periventricular leukomalacia. VASCULAR PATHOLOGY There are few studies of the detailed vascular pathology and the findings have varied widely. 3 As has been stated, atheromatous disease is extremely rare. One of the consistently documented causes of arterial occlusion has been the presence of a localized segment of arteritis, apparently in the absence of systemic inflammatory vascular disease. The etiology of this reaction is obscure. Fibromuscular dysplasia has recently been reported in children. Angiography shows the typical "string of beads" appearance due to multiple areas of stenosis involving a localized arterial segment. Aneurysms of the circle of Willis are pathologically the same as those found in adults. They are rare in infants and their incidence increases with age.

PRIMARY VASCULAR DISEASE P r i m a r y vascular disease includes two major groups. The first is t h a t of diseases involving only the vascular supply to the brain, and apparently unassociated with systemic disease or external agents such as toxins, infection or trauma. It also refers to t h o s e conditions in which the problem is due to a congenital or acquired anatomical abnormality of cerebral blood vessels. ACUTE INFANTILE HEMIPLEGIA

The most common type of cerebrovascular disease in children is arterial occlusion. If neonatal intracranial hemorrhage is excluded, this accounts for approximately 31% of all pediatric strokes. Acute infantile hemiplegia has been the rubric applied to the sudden onset of a hemiplegia in a child with no evidence of an underlying intracranial infection or definable systemic disease.5, 6 Although a clinical scenario applicable to m a n y of the children can be written, a search for a specific etiology, supplemented by appropriate neurodiagnostic studies, is mandatory. The term acute infantile hemiplegia is most appropriately used when no specific cause can be determined. 6

The child, either well or having a mild upper respiratory infection, suddenly develops a hemiparesis. This m a y or m a y not be associated with a single seizure, a group of seizures or status epilepticus, and the onset of coma. The child may die. If he survives, recovery can be complete or he m a y be left with motor, intellectual or cognitive deficits, with or without a convulsive disorder. The most severe residua and worst prognosis are found in the patients with seizures at the onset. This group contains an overrepresentation of children under 2 years of age, and it is not clear which is the most important factor. A classification of acute infantile hemiplegia based on angiographic findings has been put forth, and has some clinical usefulness. Although this has not helped define specific etiologic events, it has some predictive value for the future clinical course and prognosis. The first group described by Solomon et al. 5 is t h a t of basal vascular occlusive disease with telangiectasia. The neuroradiologic findings are stenosis or occlusion of the supraclinoid segment of the internal carotid arteries bilaterally and of the proximal end of both middle and anterior cerebral arteries. A prominent network of telangiectatic vessels is seen in the region of the basal ganglia. Similar telangiectasia can be seen in the upper brain stem, and transdural collaterals connecting the internal and external carotid circulation m a y also become apparent. This clinicopathologic complex was first reported in Japanese children and given the name ~moya-moya" syndrome, referring to the fine smoke-like haze of vessels in the basal ganglia. It has become evident t h a t the condition is not restricted to any ethnic group. Although the onset is usually heralded by the sudden appearance of a neurologic deficit, some patients have had vascular headaches, and seizures, often focal, m a y be present at the onset or, occasionally, before the neurologic deficit appears. Associated features, as the condition progresses, include a l t e r n a t i n g hemiparesis, episodes of dizziness and changes in mood with depression and hallucinations. Intracranial hemorrhage has been reported in a few cases. The prognosis is not good; the majority of patients will have residual motor weakness and a convulsive disorder, and one-third will be left with a significant cognitive deficit. The second group consists of those patients with unilateral occlusion or stenosis of the supraclinoid portion of the internal carotid artery or the origin or major branches of the middle or anterior cerebral arteries. This group rarely has seizures as an initial manifestation and the overall prognosis for r e t u r n of function is reasonably good. Those patients with a long, tapered narrowing of the internal carotid artery beginning at the origin at the common carotid artery formed the third group. Onset was frequently associated 7

with seizures and a residual motor deficit was almost uniformly present. The fourth group manifested one or more occlusions of branches of the middle cerebral artery, often with retrograde filling from collateral circulation, improvement both in clinical and radiographic findings was generally found. In this series one patient showed a corkscrew pattern in small terminal arteries. This girl began with seizures, maintained motor and intellectual deficits and died of progression of the condition. No specific t r e a t m e n t has proved useful in treating any of these syndromes. There is little or no experience with thrombectomy and very little with anticoagulation. Problems such as the motor deficit, cognitive dysfunction and behavioral disorders become apparent early in the phase of recovery, and after a number of months a prediction can be made as to the extent of recovery t h a t can be expected. Progressive impairment should not occur, although pseudoprogression due to flexion contractures and spasticity can lead to increasing functional limitation. The major delayed complication is a convulsive disorder. 7 The three factors t h a t are the most highly predictive of this problem are the presence of seizures at the onset, age under 2 years when the stroke occurred and the presence of an epileptic spike discharge on the electroencephalogram. The latter is of greatest significance in children under 2 years of age. If no seizures have occurred by the time the child is 12 years of age, the chance of later development of this condition is small. A recently described late complication is a movement disorder affecting the paretic limbs. In each case there was a good recovery of strength but either resting and intention tremors or choreoathetosis in the upper extremity developed. VERTEBROBASILAR OCCLUSION

The majority of cerebrovascular accidents in children involve the distribution of the internal carotid artery and its branches, as do most strokes in adults. However, there has been an increasing awareness of the existence of vertebrobasilar vascular disease in recent years, s These patients initially have i n t e r m i t t e n t symptoms including diplopia, vertigo, nausea and vomiting, confusion, visual abnormalities and language disturbances in any combination. A completed vascular accident m a y supervene and the child, if he survives, is generally left with a severe neurologic deficit. The "locked in" syndrome, a state of m u t e tetraplegia with alert wakefulness, has been reported2 It is important to keep this diagnosis in mind in any patient who intially seems to be unresponsive and have a flaccid tetraplegia. The locked in pa8

tient can respond to requests to voluntarily open and close his eyes and in m a n y instances a primitive communication system of eye blinks can be developed. The pathologic substrate of vertebrobasilar disease varies and there is little clearly defined postmortem material. Angiography most frequently shows complete occlusion of one or both vertebral arteries, with or without basilar artery occlusion. Congenitally tortuous vertebral vessels have been reported in one patient in which the obstruction m a y have been a function of the position of the head and neck. In another child an anomaly of the dens which allowed subluxation of C1 on C2 was demonstrated in association with a segmental occlusion of one vertebral artery and an a n e u r y s m of the other at the C2 level. Other cases of brain stem strokes have been associated with congenital heart disease and are discussed in t h a t section. ARTERIOVENOUS MALFORMATIONS Arteriovenous malformations are the most common developmental anomalies of the cerebral circulation in children. TM In one series they accounted for 13% of all childhood strokes, four times the frequency of intracranial aneurysms. Their actual incidence is probably higher because the series included a large number of patients with subarachnoid or intraventricular hemorrhages, some of whom may have had unrecognized vascular malformations. The initial presentation in most cases is t h a t of hemorrhage into both the cerebral parenchyma and the subarachnoid space. Although seizures also occur, they are less common as the first symptom. Clinically the patient suffers the acute onset of headache, lethargy and a focal neurologic deficit. Retinal hemorrhages, signs of meningeal irritation and evidence of increased intracranial pressure develop rapidly. If a cranial bruit is present, it is a useful sign, but it is not heard often enough to be dependable. The majority of arteriovenous malformations involve the cerebral hemispheres (60-80%) although others are located more deeply and include the diencephalon or rostral mesencephalon (3-10%) in their extent. Pontine angiomas also have been reported. 11 The patients typically have multiple ictal episodes with cranial nerve involvement, cerebral signs and pyramidal signs. Evidence of subarachnoid hemorrhage is present in approximately one h a l f of the cases. A few patients have a progressive, r a t h e r t h a n intermittent, clinical course which m a y be indistinguishable from t h a t of a brain stem glioma. The cerebellum also m a y be involved and the child then shows acute onset of neurologic signs and rapid development of coma22 This lesion is amenable to surgery and the prognosis is better t h a n t h a t with cerebellar hematomas in adults. 9

Treatment and prognosis are both highly dependent on the location of the malformation, its size, the n a t u r e of the feeding blood vessels and the extent of the parenchymal damage. Polar lesions can be resected surgically en bloc. Those involving the cerebral cortex and superficial white m a t t e r can generally be extirpated, especially with the use of the operating microscope. If all of the feeding vessels are not disconnected, however, recurrences are seen. Deeply situated malformations still present a major problem in management. Techniques such as embolization have not given impressive results. Long-term problems are many. Frequent subarachnoid hemorrhages occur and can lead to the production of communicating hydrocephalus. Seizures are often relatively refractory to drug theropy. MALFORMATION OF THE VEIN OF GALEN

Although generally referred to as an a n e u r y s m of the vein of Galen, this lesion really is an arteriovenous malformation produced by a direct connection between branches of the internal carotid or posterior cerebral artery and the vein of Galen. 13There are three distinct patterns of clinical presentation which are highly dependent on the age at which symptoms first become apparent. The most frequent is in the neonatal period with congestive heart failure. Examination shows cyanosis, respiratory distress, strong peripheral pulses, a hyperdynamic cardiac impulse and cardiomegaly. Findings referable to the head include evidence of hydrocephalus, a cranial bruit, dilated scalp veins and visible cutaneous vascular malformations. Cardiac catheterization characteristically reveals a wide pulse pressure and high oxygen saturations in the superior vena cava, right atrium and right ventricle. The picture on cerebral angiography is characteristic. Boys are affected much more frequently t h a n girls. Removal of the malformation is difficult but an attempt to clip the feeding vessels can be carried out with the operating microscope. Mortality rate is extremely high with or without surgery and the patients are poor operative risks because of their critical cardiac status. In infants hydrocephalus or convulsions are present, although all of the patients do have hydrocephalus secondary to compression of the aqueduct of Sylvius by the mass effect of the enlarged vein of Galen. A bruit is present in one h a l f of the patients and distended scalp veins are another useful clinical sign. Other clinical features include mental retardation, recurrent epistaxis, cardiomegaIy, proptosis and a retrosternal pulsatile mass. There is a high rate of postoperative complications. This lesion m a y first make its presence known in an older child 10

or adult. The mean age of onset is 13 years for this form and the usual presenting problem is recurrent headache, subarachnoid hemorrhage, or both. Some patients have cerebellar or oculomotor signs. Cardiac failure and hydrocephalus are rare and a bruit is not present. Skull roentgenograms m a y show calcium in the wall of the lesion. INTRACRANIAL ANEURYSMS Aneurysms of the circle of Willis are rare in children; they account for no more t h a n 4% of all childhood strokes. TM Although the pathologic substrate is almost certainly congenital, the aneurysms are infrequent in random autopsies of children but increase with age through adult life. The initial lesion m a y be either a congenital defect in the media of the arterial wall, especially at the bifurcation of vessels, or the vestige of incompletely atrophied fetal vessels. Approximately 77% involve the anterior circulation with the middle cerebral and internal carotid arteries being the most frequent sites. The anterior communicating artery is involved more often t h a n the posterior communicating or anterior cerebral arteries. In the posterior circulation the basilar and posterior inferior cerebellar arteries are affected most commonly. Giant fusiform aneurysms of the basilar artery have been reported. The first sign is almost always the sudden onset of subarachnoid hemorrhage with severe headache, photophobia, signs of meningeal irritation and obtundation. Rare patients will initially present with evidence of a mass effect or such symptoms as recurrent headache and extraocular palsies. Neurologic signs appearing following rupture of the a n e u r y s m indicate hemorrhage into the affected brain areas. This is more frequent with subsequent episodes. Seizures follow the bleeding in approximately 15% of cases. The most widely accepted t r e a t m e n t is surgical, and this approach is t a k e n in most cases although some controversy still surrounds the timing of the operation and the role of such medical t r e a t m e n t s as bed rest and administration of epsilon amino caproic acid. Delayed complications include seizures if there was parenchymal involvement and the late development of communicating hydrocephalus. Cranial nerve palsies m a y be slow in resolving. Some predisposing factors in the development of aneurysms have been defined. There is an association with coarctation of the aorta, polycystic disease of the kidneys and the Ehlers-Danlos syndrome. Familial incidence of aneurysms has been reported. In this group anterior cerebral lesions are less frequent and middle cerebral locations increase in incidence. They are diagnosed at an earlier age and m a y be multiple in the individual. 11

ANOMALIES AND STRUCTURAL DEFECTS OF VESSELS

Nontraumatic dissections of the carotic artery have been reported in children, predominantly adolescents. There usually is sudden onset of hemiplegia which is often fatal. Survivors maintain a fixed neurologic deficit. A typical angiographic appearance of a "string" sign or a long attenuated column of dye is seen. Examination of the artery reveals an intimal separation and dissection without other pathologic changes. There are a number of reports of agenesis or hypoplasia of cerebral vessels and kinks and coils of the internal carotid artery. Without knowing the incidence of these anatomical variations in asymptomatic patients, their association with vascular disease is difficult to interpret.

CEREBROVASCULAR ACCIDENTS ASSOCIATED WITH SYSTEMIC DISEASE VASCULITIS

Although localized segmental vasculitis of vessels in the internal carotid distribution is pathogenetic in m a n y cases of acute infantile hemiplegia, most of these patients have no evidence of systemic disease. The generalized vasculitides can affect the central nervous system, although anatomicopathologic correlations at necropsy m a y be difficult to make. Systemic lupus erythematosus may present with seizures, psychosis or acute focal neurologic signs. Only scattered reports of cerebral infarction due to polyarteritis nodosa, dermatomyositis or granulomatous angitis exist in children. HEMATOLOGIC DISORDERS

Hematologic disorders are routinely considered in the differential diagnosis when a child presents with subarachnoid hemorrhage. However, thrombotic strokes can occur in a number of these conditions. Sickle cell disease 15 classically produces multifocal hemorrhagic infarctions as a result of thromboses at the level of arterioles and venules. More recent observations have indicated t h a t large vessel disease m a y be prominent, with involvement of the carotid, middle cerebral, anterior cerebral and vertebral arteries. Occlusion as well as progressive stenosis have been seen. Multiple vessels m a y be involved with the emergence of a moya-moya pattern. Clinically the patients present with hemiplegia, convulsions, visual disturbances and episodes of impaired consciousness. Hypertransfusion can reverse the angiographic abnormalities but this has not been accompanied by improvement in the clinical 12

status. The possibility exists that this technique m a y be helpful in those patients with transient ischemic episodes. The risks of angiography in patients with sickle cell anemia are increased significantly but can be minimized if exchange transfusion is carried out first. Another unusual neurologic manifestation of sickle cell disease is massive fatal intracranial hemorrhage. This is typically subarachnoid, but m a y be intracerebral, subdural or epidural. The mechanism is obscure but it is known that in patients in sickle cell crisis venous dilatations and capillary ectasias appear. There also is a swelling of the endothelium. Areas of focal damage of vascular walls m a y then occur, leading to rupture. At least two patients have been reported to have bled from ruptured aneurysms. There are now several reports of neurologic deficits occurring following hyperventilation in patients with sickle cell disease. This procedure should be avoided during electroencephalography. Idiopathic thrombocytosis, although rare, has been associated with cerebral symptoms in both children and infants; the latter group also shows evidence of myocardial infarction. Presentation in the infants was with coma, slurred speech and blindness. Idiopathic thrombocytopenic purpura m a y be associated with intracranial hemorrhage, although incidence figures vary from 1 to 9%. In the majority of children who have central nervous system bleeding, this occurs in the first month of the disease. Children with hemophilia do not have intracranial hemorrhage frequently (2-7%), but when it occurs it is quite serious and is often precipitated by trauma. Nearly 40% of deaths directly related to the hemophilia are due to this cause. TM The bleeding is usually intracerebral and epidural hematomas are frequent. Leukemia involving the central nervous system has m a n y modes of presentation the most devastating of which is intracranial hemorrhage. 17 This is the principal cause of death in leukemia in m a n y series. Hemorrhage tends to be multifocal and involve the brain parenchyma, subarachnoid and subdural spaces. There is usually also hemorrhage involving other organ systems. The pathogenetic mechanisms are complex. Thrombocytopenia plays an important role but m a y be mainly involved in contributing to the bleeding once it starts. Leukemic white cells can form an infiltration around blood vessels which gives a focus for the hemorrhage. If there is a severe leukocytosis with white cell counts above 100,000/cu mm the patient is at great risk for a hemorrhage. Increase in blood viscosity m a y be the crucial factor. The dural sinuses m a y become involved with leukemic infiltrates, and occlusion of the superior sagittal sinus has been reported. Sinus thrombosis m a y not be recognized, b u t could provide an explanation for increased intracranial pressure in those cases in which no other cause could be documented. 13

CONGENITAL HEART DISEASE The associations of cerebrovascular disease and congenital heart disease are well known and understood in reasonably detailed fashion. Three groups can be defined: vascular problems primarily due to the disordered circulatory and hemodynamic relationships, is those due to secondary medical problems dependent on the presence of the congenital lesion such as subacute bacterial endocarditis and those t h a t are complications of surgical corrections of the cardiac malformation. 19 Children with cyanotic lesions are at highest risk, and between 1.5 and 3% will develop a cerebrovascular accident. Both arterial and venous thromboses are found a l t h o u g h t h e predominant lesion is venous thrombosis. The young child, especially in the first year of life, is at highest risk. An additional risk factor appears to be hypochromic microcytic anemia. Since both hemoglobin and hematocrit levels may be normal, examination of a blood smear and measurement of red cell indices is necessary. Tetralogy of Fallot and transposition of the great vessels are the most frequently encountered cardiac lesions. Hemiparesis and seizures are often accompanied by irritability, vomiting and lethargy. Progression to coma m a y occur and death m a y follow bradycardia and apneic spells. Increased intracranial pressure is frequently present. Dilatation of scalp veins is a useful clinical sign. Acyanotic lesions m a y also be associated with central nervous system problems. Coarctation of the aorta and intracranial aneurysms or embolism have been reported. Thrombotic involvement of the carotid artery also occurs. Uncontrolled hypertension leading to hypertensive encephalopathy in children is rare. Subacute bacterial endocarditis is rare in children; only 4% of cases occur before age 15 years. The symptoms do not differ from those in adults. A serious complication is the development of mycotic aneurysms which appear at the site of an infected embolus. They are typically found on branches of smaller peripheral arteries, especially in the distribution of the middle cerebral artery. Rupture is a major hazard with the sudden onset of focal neurologic signs and symptoms and evidence of subarachnoid hemorrhage. Treatment is surgical. There are a number of reasons for the development of central nervous system lesions following surgical correction of congenital h e a r t disease. Many are related to the introduction of foreign substances or thrombi during open h e a r t procedures with or without circulatory bypass. Both hypotension and severe hypot h e r m i a have been followed by neurologic residua. A most interesting pathogenetic chain of events has been reported following the Blalock-Taussig procedure for correction of tetralogy of Fallot. The altered hemodynamic relationships set 14

up a subclavian steal which then produces vertebrobasilar insufficiency and basilar artery thrombosis. A typical brain stem stroke occurs, which has been, on occasion, associated with the locked in syndrome. INTRAORAL TRAUMA The relatively exposed position of the carotid arteries within the tissues of the posterior pharyngeal wall make them easily susceptible to trauma, e~ The most common mechanism is t h a t of the child falling on a pencil or other object protruding from the mouth and injuring the posterior portion of the pharynx. Typically there is a latent interval of 3 - 24 hours and then the onset of a neurologic deficit which m a y be catastrophic in nature. Up to 30% of the patients die and m a n y of the survivors are left with a permanent deficit. The mechanism in the minority of cases is formation of a perivascular h e m a t o m a with compression of the carotid artery. The majority of cases, however, involve an intimal tear with formation of a thrombus. This may remain localized, cause embolization or produce dissection of the intima which progresses into the intracranial blood vessels. This then leads to a major hemispheric infarction. The same mechanism m a y be triggered less commonly by blunt t r a u m a to the external neck or by a whiplash mechanism. DRUG ABUSE Carotid artery occlusion following the ingestion of lysergic acid diethylamide and carotid spasm following intravenous heroin injection have both been reported but appear to be infrequent.' Vasculitis associated with central nervous system pathologic conditions has been documented following drug abuse with a number of agents. These have included intravenous injection of methamphetamine, lysergic acid diethylamide, cannabis extracts and heroin. HOMOCYSTINURIA The classic form of homocystinuria is associated with a defect in cystathionine synthetase activity and can be diagnosed by the use of the nitroprusside reaction which detects the excessive quantities of homocystine in the urine. This is the second most common inherited aminoaciduria, r a n k i n g only behind phenylketonuria. In addition to the fair skin coloration, marfanoid habitus and ectopia lentis, there are spontaneous thromboembolic accidents. 2' Involvement of cerebral arteries is common, with 15

production of focal neurologic deficits. There is some controversy as to whether the major problem lies in increased platelet adhesiveness or abnormalities in the intima of the affected vessels. MIGRAINE SYNDROMES

Transient neurologic disturbances are a well recognized part of the migraine diathesis and are the h a l l m a r k of classic migraine. 22 The symptoms m a y be referable to either the carotid or the vertebrobasilar circulation and almost always remit sponta.neously and completely. One of the more typical syndromes is t h a t of hemiplegic migraine. This can exist in either sporadic or familial forms. The sporadic type appears to be associated with an increased risk of development of a fixed neurologic deficit. Migraine should always be considered in the differential diagnosis of transient focal neurologic signs in children, and both the child's history and the family history of headache should be reviewed closely. The syndrome of alternating hemiplegia beginning before 3 years of age m a y also have a cause related to migraine. 23 The abrupt onset of neurologic signs is soon followed by contralateral headache. Recovery occurs in periods ranging from several hours to several days. Some patients have seizures at the onset which causes confusion with the syndrome of acute infantile hemiplegia. Attacks become less frequent with age but several patients were left with residual neurologic signs including retardation and dyskinesia. Symptoms of basilar artery dysfunction also occur as a migraine variantY 4 The child presents with the sudden onset of symptoms of a brain stem stroke including vertigo, cerebellar signs, pyramidal tract signs, extraocular palsies and loss of consciousness. These are present in any combination. There is rapid recovery without residua and the child m a y or m a y not have a headache. A family history of migraine is generally found, especially on the m a t e r n a l side. INFECTIONS

P u r u l e n t venous thrombosis is largely restricted to young infants, who are often febrile and dehydratedY ~ Symptoms generally appear with a calamitous onset, heralded by seizures, either focal or generalized. The child becomes irritable and t h e n further obtunded with evidence of increasing intracranial pressure. L u m b a r puncture reveals blood-tinged xanthochromic fluid with elevated protein and increased pressure. Death m a y occur and the great majority of survivors will be left with significant residua. In older children specific venous structures m a y be affected by 16

localizing infections of the head and face, mastoids and paranasal sinuses. P u r u l e n t involvement of the paranasal sinuses can extend into and involve the cavernous sinus. There is a typical constellation of symptoms, the most prominent of which are proptosis, chemosis and ophthalmoplegias. Papilledema and retinal hemorrhages are present and the patient appears septic. Lateral sinus thrombosis is a complication of mastoiditis. The symptoms are more insidious t h a n those of cavernous sinus thrombosis, and the only manifestation m a y be increased intracranial pressure. Arterial structures can also be directly involved by pyogenic infections. Bacterial meningitis, especially in those cases in which there has been a delay in treatment, has produced multiple focal areas of arteritis with thrombosis of intracranial vessels. 2~ The angiographic picture is quite characteristic. TRAUMATIC INTRACRANIALHEMORRHAGE Craniocerebral t r a u m a does not cause strokes in children in the usual sense but it is important in the differential diagnosis of the child with bloody cerebrospinal fluid with or without a focal neurologic deficit. Traumatic subarachnoid hemorrhage by itself is of no significance; it gains importance only as a function of the underlying damaged brain. The injury may be insignificant or have produced a cerebral contusion or laceration. These lesions give focal neurologic signs, depression in the state of consciousness and, in some patients, seizures. If a significant intracerebral or extracerebral hematoma is present, surgery is indicated, although at t h a t point survival is jeopardized with or without operative intervention. Epidural hematoma is relatively uncommon in children. 27 The classic course of initial loss of consciousness, lucid interval and secondary unconciousness is also unusual in the pediatric age group. The lucid interval is often absent; the child either remains unconscious from the time of the injury or only becomes unconscious after a delay. One half of patients will not have a definable fracture of the cranial vault. Signs are not specific but consist of a depressed state of consciousness, focal neurologic abnormalities and findings of external t r a u m a to the head. If epidural hematoma is suspected initially, or if the patient's condition deteriorates, diagnostic studies should be carried out as an emergency, and surgical intervention is m a n d a t o r y if a h e m a t o m a is found. Chronic subdural h e m a t o m a has its highest incidence in infancy. The presentation may be subtle with failure to thrive or vomiting. Other infants have more dramatic s y m p t o m s - s e i zures, rapidly increasing head circumference, anemia and retinal hemorrhages. 17

The pathophysiology of these hematomas is not fully defined. T r a u m a is considered to be the precipitating event, although a history of head injury m a y not be obtainable. Persistence and growth of the lesion seem to require pathologically permeable capillary endothelium in the membranes t h a t form around the clot. Repeated small hemorrhages m a y also play a role. Proper treatment has been a source of controversy and has passed through several phases. 2s Initially it was felt necessary to perform repeated needle punctures and drainage of the lesions. If the fluid recurred, surgery was carried out to remove the membranes. This latter procedure then was discarded by m a n y surgeons who took a more conservative approach and placed a shunt from the h e m a t o m a to the peritoneal cavity. There is now good evidence t h a t it is only necessary to tap the collection if symptoms are present or if there is increased intracranial pressure or an abnormally increasing head circumference. Taps are done on a symptomatic basis and the lesion is allowed to resolve on its own.

INTRACRANIAL BLEEDING IN THE NEONATE If these problems are considered under the general category of cerebrovascular accidents, they account for approximately 25% of cases. The typical lesions t h a t are found are highly age-specific and can be considered in two groups. Premature infants typically have intraventricular hemorrhage, whereas full-term infants more frequently have bleeding caused by birth trauma. INTRAVENTRICULAR HEMORRHAGE IN THE PREMATURE INFANT

A frequent terminal event for the premature infant is the sudden development of intraventricular hemorrhage. 29 The typical clinical picture is t h a t of a small premature infant with respiratory distress, frequently due to hyaline membrane disease. The infant is usually male and in addition to being prem a t u r e m a y be small for gestational age. During the first 2 days of life he will suddenly develop lethargy, become hypotonic and have a seizure. Cyanotic attacks, hyperpyrexia and feeding difficulties are present. A rapidly falling hematocrit is found. The great majority of the infants will die, and most of the survivors will have severe residua including spastic tetraplegia, mental retardation and hydrocephalus. The pathophysiology of this condition is now fairly well defined.3~ The infant has anoxia because of the respiratory problems. Circulatory failure ensues which in t u r n leads to thrombosis of deep cerebral veins and hemorrhagic infarction of the highly cellular subependymal germinal cell layer. This area of necrosis can extend and involve deep structures or it m a y progress 18

through the ependymal lining and produce intraventricular hemorrhage. Brain edema and the progression of the hemorrhage through the ventricular system produce compression of the brain stem and death. A more recently defined syndrome is t h a t of massive cerebellar hemorrhage in low birth weight infants. The consistent clinical features are repeated episodes of apnea associated with a major fall in hematocrit. Subarachnoid hemorrhage and, in some cases, intraventricular bleeding are found. The majority of affected infants have had birth t r a u m a or perinatal asphysia and so these stresses m a y be important to the pathogenesis. INTRACRANIAL BLEEDING IN THE FULL-TERM INFANT

Intracranial hemorrhage also counts for a significant percentage of the deaths in this age group. 31 The usual cause is obstetrical trauma. The bleeding results from tearing of major cerebral veins or dural sinuses. The infant manifests the results of the t r a u m a immediately, and this may be one cause of failure to initiate respirations in a full-term infant. No specific clinical signs can be outlined, and death generally occurs within 1 or 2 days.

DIAGNOSTIC APPROACH The diagnostic approach to the child who has had a stroke revolves around determining the answers to a series of questions. 1. Is the cerebrovascular accident primarily vascular disease, or is the event secondary to some systemic illness? 2. Has the incident been associated with a significant degree of subarachnoid hemorrhage? 3. What is the extent of the central nervous system damage? 4. What is the specific vascular pathology? It should be obvious t h a t statements concerning treatment, recovery potential, and long-term prognosis are secondary d a t a t h a t can be extrapolated from the pathophysiologic questions. The search for an underlying illness cannot be easily outlined because of the multiplicity of causes, but the major categories of concern have already been discussed. The most important information can be derived from a complete and detailed analysis of the patient's past medical history, the details of onset and progression of the vascular accident and a thorough physical examination. Historical data should include a careful assessment of the family history, especially in those instances where the vascular symptoms were transient. Complicated migraine can have manifold manifestation and historical clues m a y be most useful. Routine laboratory work t h a t is obtained without the direction 19

t h a t comes from the history and examination is of little use. Certain obvious things such as obtaining a sickle cell preparation in black patients need to be done. For these reasons, no ~screening tests" or ~routine test battery" can be recommended. There is some controversy about the need to document the presence of subarachnoid hemorrhage. One a r g u m e n t states t h a t all data t h a t can be safely obtained are important and t h a t this may give a framework in which to interpret other neurodiagnostic studies. For example, a patient with subarachnoid hemorrhage but with a normal cerebral angiogram is still suspect for the presence of an aneurysm or arteriovenous malformation. The other a r g u m e n t states t h a t the neurodiagnostic studies give primary data and so they are all t h a t is needed. The approach outlined here suggests a lumbar puncture in the majority of patients who do not have either evidence of increased intracranial pressure or clinical evidence of a progressive mass lesion such as a hematoma in the temporal lobes or the posterior fossa. As stated, it is important to have the m a x i m u m amount of relevant information that can be obtained safely. A strong presumption of subarachnoid hemorrhage can be made on the basis of certain clinical features. The most prominent sign is the sudden onset of a severe generalized headache which the patient will characterize as being different t h a n others in the past. Associated features include lethargy, irritability and photophobia. Meningeal signs such as nuchal rigidity, Kernig's sign and Brudzinski's sign soon develop. If there is a good deal of blood in the subarachnoid space or if there is a vascular malformation involving the spinal cord, back pain with lumbar radicular signs occurs. If a decision to carry out a lumbar puncture is made, it is imperative t h a t it be performed properly and t h a t specimens be handled expeditiously. Hazard can largely be avoided by initially determining if the patient has markedly increased intracranial pressure or a progressive mass in the temporal area or posterior fossa t h a t might lead to a herniation syndrome. A plan of action should be developed so t h a t the m a x i m u m information can be obtained from a m i n i m u m of fluid. Every effort should be made to perform the puncture with as few attempts as possible. Immediately after the needle is in place a m a n o m e t e r should be attached so t h a t the pressure can be measured. If it is unexpectedly elevated, the fluid within the manometer can be saved for cell count and the needle withdrawn immediately. If the pressure is normal, several cubic millimeters of fluid can be t a k e n for analysis. At least three tubes should be obtained if the fluid is bloody, so t h a t comparative cell counts in the first and final tubes can be made. If the fluid clears completely it indicates t h a t the tap was traumatic, but if clearing is only partial no firm conclusion can be drawn. There is only one way to prove conclu2o

sively that blood in the cerebrospinal fluid was not introduced during the lumbar puncture and that is to demonstrate that the supernatant, after centrifugation in a small test tube, is xanthochromic. A microhematocrit tube is inadequate. The fluid will become pink because of the presence of oxyhemoglobin within approximately 2 - 4 hours after a subarachnoid hemorrhage, and begin turning yellow within about 8 hours. Although m a n y laboratories persist in reporting the percentage ofcrenated red blood cells, this is valueless information. Crenation depends only on the relative osmolalities of the red cell contents and the spinal fluid and the absence in the fluid of lipids that are necessary to stabilize the structure of the red cell membrane. The extent of the central nervous system damage can be generally determined from the neurologic examination, b u t another dimension is added if the anatomical limits can be defined. This may also clarify the degree to which the neurologic deficits represent affected brain and the part played by surrounding edema. Further studies are also useful in delineating hematomas, both intracerebral and extracerebral. The procedures available include radioisotope brain scans, computerized transaxial tomography and cerebral angiography. Radioisotope brain scans have limited value since the development of the newer radiographic techniques. Definition is not as good and an additional problem is that infarcted brain m a y not pick up the radioisotope for a period of as long as one week after the accident. Dynamic scans m a y assist in giving information on the relative blood flow of the two hemispheres, b u t would provide only redundant information if angiography is planned. The major advantage of isotope studies is that they are relatively noninvasive. Computerized transaxial tomography is the most useful procedure currently available to outline the extent of the damage and the surrounding cerebral edema. It also will clearly define areas of major hemorrhage and both intracerebral and extracerebral hematomas. With contrast enhancement it is a good method for determining the presence and extent of arteriovenous malformations. The major limitation of the procedure is the difficulty in defining lesions that lie in close approximation to bone, especially at the base of the skull. Cerebral angiography was for a long period of time the major procedure used to outline the extent of the lesion. Although this role has been taken over by computerized tomography, angiography remains the only procedure giving clear definition of the detailed vascular pathologic condition. It is probably indicated in any child with a completed stroke, and certainly one unassociated with underlying systemic disease. If the cerebrovascular accident is secondary to another condition, the procedure is not mandatory b u t it still m a y be useful. A femoral or brachial approach is the 21

most useful in children and is somewhat easier than direct carotid puncture. This route allows definition of all of the major blood vessels if it should prove necessary, and in addition allows visualization of the bifurcation of the carotid arteries. A difficult problem is that of the child with repeated episodes of neurologic dysfunction with rapid recovery. If there is not good evidence for an underlying medical condition, and if there is no strong suspicion of complicated migraine, angiography should be carried out. Although seizures m a y occasionally mimic transient ischemic attacks, this is generally not the case. THERAPY The major issue in treatment is the delineation of an underlying medical condition and institution of specific therapy, if available. Although this probably will n o t significantly modify the outcome of the cerebrovascular accident, further progression or recurrence might be prevented. Other aspects of t r e a t m e n t include the acute m a n a g e m e n t of both the cerebral and vascular pathology and the long-term t r e a t m e n t of secondary complications that can increase the patient's functional disability. ACUTE TREATMENT--CEREBRAL PATHOLOGY

There are three major problems, other than the presence of the neurologic deficit, that require evaluation and, under certain circumstances, treatment. These are the development of cerebral edema, the presence of intracerebral or extracerebral hematomas and the occurrence of seizures. Cerebral edema surrounds every area of acute necrosis of brain tissue, but it is not often severe enough to produce a herniation syndrome with cerebrovascular accidents. It will affect the patient's level of consciousness and severity of the neurologic signs, making both evaluation and clinical care more difficult. The edema following a stroke is vasogenic due to increased permeability of brain capillary endothelial cells and primarily involves white matter/2 Many neurologists use corticosteroids to treat the edema, b u t firm evidence for their efficacy in these conditions is minimal. This may be due to delay in starting the steroids after the insult m a x i m u m benefit requires prompt administration. Osmotically active agents such as mannitol will provide an acute therapeutic effect by reducing the volume of the surrounding normal brain tissue. It is difficult, however, to sustain this over a period of several days. In addition, mannitol can leave the injured vascular system and enter the necrotic area, increasing the potential for a rebound effect. Fluid restriction plays an important role in minimizing cere-

22

bral edema. The patient's weight, urine volume and specific gravity, and serum sodium and osmolality should be followed carefully. This will also allow prompt recognition of inappropriate release of antidiuretic hormone. The fluid restriction already instituted will prevent unexpected overhydration and hyponatremia. Major restriction of fluids would be inappropriate in patients with sickle cell disease. Another useful therapeutic modality for short-term t r e a t m e n t of cerebral edema is hyperventilation, which constricts cerebral blood vessels, decreases cerebral blood flow, and decreases the volume of blood within the cranial cavity thereby lowering the intracranial pressure. An effective level is a Pco2 of 20 m m Hg. It is important to m a i n t a i n good oxygenation to prevent hypoxia. Although there is theoretical concern about increasing infarction in partially compromised areas, this has not proven to be a clinically significant problem. As previously noted, hyperventilation should be avoided in sickle cell disease. Hypothermia is another clinically useful method of lowering intracranial pressure. Therapeutic hypothermia is difficult to institute and m a i n t a i n and is a particular problem in young children. Shivering must be avoided and chlorpromazine is useful in t h a t capacity. The child should not be allowed to m a i n t a i n an abnormally elevated body temperature even if therapeutic hypot h e r m i a is not used. The presence of a hematoma, either intracerebral or extracerebral, can be diagnosed rapidly and with a high degree of accuracy by using computerized tomography. The m a n a g e m e n t of nontraumatic intracerebral hematomas remains a controversial issue. Although a priori it would make sense to remove this obvious mass, the survival rate is low for patients with major hematomas whether or not surgery is done. If the clot is associated with a ruptured aneurysm, the two problems are generally attacked at the same time. Extracerebral hematomas fall into several groups. Epidural clots are almost always symptomatic and progressive. Surgical results are uniformly good if brain herniation has not developed and if the underlying lesion has not caused major brain damage. Acute subdural hematomas generally are associated with a severe pathologic condition, either cerebral laceration or a severe contusion. For this reason the evacuation of the clot is rarely associated with major improvement in the patient's clinical status. Chronic subdural hematomas are unusual complications of cerebrovascular disease in children. An increasingly conservative approach to therapy has developed. If the child is asymptomatic and there is no evidence of increased intracranial pressure, he should be followed and the collection need not be tapped, shunted or drained. 2s 23

The acute m a n a g e m e n t of seizures adds an important aspect to care because anoxia during convulsions can increase cerebral edema and potentially could increase the extent of compromised brain tissue. 33 If the child presents in status epilepticus, the most rapid and efficacious drug is diazepam 0.3 mg/kg given intravenously at a rate of 5 mg/minute. The effect ofdiazepam is often short-lived and so the child should receive coverage with a longer acting anticonvulsant. Phenobarbital given in a loading dose of 6 mg/kg parenterally is effective but it causes sedation in some children and can interfere with clinical assessment of the state of consciousness. Phenytoin, at the same dose level, does not have this problem but it is not efficacious as rapidly. It has the potential advantage of preventing inappropriate secretion of antidiuretic hormone. Phenytoin must be given intravenously because absorption from intramuscular sites is poor and irregular. Seizure prophylaxis should be continued in those children who have had a convulsion. Phenobarbital or phenytoin in doses appropriate for age and weight are both satisfactory. If the child has not had a convulsion, there is no strong indication for instit u t i n g anticonvulsant prophylaxis. ACUTE TREATMENT--VASCULAR PATHOLOGY Experience with the medical t r e a t m e n t ofcerebrovascular disease in children is limited. Anticoagulants have not proved to be useful in completed strokes and they m a y increase the risk of extension with a hemorrhagic lesion or conversion of a bland infarction into a hemorrhagic infarction. If thromboemboli from a defined source, such as aortic or mitral valve prosthesis, are involved, anticoagulation is appropriate. Specific medical conditions associated with a hypercoagulable state are another indication for treatment. The issue of transient ischemic attacks is rarely an important one in children and the cause is not likely to be atheromatous. Specific causes should be sought and anticoagulants used only if indicated. There is little use in pediatrics for vasodilating drugs. In addition, clinical experience is extremely limited. The comparatively low incidence of cerebrovascular disease in children has made it difficult for any one center to obtain extensive surgical experience with a homogeneous group of patients. Carotid occlusion is most frequently inflammatory in origin, and in other cases, traumatic. The results of surgical thrombectomy do not provide a good deal of encouragement. Surgery after a stroke is completed should not be expected to lead to major improvement and transient ischemic attacks are unusual in children. The same issues and problems are relevant to surgical ap24

proaches to intracranial vessels. Neither thrombectomy nor anastomoses of external carotid blood supply to internal carotid branches have proved to be useful. The t r e a t m e n t of arteriovenous malformations and aneurysms has been discussed. LONG-TERM TREATMENT The medical, nonrehabilitative aspects of t r e a t m e n t are import a n t in the m a n a g e m e n t of a child with a stroke, since problems such as uncontrolled seizures, abnormal behavior and hydrocephalus can produce further deficits in functional ability. The incidence of seizures in the child with an acquired hemiparesis ranges from 40 to 70% in different series. The risk is greatest in the younger child, especially if the cerebrovascular accident occurs within the first 2 years of life. If seizures have not occurred by early adolescence, they are unlikely to appear at any time. The presence of focal spikes on the electroencephalogram is a second factor predictive of the later onset of a convulsive disorder. Before age 2 years this abnormality increases the risk of seizures from 18 to 56%. Focal spikes on the electroencephalogram predict a 40% incidence of seizures if they are present after age 2 years. If the electroencephalogram is normal in a child older t h a n age 2 years, the risk is only 2%. The therapy of seizures is straightforward but may be diffic u l t y An attempt at using one drug, either phenytoin or phenobarbital, is appropriate. Phenobarbital must be approached with some caution because children with organic brain damage may become hyperactive and irritable. If the drugs, alone or together, do not control seizures, mysoline should be substituted for the phenobarbital and then carbamazepine can be added. With continued failure to control symptoms it may be necessary to go either to secondary drugs or to newer agents such as some of the diazepate congeners and sodium valproate. The latter should be available in this country in the near future. The same general principles of m a n a g e m e n t hold t h a t are used for any child with a convulsive disorder. Drugs should be used singly or in combination with as few others as possible. Changes in regimen should be made in only one medication at a time or it becomes difficult to ascribe changes in clinical status to changes in drug. It also is important to wait long enough between changes, especially following the institution of a new compound, so t h a t an adequate therapeutic level can be obtained. The most important aid in the m a n a g e m e n t of antiepileptic drugs is the availability of anticonvulsant blood levels. This provides assurance t h a t adequate concentrations are present and helps the physician monitor patient compliance. Drug interac25

tions, such as the increase in barbiturate levels if sodium valproate is added, can be monitored and proper dose adjustments made. Early warning of toxicity also becomes possible. It is difficult to detect minor changes in motor function due to drug toxicity in a patient who already has a major motor deficit. Despite the use of new medications and m e a s u r e m e n t of blood levels, there are some patients whose seizures are drug-resistant and in whom this becomes the major factor limiting the child's functional abilities. Social normalization and school performance present great difficulties if there are uncontrolled convulsions. Even the severely handicapped, severely retarded child can be cared for more easily if seizures are under reasonably good control. Many other patients may be brought under adequate control only with toxic levels of medication which cause obtundation, learning problems and increased motor disability. Some of these patients can be considered for hemispherectomy24 The best candidates are school-age and early adolescent children who have, in addition to the seizures, a severe hemiparesis and a personality disorder. The procedure itself is associated with a low mortality rate and the effectiveness may be striking. If seizure control is obtained, drug doses can then be reduced and in some cases medication can be discontinued. Long-term morbidity can introduce new problems the most common of which are repeated episodes of subarachnoid hemorrhage and the development of hydrocephalus. There are several new surgical approaches being applied to the patient with intractable seizures. Several children have had corpus callosum section with good initial results. 3~It is still too early to assess the long-range usefulness of this procedure. Behavior problems are another area in which drug t r e a t m e n t can play a useful role. The behavioral symptoms vary; some of the most common are hyperactivity with a short attention span and negativistic acting out. Some of the problems of the inattention syndrome m a y improve following t r e a t m e n t with s t i m u l a n t drugs. Both methylphenidate and dextroamphetamine are equally effective and associated with similar side effects. Many parents are concerned about the use of amphetamines and find methylphenidate more acceptable. Experience with pemoline is still not extensive. There is no contraindication to using any of these drugs in patients with a convulsive disorder. Medical therapy for the child with aggressive acting out has met with little success. Stimulant drugs may accentuate the behavior and large doses of major tranquilizers either do not improve the situation or cause unacceptable levels of sedation. They also lower the seizure threshold in some patients. The most consistently useful techniques have included behavior modification and parent training. One other area of neurosurgical m a n a g e m e n t is in the treat26

ment of hydrocephalus secondary to intracranial bleeding in infants. This is most frequent in the small number of premature infants who survive central nervous system hemorrhages. They tend to show slow growth of head circumference when they are sick and a rapid increase as they improve, which diminishes the diagnostic usefulness of this clinical tool. Computerized tomography, repeated after a period of time in borderline situations, gives the most direct information. If the hydrocephalus is progressive, an appropriate shunt procedure is indicated. Rehabilitation is obviously important to maximize the child's future functional abilities. The issues, techniques and problems have been thoroughly covered by Molnar and Taft in this series of monographs? ~ PREVENTION There are fewer strategies to prevent cerebrovascular disease in children than in adults. Both atherosclerosis and hypertension, major causative factors in adults, are unusual in children. Any attempts at prevention must be aimed primarily at those systemic diseases that can be treated. Examples are the use of transfusion and the avoidance of hyperventilation in patients with sickle cell disease, careful monitoring and correction of hematocrit level and red cell indices in children with cyanotic congenital heart disease, and training children not to walk or run with objects in their mouths. REFERENCES 1. Gold, A. P., Challenor, Y. B., Gilles, F. H., Hilal, S. P., Leviton, A., Rollins, E. I., Solomon, G. E., and Stein, B. M.: Report of Joint Committee for Stroke Facilities. IX. Strokes in children (Part 1), Stroke 4:834, 1973. 2. Banker, B. Q.: Cerebral vascular disease in infancy and childhood. I. Occlusive vascular disease, J. Neuropathol. Exp. Neurol. 20:127, 1961. 3. Harvey, F. M., and Alvord, E. C.: Juvenile arteriosclerosis and other arteriopathies of childhood-six autopsied cases, Acta Neurol. Scand. 48:479, 1972. 4. Friede, R. L.: Developmental Neuropathology (New York: Springer-Verlag, 1975). 5. Solomon, G. E., Hilal, S. K., Gold, A. P., and Carter, S.: Natural history of acute hemiplegia of childhood, Brain 93:107, 1970. 6. Box, M., and Mitchell, R. (eds.): Acute Hemiplegia in Childhood, Little Club Clinics in Developmental Medicine, no. 6 (London: William Heinemann Medical Books Ltd., 1962). 7. Gibbs, F. A., Gibbs, E. L., Perstein, M. A., and Rich, C. L.: Electroencephalographic prediction of epilepsy as a complication of cerebral palsy, Neurology 13:143, 1963. 8. DeVivo, D. C., and Farrell, F. W.: Vertebrobasilar occlusive disease in children, Arch. Neurol. 26:278, 1972. 9. Golden, G. S., Leeds, N., Kremenitzer, M. W., and Russman, B. S.: The "locked-in" syndrome in children, J. Pediatr. 89:596, 1976. 10. Moyes, P. D.: Intracranial and intraspinal vascular anomalies in children, J. Neurosurg. 31:271. 1969. 27

11. Zeller, R. S., and Chutorian, A. M.: Vascular malformations of the pons in children, Neurology 25:776, 1975. 12. Erenberg, G., Rubin, R., and Shulman, K.: Cerebetlar haematomas caused by angiomas in children, J. Neurol. Neurosurg. Psychiatry 35:304, 1972. 13. Gold, A. P., Ransahoff, J., and Carter, S.: Vein of Galen malformation, Acta Neurol. Scand. 40 (Suppl. 11):1, 1964. 14. Amacher, A. L., and Drake, C. G.: Cerebral artery aneurysms in infancy, childhood and adolescence, Child's Brain 1:72, 1975. 15. Portnoy, B. A., and Herion, J. C.: Neurological manifestations in sickle cell disease with a review of the literature and emphasis on the prevalence of hemiplegia, Ann. Intern. Med. 76:643, 1972. 16. Silverstein, A.: Intracranial bleeding in hemophilia, Arch. Neurol. 3:141, 1960. 17. Pierce, M. I.: Neurologic complications in acute leukemia in children, Pediatr. Clin. North Am. 9:425, 1962. 18. Phornphutkul, C., Rosenthal, A., Nadas, A. S., and Berenberg, W.: Cerebrovascular accidents in infants and children with cyanotic congenital heart disease, Am. J. Cardiol. 32:329, 1973. 19. Terplan, K. L.: Patterns of brain damage in infants and children with congenital heart disease, Am. J. Dis. Child. 125:175, 1973. 20. Pitner, S. E . Carotid thrombosis due to intraoral trauma, N. Engl. J. Med. 274:764, 1966. 21. Schimke, R. N., McKusick, V. A., Huang, T., and Pollack, A. D.: Homocystinuria, JAMA 193:711, 1965. 22. Whitty, C. W. M.: Migraine variants, Br. Med. J. 2:38, 1971. 23. Verrett, S., and Steele, J. C.: Alternating hemiplegia in childhood: A report of eight patients with complicated migraine beginning in infancy, Pediatrics 47:675, 1971. 24. Lapkin, M. L., and Golden, G. S.: Basilar artery migraine: A review of 30 cases, Am. J. Dis. Child., in press. 25. Yang, D. C., Sohn, D., and Anand, H. K.: Thrombosis of the superior longitudinal sinus during infancy, J. Pediatr. 74:570, 1969. 26. Leeds, N. E., and Goldberg, H. I.: Angiographic manifestations in cerebral inflammatory disease, Radiology 98:595, 1971. 27. Hawkes, C. D., and Ogle, W. S.: Atypical features of epidural hematomas in infants, children, and adolescents, J. Neurosurg. 19:971, 1962. 28. McLaurin, R. L., Isaacs, E., and Lewis, H. P.: Results of nonoperative treatment in 15 cases of infantile subdural hematoma, J. Neurosurg. 34:753, 1971. 29. Fedrick, J., and Butler, N. R.: Certain causes of neonatal death. II. Intraventricular hemorrhage, Biol. Neonate 15:257, 1970. 30. Banker, B. Q., and Larroche, J. C.: Periventricular leukomalacia of infancy, Arch. Neurol. 7:386, 1962. 31. Natelson, S. E., and Sayers, M. P.: The fate of children sustaining severe head trauma during birth, Pediatrics 51:169, 1973. 32. Batzdorf, U.: The management of cerebral edema in pediatric practice, Pediatrics 58:78, 1976. 33. Dodson, W. E., Prensky, A. L., DeVivo, D. C., Goldring, S, and Dodge, P. R.: Management of seizure disorders: selected aspects, J. Pediatr. 89:527,695, 1976. 34. Wilson, P. J. E.: Cerebral hemispherectomy for infantile hemiplegia: A report of 50 cases, Brain 93:147, 1970. 35. Luessenhop, A. J., de la Cruz, T. C., and Fenichel, G. M.: Surgical disconnection of the cerebral hemispheres for intractable seizures: results in infancy and childhood, JAMA 213:1630, 1970. 36. Molnar, G. E., and Taft, L. T.: Pediatric rehabilitiation, Part I: Cerebralpalsy and spinal cord injuries, Current Problems in Pediatrics, Vol. VII, no. 3 (Chicago: Year Book Medical Publishers, Inc. 1977). 23

Tics, Twitches and Habit Spasms THE APPEARANCE OF ABNORMAL involuntary movements in a child is a frightening event for the patient, the parents and the physician. Although the most common diagnosis is tic, problems ranging from tension in school to the presence of a brain tumor m a y be involved. In fact, the movements m a y be as benign and universal as myokymia, the brief twitching of isolated muscle fasciculi experienced by everyone, or m a y be serious enough to herald a genetic and potentially fatal condition such as Wilson's disease. The differential diagnosis must be rapid and accurate and appropriate therapy and counseling must begin.

MOVEMENT DISORDERS The movement disorders are quite heterogeneous in clinical presentation, pathophysiology and response to t h e r a p y ) They are traditionally considered together for two reasons. First, they share certain clinical features. None of the conditions is under the patient's voluntary control except for relatively brief periods of time. The movement disorders are purposeless, they occur at rest but also m a y interfere with the accuracy of voluntary movements and they disappear during sleep. The second unifying concept is that they all represent dysfunction, either anatomical or neurochemical, of portions of the cortically originating extrapyramidal system. The initial differential diagnosis is based on clinical features. It is important to remember that although discrete definitions are put forth, it is often impossible to assign the patient to one group with confidence at the bedside. Tics Tics are frequently repeated, rapid, stereotyped movements. They are not rhythmic and the frequency varies greatly over time; they become worse under emotional stress. The muscles of the face and neck are involved most frequently b u t any muscle group can be affected. The movements are rotational and away from the midline. MYOCLONUS Myoclonic jerks are also rapid, stereotyped and nonrhythmic. The frequency varies but they often occur in flurries and are not highly responsive to emotional factors. Some types are precipitated by attempts at voluntary movement. Unlike tics, there is 29

no predisposition for any part of the body or muscle group, and the movements are in random directions in relation to the body axis. CHOREA

Unlike tics and myoclonus, chorea is not stereotyped in character but skips from one muscle group to another. There is variable frequency and no rhythmicity. Stress can increase the symptoms. The patient may convert the involuntary movements into pseudovoluntary movements; this is less common with tics. Frequently the face is involved. Movements of the limbs vary considerably in direction but may predominate in a plane at right angles to the body axis. BALLISMUS

This is the rarest of the involuntary movements in children. The wild, large amplitude flinging movements of the limbs are rapid, nonrhythmic and irregular. Although muscles at a single joint, usually proximal, are usually involved, the direction of motion of the limb changes and varies constantly. ATHETOSIS

Athetoid movements are slow, unlike all those listed above. They are continuous, not rhythmic, and are most prominent distally. The frequency and intensity increases when the patient is under stress. Although there is not stereotypy, prolonged observation shows a repetition of a general pattern within the larger variety of movements. The direction is most prominently axial and has a writhing character. DYSTONIA

These movements are even slower t h a n those in athetosis and may be maintained in a state of tension for prolonged periods of time. They are stereotyped in general and m a y involve the face, neck, axial musculature or limbs. The direction is not constant, although often it is rotatory. Stress accentuates symptoms. TREMOR

The distinguishing features of tremors are that they are rhythmic and stereotyped. They vary in speed and direction and often 30

involve the muscles around a single joint. Their location is most frequently distal. Some tremors increase in intensity when the patient is anxious. ACUTE DYSKINESIA This reaction to phenothiazine and butyrephenone drugs often involves children and adolescents. There is acute onset of involuntary movements, alterations in muscle tone and abnormalities of posture. Any portion of the body can be involved, facial and oral movements occur frequently. The movements are uncoordinated and resemble dystonia. Like dystonia they m a y have a stereotyped component. TARDIVE DYSKINESIA

Unlike the acute syndrome, this is rare in children. The movements are similar b u t start after long periods of t r e a t m e n t with high doses of the antipsychotic drugs. As a related problem, reduction of drug dose may lead to an emergent dyskinetic syndrome with buccolinguomasticatory movements and choreiform movements of the limbs. FOCAL SEIZURES Although not a movement disorder in the usual sense, focal seizures contribute to the differential diagnosis. When associated with an alteration in the state of consciousness, they present no particular difficulties. In some cases, however, there can be focal seizures that show no tendency to spread and are unassociated with any changes in the level of alertness or cognitive functions. These movements are regular and stereotyped and most closely resemble tremor, although the amplitude is generally larger. The difference is in the pattern. Seizures generally have a paroxysmal onset with periods of normality between episodes, whereas tremors are usually continuous. The difficulty is with extremely prolonged focal seizures. An electroencephalogram can provide important diagnostic assistance. MANNERISMS

Stereotyped mannerisms are frequently part of the behavioral repertory of retarded and psychotic children and are not among the movement disorders as defined. They are highly stereotyped and repetitive and often take certain characteristic forms. They include hand flapping, waving the hands in front of the eyes 31

and rocking. Some patients show the onset or accentuation of movements in specific environmental or social situations.

TIC DISORDERS Although a pathophysiologic classification of tic disorders does not exist, the disorders have been divided into three major groups depending on the nature of the primary symptoms and the associated symptoms. A new classification, being developed for the Diagnostic and Statistical Manual of Mental Disorders, third edition, should do away with some of the problems. Simple tic or habit spasm is the term applied if the patient has only one tic. This may be transient or life-long, and if transient can be replaced by other simple tics. A diagnosis of multiple chronic tics implies t h a t the tics are all motor, more t h a n one is present at any given time, and the condition is chronic. The repertory m a y change. It is difficult to divide clearly this syndrome from one in which only one tic is present at a time but is replaced by another type on a n u m b e r of occasions. If vocal tics are present in addition to motor tics, the term motor-verbal tic disorder is appropriate. This usage is equivalent to the Gilles de la Tourette syndrome and does not require the presence of associated features such as coprolalia and echolalia.

SIMPLE TICS AND MULTIPLE CHRONIC TICS CLINICAL FEATURES The majority of tics fall into these groups and the majority of patients have a single tic at any given point in time. 2 Eye blinks, either unilateral or bilateral, and rotatory movements of the head are most common. The shoulder is affected with the next greatest frequency and then the trunk, limb girdles and distal extremities. Movements are exacerbated by stress but persist even when the patient is relaxed. They stop during sleep. Voluntary suppression is possible for brief periods of time but there is then a rebound of activity. Symptoms are most frequent in boys. The appearance of tics is generally sudden and a given tic m a y appear with a frequency t h a t is maintained long-term. There often appears to be an environmental factor as the precipitating agent (e.g., hair in the eyes producing head jerking) but objective proof is difficult to obtain. Onset m a y also appear to follow the occurrence of a particularly emotionally disturbing event. The average age of onset is 7 years. Tics rarely appear before the age of 4 years, and almost never after late adolescence. The disorder does not cause any physical impairment of func32

tion but m a y make the patient withdraw from social contacts because of embarrassment. A cycle of anxiety, increased tic activity and further anxiety is easily effected. The situation of the individual with multiple motor tics is somewhat more complex. The tics m a y change in p a t t e r n without any apparent cause, substituting one symptom for another. At other times a new tic is added without loss of the previous one. The other features are the same as in those patients with single tics. INCIDENCE The incidence of tics is difficult to determine with any accuracy, due in part to their transient n a t u r e and the necessity of relying on historical data?' 4 Simple transient tics have been reported to occur in 4 - 23% of all children. The peak age of incidence is 6 - 7 years. No data on the incidence of multiple tics in an unselected population are available, and there is no good information on the prevalence of any of the tic disorders. There appears to be an increased incidence of tics within families. Children without tics have affected relatives in 10 - 14% of families, while children with tics have affected relatives in 38% of cases. ETIOLOGY The vast amount of literature on the etiology of tics provides psychodynamic explanations. 5 Although there have been m a n y formulations, most theories fit into one of two conceptual frameworks. Psychoanalytic studies are usually based on detailed analysis of individual cases. The tics are seen as being the symbolic representation of repressed desires or conflicts. The second major approach is derived from learning theory. It states t h a t tics are conditioned avoidance responses t h a t are initially evoked by stress and then reinforced by the reduction of anxiety. This psychological approach is supported by the following clinical features: 1. the occurrence, in some cases, of a traumatic emotional event precipitating the symptoms, and the exacerbation of symptoms in almost all patients when under stress; 2. the high incidence of associated emotional-behavior problems; 3. the frequent presence of family conflicts and parents with emotional difficulties; 4. the remission of symptoms in some patients during psychiatric or behavioral treatment; and 5. the absence of any clearly defined consistent neurologic abnormalities. 33

Evidence used to ascribe an organic basis to tics is generally based on analogies with other movement disorders. Evidence for this viewpoint includes6: 1. an increased incidence of prenatal and perinatal difficulties; 2. frequent histories of motor restlessness or hyperactivity; 3. nonspecific electroencephalographic abnormalities present more often than in a control group; 4. production of a tic syndrome in some patients treated with /-dopa; 5. reduction of symptoms during treatment with haloperidol; and 6. the absence of any clearly defined consistent psychiatric abnormalities. It should be obvious that the two potential etiologies are not mutually exclusive. This is discussed in more detail in the last section of this monograph. TREATMENT

Treatment strategies can also be divided into behavioral and organic approaches and obviously will vary according to which view of etiology is held. The classic approach is centered around the advice that the parents should ignore the child's tic, not call his attention to it and refrain from trying to convince him to stop the movements. This should help avoid accentuating the ticanxiety-tic cycle, and in fact, many simple tics will disappear when this approach is taken. It is known, however, that many tics stop spontaneously and there is no controlled evidence proving the efficacy of this simple therapeutic approach. Psychotherapeutic approaches have been based mainly on the psychoanalytic formulation of the underlying mechanism and have been directed to t r e a t m e n t of underlying disturbances. 5 There is also little controlled evidence, mainly because the literature focuses on individual case reports. One series shows no improvement in outcome with or without psychotherapy. A number of behavioral therapies have been used. In massed practice the child is made to voluntarily and deliberately reproduce the movement in an attempt to extinguish it. Operant techniques, adversive techniques, biofeedback and relaxation techniques have all been used, with some reports documenting successful outcomes and others, negative results. Unfortunately, it is not possible to obtain extensive data comparing any of these techniques to the rate of spontaneous remissions in controlled series. Drug t r e a t m e n t has been built mainly around the use of diazepam, phenothiazine tranquilizers and haloperidol, a butyrephenone derivativeY Diazepam is a potent anxiety-relieving agent but has proved to be of little use in the treatment of tics. 34

Chlorpromazine and other phenothiazine drugs are major tranquilizers, but they also provide little benefit, even when given in large doses. The greatest success rate has been with the use of haloperidol, a potent and highly specific postsynaptic dopamine receptor blocking agent. The major difficulty with this medication is obtaining a satisfactory therapeutic level while avoiding side effects. The most troublesome side effects are somnolence with concentration and memory difficulties and acute extrapyramidal reactions. These occur in up to one half of the treated patients. The most useful approach is to start with a small dose of the medication (e.g., 0.5 mg at bedtime) and increase at a rate of no more t h a n 0.5 mg every 4 - 5 days. PROGNOSIS

The disappearance of tics within several months of their appearance is a well-known phenomenon. 2 There are few large series, but a reasonable expectation would be t h a t over one h a l f of patients should show some improvement and another 40% complete remission. Those patients who do not have a remission within a brief period of time m a y lose their symptoms in late adolescence, a second peak time for spontaneous cure. The best prognosis is in the group whose symptoms appear between 6 and 8 years of age. The worst outlook is for those patients who have multiple tics or a constantly changing repertory. Aside from these rough guidelines, there are few criteria useful for predicting remission in any individual case. This makes counseling difficult. The high rate of improvement also calls for great caution in ascribing positive benefit to any t r e a t m e n t modality.

TOURETTE SYNDROME Tourette syndrome is not as rare as generally stated. It is seldom diagnosed promptly, is frequently misdiagnosed and is treated improperly w i t h great r e g u l a r i t y / The syndrome is named for the French neurologist who, in 1885, first reported eight patients with an u n u s u a l condition, s The primary symptoms were chronic multifocal motor tics and accompanying vocal tics. One half of the patients had coprolalia, the involuntary utterance of obscene or blasphemous words, and some had echolalia. Except for several brief reports, the condition dropped below the level of clinical recognition until 1946 when it was "rediscovered" and began to be reported in the psychiatric literature. The presenting complaint was almost always coprolalia. This was the symptom bringing the patient to psychiatric referral and it was felt to be the diagnostic key to the condition. In 1961 the beneficial effect of haloperidol on the symptoms was discovered. 9 Since t h a t time there has been an increasing body of 35

evidence t h a t the basis of the disease is organic and t h a t coprolalia is not a necessary symptom. The discussion below is based on the current view of the condition which is held by m a n y of those who have seen large numbers of patients. 7' lo CLINICAL FEATURES The diagnostic symptom complex is the presence of motor and vocal tics. The onset of symptoms in the typical patient is sometimes between 4 and 12 years of age, with a median of 7 years. A simple tic, often eye blinking or facial grimacing, first appears. This will then either be replaced by or supplemented with a second tic. Over a period of time the repertory will change and the severity of the symptoms will wax and wane. There m a y be transient complete remissions. As the motor tics progress some patients will go on to complex stereotyped movements. Some of the more common ones are squatting, skipping and hopping while walking. Simultaneous with the progression of the motor symptoms is the appearance of vocal phenomena. Frequently there is a nervous cough, sniffing or snorting sounds, and these m a y seem to be no more t h a n common childhood complaints. Some children do not go beyond this stage whereas others progress. The noises m a y become loud cries, yelps or animal sounds. There m a y be the utterance of articulate words and approximately 20% of children will have coprolalia. A smaller number show echolalia or palilalia. Although the typical progression of symptoms has been outlined, any given patient m a y have a very different pattern. The onset is occasionally explosive with the sudden onset ofcoprolalia or multiple motor tics. The more usual pattern is one in which the initial symptoms appear both common and benign. The misconception t h a t all patients m u s t be coprolalic frequently leads to a delay in diagnosis which averages 4 years. Eighty per cent of patients are still initially diagnosed by their parents, often from information in articles in the lay press or through the publicity efforts of the Tourette Syndrome Association.* Many patients will show one or more of a number of other unusual symptoms. There m a y be compulsive sniffing or licking or biting of objects or the patient's own hands. Rarely, this is severe and becomes self-mutilation. Compulsive touching of objects, people or self also occurs, and this often has a frankly sexual n a t u r e even in relatively young children. Compulsive rituals occur on occasion. A few patients complain of mental coprolalia, the interjection into their thoughts of obscene words. This symptom may occur with or without manifest verbal coprolalia. *Bell Plaza Building,42-20 Bell Boulevard,Bayside,N Y 36

11361.

Many of the children have a behavior pattern t h a t earns for them the label of ~'hyperactive." This is due to increased motor restlessness, impulsivity and a short attention span. Attempts to treat these symptoms with methylphenidate, dextroamphetamine or pemoline m a y lead to a severe exacerbation of symptoms. n The incidence of poor school performance is high and appears to be unrelated to the presence of the tics, as some of the children have had learning disabilities before the motor and vocal symptoms ever became manifest. INCIDENCE No community-wide data for either incidence or prevalence are available. Although Tourette syndrome is stated to be rare, this has not been the impression of those who have developed an interest in the syndrome and have been able to serve as referral resources. An international registry has shown t h a t the condition has a world-wide distribution. TM Family incidence was seen in approximately 25% of cases in an unselected series, and another 25% of families had individuals with multiple or single motor tics but without vocalizations. TM There is no clear cut ethnic preponderance. An increased frequency among Ashkenazic Jews m a y be a real phenomenon or an artifact of the referral population base involved in some of the largest series.14 ETIOLOGY It was postulated initially t h a t the condition is purely psychiatric in nature. 2 The tics were considered to represent hostile impulses. Coprolalia played the role of removing the individual from society, thereby reducing anxiety. Recent psychiatric and psychological studies of a large series of patients, however, have failed to reveal either a specific underlying personality structure or the presence of severe psychopathology in the majority of patients. Evidence for an organic etiology is accumulating rapidly. There has been no consistent structural pathologic condition, and so efforts have turned toward documenting a neurochemical base. The leading theory at this time is t h a t there is an increased turnover of central nervous system dopamine. Indirect evidence for this comes from several clinical experiences. The patients respond well to haloperidol,9 a potent dopamine blocking agent, and to pimozide, an experimental drug which is also a highly specific blocker of dopamine receptors. Many patients will tolerate very large doses of these drugs. Medications t h a t cause increased dopamine turnover, including the majority of central nervous system stimulants, will produce an exacerbation of 37

symptoms, and they have apparently triggered the onset of the condition in several children. H A Tourette-like syndrome can occur in parkinsonian patients given/-dopa. More direct evidence is now available. The rate of rise and final level of the acidic breakdown products of central nervous system biogenic monoamines can be measured in lumbar cerebrospinal fluid following the administration ofprobenecid. This drug blocks the transport of these substances through the choroid plexus into the bloodstream. An increased level of metabolite following probenecid treatment, compared to controls, indicates increased turnover of the amine being studied. Patients with Tourette syndrome show markedly elevated cerebrospinal fluid levels of homovanillic acid, which provides strong primary evidence for increased dopaminergic activity. '5 This hypothesis is appealing because two of the major dopamine systems of the brain are the nigrostriatal, a motor system, and the mesolimbic, a '~behavioral" system. TREATMENT

Psychiatric and behavioral approaches to t r e a t m e n t have been unrewarding, except in isolated cases. They are important in providing appropriate patients with support and helping them adjust to and live with their terribly trying symptoms. General reduction of anxiety, if achieved, m a y also help decrease symptoms to some extent. The only psychopharmacologic agent available in this country that has been consistently useful is haloperidol. TM It is used in the same manner as outlined in the section on simple and multiple tics. It m a y be necessary to use large doses to achieve reasonable control of symptoms, and these are better tolerated if the dose is increased slowly. Verbal tics generally respond promptly to relatively small doses but motor tics are more resistant. A common phenomenon is a breakthrough of symptoms following a period of good control on a stable level of medication. A response to a slightly larger dose is usually obtained, but not always. The patient m a y have to go through several cycles of breakthrough and increasing dose. It is not clear whether this represents the development of tolerance, a change in drug metabolism or a change in the severity of the underlying disease process. Overall t r e a t m e n t results show a good response in 85% of patients, but there is some level of undesirable side effects in almost one half. If extrapyramidal reactions occur, an antiparkinsonian agent can be added. It is not necessary to use these prophylactically, as the majority of the patients will not need them. It is often necessary to establish a compromise and it m a y be impossible to achieve complete suppression of symptoms. The 15% of patients who either do not respond or cannot tolerate 38

haloperidol are a troublesome group and often are the patients with the most severe symptoms. Occasional individuals respond to one of a variety of other agents such as diazepam, chlorpromazine or carbamazepine, but this is unusual. PROGNOSIS Data are now being accumulated on the long-term follow-up of both treated and untreated patients in an a t t e m p t to develop criteria upon which prognostic statements can be formulated. On the basis of anecdotal experiences, there are a small n u m b e r of patients who have a spontaneous and complete remission during late adolescence, independent of organic or psychological t r e a t m e n t and independent of t r e a t m e n t response. Many other patients have a great reduction in symptoms at the same period of life and then can cope without medication or with the use of medication only during periods of major stress. The only useful guideline is t h a t the more severely affected patients are probably less likely to improve, but this is by no means absolute. General adjustment, independent of t r e a t m e n t response or symptom remission, presents a mixed picture and depends on the individual's strengths and coping ability. Some patients bec o m e housebound and isolated with relatively mild tics, whereas others pursue business careers and professions in the face of more severe symptoms. Obviously, coprolalia or loud vocalizations puts the patient at a major social disadvantage.

SPECULATION The a r g u m e n t already has been presented t h a t despite any superimposed or intermixed psychologic factors there is a fundamental organic basis in Tourette syndrome. 1~ The evidence available is less secure for other tic syndromes. The hypothesis to be developed is t h a t the various tic syndromes, including Tourette syndrome, are not really distinct entities but represent increasing degrees of severity along the spectrum of a single pathophysiologic abnormality. If this were true, the implication would be that all the tic syndromes have a common organic basis. Corbett carried out an analysis of three groups of patients. 17 The first had vocal and body tics, the second vocal and multiple body tics and the third coprolalia and multiple body tics. The only differences of note were the increased percentage of males in the coprolalia group and an increasing age as one moved up from one group to the next. The author stated t h a t all the differences could be explained on the phenomenon of increasing age. His conclusion was t h a t there was no difference between the syndromes and t h a t there was no difference, except for the vocal tics and coprolalia, between these syndromes and simple tics. Similar 39

responses are found when patients are treated with haloperidol, behavior therapy and psychotherapy. The second line of evidence comes from family studies. As noted previously, there is a familial incidence of tic syndromes in about one h a l f of those families of children with Tourette syndrome.13, 14 In the families showing familial incidence, one-half have other affected individuals with Tourette syndrome and the remainder have chronic tics without vocalizations. Three families were found in which the propositus had Tourette syndrome, other members also had Tourette syndrome, and still others had chronic motor tics. Some of the families contained siblings or parents who had simple tics, which were either chronic or transient. This spread of clinical phenomena and symptom severity within single families suggests t h a t no f u n d a m e n t a l differences between the tic syndromes exist. F u r t h e r evidence comes from an examination of the usual evolution of symptoms in the child who eventually develops fullblown Tourette syndrome. The initial symptoms, simple tics, are identical to those in patients who never progress beyond t h a t stage. The portion of the body involved, frequency, character, response to stress and response to therapy are identical. It is only with further evolution t h a t the symptoms diverge. These three groups of data support the conclusion t h a t the tic syndromes are all manifestations of the same underlying process. If further evidence for an abnormality of dopaminergic systems in the central nervous system in Tourette syndrome can be obtained, the conclusion t h a t all of the tic syndromes are biochemically based can be tested more directly. Pharmacologic therapy appears to be biochemically specific. This does not negate the importance of secondary psychological factors which can be involved in the initial triggering of the condition and its worsening during periods of stress. Psychological therapy should be directed toward three areas. (1) The overall reduction of anxiety will help ameliorate those symptoms t h a t are increased by stress. (2) M a n y of the children m a y have psychological difficulties independent of the tic, and these should be treated if they are of great enough severity. (3) One of the most important areas of t r e a t m e n t is usually ignored. This is working with the patient on the feelings and disturbances t h a t develop when one's body is out of voluntary control and doing strange, bizarre and incomprehensible things. This is an area of major concern to all patients with Tourette syndrome and their families, and is of probably no less concern to any person with milder tic syndromes. REFERENCES 1. Lockman,L. A.: Movementdisorders, in Swaiman, K. F., and Wright, F. S. (eds.): The Practice of Pediatric Neurology (St. Louis:C. V. MosbyCo., 1975). 40

2. Corbett, J.: Tics and Tourette's syndrome, in Rutter, M., and Hersov, L. (eds.): Child Psychiatry: Modern Approaches (Oxford: Blackwell Scientific Publications, 1977). 3. Torup, E.: A follow-up study of children with tics, Acta Paediatr. 51:261, 1972. 4. LaPouse, R., and Monk, M.: Behavior deviations in a representative sample of children: variation by sex, age, race, social class, and family site, Am. J. Orthopsychiatr. 34:436, 1964. 5. Hersen, M., and Eisler, R. M.: Behavioral approaches to study and treatment of psychogenic tics, Genetic Psychol. Monogr. 87:289, 1973. 6. Abuzzahab, F. S., and Anderson, F. O.: Current knowledge of the syndrome, in Abuzzahab, F. S., and Anderson, F. (eds.): Gilles de la Tourette's Syndrome (St. Paul: Mason Publishing Co., 1976). 7. Golden, G. S.: Tourette's syndrome: The pediatric perspective, Am. J. Dis. Child. 131:531, 1977. 8. Gilles de la Tourette, G.: Etude sur une affection nerveuse, caracterisee par de l'incoordination motrice, acompagnee d'echolalie et de coprolalie, Arch. Neurol. 9:19, 158, 1885. 9. Seignot, J. N.: Un cas de maladie des tics de Gilles de la Tourette gueri par le R-1625, Ann. Med. Psychol. 119:578, 1961. 10. Shapiro, A. K., Shapiro, E., Wayne, H. L., Clarkin, J., and Bruun, R.: Tourette's syndrome: summary of data on 34 patients, Psychosom. Med. 35:419, 1973. 11. Golden, G. S.: The effect of central nervous system stimulants on Tourette syndrome, Ann. Neurol. 2:69, 1977. 12. Abuzzahab, F. S., and Anderson, F. O.: Gilles de la Tourette's syndrome: Cross-cultural analysis and treatment outcome, Clin. Neurol. Neurosurg. 1:66, 1974. 13. Golden, G. S.: Tics and Tourette's: a continuum of symptoms? Ann. Neurol. (abstract) 2:260, 1977. 14. Eldridge, R., Sweet, R., Lake, C. R., Ziegler, M., and Shapiro, A. K.: Gilles de la Tourette's syndrome: clinical, genetic, psychologic, and biochemical aspects in 21 selected families, Neurology 27:115, 1977. 15. Van Woert, M. M., Jutkowitz, R., Rosenbaum, D., and Bowers, M. B.: Gilles de la Tourette's syndrome: biochemical approaches, in Yahr, M. D. (ed.): The Basal Ganglia (New York: Raven Press, 1976). 16. Shapiro, A. K., Shapiro, E., and Wayne, H. L.: Treatment of Tourette's syndrome, Arch. Gen. Psychiatr. 28:92, 1973. 17. Corbett, J. A.: The nature of tics and Gilles de la Tourette's syndrome, in Abuzzahab, F., and Anderson, F. (eds.): Gilles de la Tourette's Syndrome (St. Paul: Mason Publishing Co., 1976).

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