Child's Nerv Syst (1991) 7:305-308 m NS 9 Springer-Verlag 1991 Idiopathic ischemic infarction of the brain stem in children Richard G. Curless Department of Neurology and Department of Pediatrics, University of Miami School of Medicine, Miami, FL 33101, USA Received January 8, 1991 Abstract. T h r e e cases o f i d i o p a t h i c b r a i n - s t e m i n f a r c t i o n are a d d e d to the l i t e r a t u r e o n 12 children. T h e r e is n o age p r e d i l e c t i o n , a n d the y o u n g e s t case is 3 y e a r s old. H o w e v er, there is a s t r i k i n g m a l e p r e p o n d e r a n c e o f 13:2. T h e r e s i d u a l n e u r o l o g i c a l deficit covers the r a n g e o f n o r m a l to q u a d r i p a r e s i s . L a b o r a t o r y studies i n v e s t i g a t i n g h y p e r c o a g u l o p a t h y , p l a t e l e t d y s f u n c t i o n a n d a t r i a l septal defect m a y p r o v i d e a n e t i o l o g y for s o m e cases in the future. Key words: B r a i n - s t e m i n f a r c t i o n - O c c l u s i o n - C o m p u t ed t o m o g r a p h y - M a g n e t i c r e s o n a n c e i m a g i n g - A n g i o g raphy T h e incidence o f b r a i n - s t e m i n f a r c t i o n s in c h i l d r e n is relatively low c o m p a r e d to t h a t in adults. H o w e v e r , b r a i n stem lesions w i t h o r w i t h o u t c e r e b e l l a r i n v o l v e m e n t represent a small p e r c e n t a g e in b o t h age g r o u p s [10]. R a d i o logical d e v e l o p m e n t s in the p a s t 15 y e a r s h a v e p r o v i d e d more accurate anatomical information and additional theories o f p a t h o g e n e s i s . R e c e n t experience in o u r center with two s c h o o l - a g e cases p r o m p t e d this review. A t h i r d case is a d d e d f r o m the p r e - c o m p u t e d t o m o g r a p h y (CT) era. A l t h o u g h n o e t i o l o g y c o u l d be identified in a n y o f the p a t i e n t s , the d i a g n o s t i c studies r e q u e s t e d reflect changing thoughts regarding possible mechanisms. Case reports Cases 1 12 Case 13 A 12.5-year-old black female was in good health until 10 h before admission on 5 June 1978 when she awakened, attempted to reach the bathroom, and was found on the floor, conscious but unable to walk. Two brief generalized clonic seizures developed in the 1st h. Past medical history revealed normal growth and development and good school performance. There were no prior seizures, head injuries, or periods of hospitalization. Her menarche began 2 days prior to admission. The family history was devoid of neurological problems including childhood or young adult strokes or seizures. Neurological examination demonstrated a flaccid quadriparesis with symmetrically active deep tendon reflexes and bilateral extensor plantar responses. Facial diplegia was present, and she refused or was unable to speak. Speech evaluation several days later suggested an unwillingness to speak because of severe dysarthria. Her blood pressure was 115/75, and her respiratory pattern was normal. She did not have a marfanoid habitus. Ocular examination was normal. CT scan with and without contrast was normal, but the posterior fossa views were of low resolution when compared with current CT technology. Spinal fluid analysis revealed no white blood cells or red blood cells, a protein of 16 mg/dl and glucose of 77 mg/dl. Stains and cultures of the cerebrospinal fluid were normal. Cerebral angiography obtained 3 days after admission demonstrated complete occlusion of the basilar artery just beyond the anterior inferior cerebellar arteries. The posterior cerebral arteries filled from the ipsilateral carotid vessels. No mass effect was present. Laboratory studies included urine negative for homocystine and sickle cell preparation. Clotting studies revealed a normal partial thromboplastin time (PTT) and platelet count. All cardiac studies were normal including auscultation, electrocardiography (ECG), echocardiography and a gated-flow study. On follow-up examination 3 years later she was ambulatory with a right hemiparesis and mild dysarthria. The left facial weakness and left Babinski sign were no longer present. No new neurological problems had developed. The data are summarized in Table 1. Case 14 Offprint requests to: G. Curless, Department of Neurology (Pediatric), University of Miami School of Medicine, Mailman Center, P.O. Box 016820, Miami, FL 33101, USA A 7-year-old male was brought to the hospital on 28 May 1986 with a history of collapsing to the floor and inability to arise without aid. At that time he was awake and talking. He complained of double vision and became increasingly lethargic. There was no history of prior significant medical problems. The family history revealed no neurological problems in children or young adults. 306 Table 1. Idiopathic brain-stem infarction in childhood. CT, Computer tomography; MRI, magnetic resonance imaging Author Case no. Age/ Neurological symptoms/signs sex (years) Diagnostic studies Outcome Fowler [8] 1 7/M Coma, miosis, left VII, bilateral CS tract signs Died of pneumonia 10 weeks after stroke Dooly and Smith [4] 2 6/M Ouvrier and Hopkins [221 3 9/M Angiogram: bilateral vertebral occlusion (complete on right) Moderate dysarthria and ataxia at 3 months 4 7/M Two brain-stem TIAs: weeks later hemiparesis, trunk and gait ataxia 3 months of brain-stem TIAs; III nerve, hemiparesis and ataxia Left hemiparesis, anisocoria Normal carotid angiogram; midbrain infarct on PM examination Angiogram: basilar art. occlusion DeVivo and Farrell [3] 5 10/M Marked incoordination of left arm at 12 months; Left arm ataxia at 12 months Latchaw et al. [18] 6 7/M Angiogram: left vertebral occlusion Angiogram: bilateral vertebral occlusion, left> right Angiogram: left basilar artery occlusion 7 ll/M Klein et al. [16] 8 8/M Pascual-Castroviejo et al. [24] Ackerman et al. [1] 9 3/M 10 10/M Mori et al. [21] 11 13/M Jain et al. [14] 12 16/F Curless (present study) 13 12/F 14 7/M 15 14/M 8 months of brain-stem TIAs; right hemiparesis and dysmetria Right hemiparesis, dysarthria and diplopia; much worse 48 h after admission Left hemiparesis; left XII; semicomatose. Mild head injury; 24 h PTA Vertigo, horizontal nystagmus, hemiparesis Bilateral VII; unable to stand; bilateral dysmetria Diplopia, vertigo, unable to stand. Recovered in 5 days; 10 days later: mute, quadriplegic and facial diplegia Right hemiparesis; aphonic Brain-stem TIAs for 2 months; dysarthria, ataxic gait, hemiplegia Sudden flaccid quadriparesis, bilateral VII, aphonic Drop attack progressing to coma; vertical nystagmus, quadriparesis Unable to walk or talk within minutes. LMN VII, left gaze preference, left hemiparesis On examination he was comatose with no response to verbal or visual stimuli. Vital signs revealed a normal respiratory pattern and blood pressure of 110/70. Noxious stimulus of the right arm produced flexion withdrawal. Midline noxious stimulation resulted in extension posturing of all extremities. Bilateral extensor plantars were present. Occular examination revealed normal fundi, skew deviation of the eyes, and upbeating nystagmus, Arachnodactyly was not present. CT on admission was normal except for a small enhancing area in the right occipital lobe. Four-vessel angiography revealed complete occlusion of the basilar artery, just distal to the anterior inferior cerebellar artery origin. The left posterior cerebral artery was also occluded (Fig. 1). CT scan 2 days following angiography showed areas compatible with infarction in the left thalamus, left occipital lobe, midbrain and pons (Fig. 2). No right occipital abnormality was seen. The following laboratory studies were normal: urine for homocystine, hemoglobin electrophoresis, PTT and platelet count, antinuclear antibody (ANA), syphilis serology (FTA -abs; fluorescent Angiogram: basilar occlusion 99% recovery at 3 months Spastic quadriptegia, aphonic; mentally alert 4 years later Left hemiparesis and psychosocial delay at 2 years Angiogram: partial vertebral occlusion Angiogram: bilateral vertebral occlusion CT: pontine infarct Angiogram: basilar occlusion Mild nystagmus and occasional vertigo at 4 months Normal examination at 1 month and 3 years Mild quadriparesis at 1 month CT: left pontine infarct Angiogram: basilar occlusion CT: possible cerebellar infarction Angiogram: basilar occlusion CT: normal Angiogram: basilar occlusion CT (at 2 days): multiple infarcts including pons and midbrain Angiogram: basilar occlusion CT: normal MRI: fight pontine infarct Angiogram: normal Marked improvement at 1 month Marked hemiparesis, bilateral ataxia, and dysarthria at 1 month Right hemiparesis and mild dysarthria at 1 year Quadfiplegia and possible "locked-in"; state at 1 month Beginning ambulation and dysarthric at 2 weeks treponemal antibody-absorption), purified protein derivative, serum complement, serum electrolytes, complete blood count and ammonia level. Normal cardiac evaluation included auscultation, ECG and echocardiogram. After i week he was discharged to a regional center. At that time he was quadriparetic with some characteristics of a deferented, locked-in syndrome. Evaluation 4 years later revealed spastic lower extremities, left greater than fight, and an inability to stand. The right arm was nearly normal in function, but marked spasticity was present in the left arm. Neck strength was poor and moderate dysphagia and dysarthria persisted. Case 15 A 14-year-old black male was brought to the emergency room on 12 February 1989 because 1 h earlier, while watching television, he complained of "feeling bad all over." Within a few moments he was unable to speak or stand. There was no history of previous signifi- 307 gaze preference and a left hemiparesis. There was no arachnodactyly. CT scan was normal, but magnetic resonance imaging (MRI) revealed a right pontine lesion compatible with an ischemic infarct (Fig. 3). Four-vessel angiography was normal. The following studies were also normal: ECG, echocardiogram with bubble technique, prothrombin time and PTT, platelet aggregation studies, anticardiolipin antibody, ANA and a double-stranded DNA, plasma lipid profile, urine amino acids, and an electroencephalogram. A cardiac Holter monitor revealed frequent premature ventricular contractions. Gradual neurological improvement was noted over a 10-day hospitalization. He was discharged to a rehabilitation facility with dysarthria, a left hemiparesis and early attempts at ambulation. Eighteen months after the stroke no neurological deficit could be found. The patient indicated complete recovery 2 months following discharge from the hospital. Fig. 1. Vertebral angiography of case 14 demonstrates a complete occlusion of the basilar artery just distal to the origin of the anterior inferior cerebellar artery Fig. 2a, b. CT of case 14 with 5-mm cuts through the posterior fossa reveals areas of decreased attenuation in the midbrain (a) and pons (b) compatible with infarctions Fig. 3a, b. T2-weighted magnetic resonance imaging of case 15 reveals a right pontine lesion of high signal intensity in a transaxial plane (a) and sagittal plane (b) compatible with an infarction cant medical illnesses. The family history revealed no neurological disorders of childhood or young adults. Examination demonstrated normal vital signs including a blood pressure of 120/60. He was stuporous, followed simple commands, but refused or was unable to speak. Cranial nerve examination demonstrated a left facial weakness. By the 3rd hospital day this was identified as a lower motor neuron deficit. He had a left conjugate Discussion These cases are examples o f idiopathic brain-stem infarction w i t h o u t clinical evidence for cerebellar or cerebellar outflow involvement. Two additional children with brain-stem infarctions were discovered in reviewing 13 years o f our records, but b o t h had identifiable etiologies: one had chronic, repeated, self-inflicted neck t r a u m a producing a vascular a b n o r m a l i t y o f the vertebral artery, and the other had C N S tuberculosis. A third case was excluded because the diagnosis was complicated migraine, and only a cerebellar lesion was d e m o n s t r a t e d in spite o f p r o m i n e n t brain-stem signs c o m b i n e d with ataxia. The clinical description suggested basilar artery migraine progressing f r o m transient ischemic attacks to an infarction [5, 9]. A 20-year review o f the literature c o m b i n e d with our 3 cases p r o d u c e d 15 examples o f idiopathic brain-stem ischemia with or w i t h o u t cerebellar s y m p t o m s and signs developing prior to 16 years o f age (Table 1) [1, 3, 4, 8, 14, 16, 18, 21, 22, 24]. Only 2 o f these were females: a 16-yearold with a basilar artery occlusion (case 12), and a similar lesion at 12 years o f age in the current report (case 13). The age ranged f r o m 3 to 16 years with a relatively even distribution except for a cluster o f 4 cases at ages 6 and 7. Because o f the time covered by the review, a variety o f radiographic techniques were relied u p o n to confirm the diagnosis. Case 15 is the only one in which M R I was used, and in this patient the C T and a n g i o g r a m were normal. In 9 o f the 15 neither C T n o r M R I was available so the diagnosis was a c o m b i n a t i o n o f clinical examination with posterior circulation a n g i o g r a p h y or a postm o r t e m examination as in case 1. O f the remaining 6, 5 had a b n o r m a l a n g i o g r a m s and 4 o f these had a b n o r m a l CTs. A n g i o g r a p h y in case 13 d e m o n s t r a t e d a basilar artery occlusion, but the early-generation C T failed to reveal an abnormality. As noted earlier, case 15 h a d a normal C T and angiogram, but a large pontine lesion was seen on M R I . O f the 12 cases with a b n o r m a l angiograms, 5 involved a vertebral artery, 5 had basilar artery occlusions. B o t h females had basilar artery occlusions. As expected, M R I provided the clearest image o f the brain stem, and in case 15 d e m o n s t r a t e d a structural lesion in the absence o f 308 a C T abnormality. A n g i o g r a p h y failed to identify evidence for vasculitis or a vascular m a l f o r m a t i o n . O f the 6 cases with c o m p u t e r i z e d imaging studies (cases 1 0 - 1 5 ) 3 h a d pontine lesions, I h a d b o t h a pontine and m i d b r a i n lesion, 1 h a d a questionable cerebellar lesion, a n d 1 was normal. O n follow-up, 2 o f the patients with pontine lesions d e m o n s t r a t e d only a mild residual deficit, b u t the remaining 4 retained a severe disability. U n f o r t u nately the follow-up d u r a t i o n was short in m a n y cases. The etiology o f n o n - e m b o l i c brain infarcts in children includes sickle cell disease, h o m o c y s t i n u r i a , vascular malf o r m a t i o n s and vasculitis [6, 28]. R e c e n t descriptions a d d chronic disorders such as nephrotic s y n d r o m e [12], neoplasia [23], m i t o c h o n d r i a l m y o p a t h y , e n c e p h a l o p a t h y , lactic acidosis, a n d stroke ( M E L A S ) [25], and toxins including cocaine [17] and p h e n y l p r o p a n o l a m i n e [7]. O t h e r m e c h a n i s m s for stroke in children include the h y p e r c o a g ulable states o f protein C a n d S deficiency [13, 20, 26, 27, 29], antiphospholipid antibodies [15, 19] and platelet dysfunction [2]. Two-dimensional e c h o c a r d i o g r a p h y revealing silent atrial septal defects responsible for central embolization w i t h o u t s y m p t o m a t i c distal venous t h r o m b o sis has been reported in adults b u t n o t in children [11]. Studies for a h y p e r c o a g u l a b l e state a n d two-dimensional e c h o c a r d i o g r a p h y were n o t d o n e on any o f the cases obtained f r o m the literature the first two cases in this report. A careful history and e x a m i n a t i o n will p r o v i d e clues to m a n y o f these etiologies, b u t w i t h o u t an awareness o f the diagnostic possibilites, the questions asked a n d l a b o r a t o ry studies o b t a i n e d will be inadequate. I n the presence o f platelet dysfunction, we r e c o m m e n d aspirin and or d i p y r i d a m o l e t h e r a p y as prophylaxis following an idiopathic infarction. T h e adult dose for aspirin is 5 grains once a day and for persantin 75 m g 3 times a day. H a l v i n g these adult dosages is r e c o m m e n d e d for children weighing less t h a n 30 kg. U n f o r t u n a t e l y , there is no long-term follow-up study which proves the effectiveness o f this treatment. NeW radiographical techniques including M R I a n g i o g r a p h y p r o v i d e non-invasive m e t h ods for localizing the lesion, b u t m u c h m o r e i n f o r m a t i o n regarding pathogenesis is needed before effective p r o p h y lactic or therapeutic measures can be contemplated. References 1. Aekerman ES, Levinsohn MW, Richards D, et al (1977) Basilar artery occlusion in a ten-year-old boy. Ann Neurol 1:204-205 2. Check WA (1984) Possible platelet syndrome suggested by early stroke. 9th International Conference on Stroke and Cerebral Circulation, Tampa 1984. JAMA 252:597-598 3. DeVivo DC, Farrell FW (1972) Vertebrobasilar occlusive disease in children. Arch Neurol 26:278-281 4. Dooley JM, Smith KR Jr (1968) Occlusion of the basilar artery in a six-year-old boy. Neurology 18:1034-1036 5. Dunn DW (1985) Vertebrobasilar occlusive disease in childhood migraine. Pediatr Neurol 1:252-254 6. Egg-Olofsson O, Ringheim Y (1983) Stroke in children; clinical characteristics and prognosis. Acta Paediatr Scand 72:391 -395 7. Forman HP, Levin S, Stewart B, et al (1989) Cerebrovasculitis and hemorrhage in an adolescent taking diet pills containing phenylpropanolamine; case report and review of the literature. Pediatrics 83:737-741 8. Fowler M (1962) Two cases of basilar artery occlusion in childhood. Arch Dis Child 37:78-82 9. Golden GS, French JH (1975) Basilar artery migraine in young children. Pediatrics 56:722-726 10. Gudmundsson G, Benedikz JE (1977) Epidemiological investigation of cerebrovascular disease in Iceland. 1958-1968 (ages 0-35 years): a total population study. Stroke 8:329-331 11. Harvey JR, Teague SM, Anderson JL, etal (1986) Clinically silent atrial septal defects with evidence for cerebral embolization. Ann Intern Med 105:695-697 12. Igarashi M, Roy S, Stapleton FB (1988) Cerebrovascular complications in children with nephrotic syndrome. Pediatr Neurol 4:362-365 13. Israels SJ, Seshia SS (1987) Childhood stroke associated with protein C or S deficiency. J Pediatr t 11:562-564 14. Jain S, Maheshwari MC, Tandon PN, et al (1984) Idiopathic basilar artery occlusion in childhood (case report). Stroke 15:563 -565 15. Kelley RE, Berger JR (1987) Ischemic stroke in a girl with lupus anticoagulant. Pediatr Neurol 3:58-61 16. Klein RA, Snyder RD, Schwartz HJ (1976) Lateral medullary syndrome in a child; arteriographic confirmation of vertebral artery occlusion. JAMA 235:940-941 17. Klonoff DC, Andrews BT, Obana WG (1989) Stroke associated with cocaine use. Arch Neurol 46:986-993 18. Latchaw RE, Seeger JF, Gabrielsen TO (1974) Vertebrobasilar arterial occlusion in children. Neuroradiology 8:141-147 19. Levine SR, Welch KMA (1987) The spectrum of neurologic disease associated with antiphospholipid antibodies. Arch Neurol 44:876-883 20. Miletich J, Sherman L, Broze G (1987) Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 317:991-996 21. Mori K, Miwa S, Murata T, et al (1979) Basilar artery occlusion in childhood; report of a case. Arch Neurol 36:100-102 22. Ouvrier RA, Hopkins IJ (1970) Occlusive disease of the vertebrobasilar system in childhood. Dev Med Child Neurol 12:186-192 23. Packer RJ, Rorke LB, Lange BJ, et al (1985) Cerebrovascular accidents in children with cancer. Pediatrics 76:194-201 24. Pascual-Castroviejo I, Pascual-Pascual JI, Mulas F, et al (1977) Bilateral obstruction of the vertebral arteries in a three-year-old child. Dev Med Child Neurol 19:232-237 25. Pavlakis SG, Phillips PC, DiMauro S, et al (1984) Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Ann Neurol 16:481-488 26. Pegelow CH, Curless R, Bradford B (1988) Severe protein C deficiency in a newborn. Am J Pediatr Hematol Oncol 10: 326329 27. Sacco RL, Owen J, Mohr JP, et al (1989) Free protein S deficiency: a possible association with cerebrovascular occlusion. Stroke 20:1657-1661 28. Solomon GE, Hilal SK, Gold AP, et al (1970) Natural history of acute hemiplegia of childhood. Brain 93:107-120 29. Wintzen AR, Broekmans AW, Bertina RM, et al (1985) Cerebral hemorrhagic infarction in young patients with hereditary protein C deficiency; evidence for spontaneous cerebral venous thrombosis. Br Med J 290:350-352