References 1. Maxwell GM, Thong YH, Manson JI, et al: Herpes simplex encephalitis: Treatment with adenine arabinoside and cytosine arabinoside. Med J Aust 1978;1:181-183. 2. Whitley RJ, Soong S-J, Dolin R, et al: Adenine arabinoside therapy of biopsy-proved herpes simplex encephalitis: National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study. N Engl Med 1977;297:289-294. 3. Sacks SL, Smith JL, Pollard RB, et al: Toxicity of vidarabine. JAMA 1979;241:28-29. 4. Ross AH, Julia A, Balakrishnan C: Toxicity of adenine arabinoside in humans. J Infect Dis J Khang-Loon Ho, MD, Kenneth R. Meyer, MD tension and atherosclerosis but has a higher incidence of bilateral involvement and a worse prognosis. (Arch Neurol 1981;38:385-387) ''The medial medullary syndrome has been recognized as a clinicopathologic entity since Spiller's1 first clini¬ cal description in 1908.- ' It is charac¬ terized by contralateral hemiparesis and hemisensory disturbance of poste¬ rior column function with ipsilateral paralysis of the tongue. It results from infarction of the paramedian region of the medulla due to occlusion of the vertebral or anterior spinal artery or their small branches. In this report, we describe an additional case of the medial medullary syndrome, along with a review of the 14 clinically and pathologically verified cases that have previously been reported. REPORT OF A CASE A hypertensive, diabetic woman was admitted to the hospital in 1965 at the age of 55 years, because of right hemiplegia. On the day of admission, she awoke with weakness of the right arm and slowing of speech. During the next several hours, there was progression of the weakness to Accepted for publication Oct 5, 1980. From the Department of Pathology (Neuropa- thology) (Dr Ho), Wayne State University School of Medicine, Detroit, and the Department of Pathology (Dr Meyer), Oakwood Hospital, Dearborn, Mich. Reprint requests to Department of Pathology, Wayne State University School of Medicine, 540 E Canfield Ave, Detroit, MI 48201 (Dr Ho). 43-55. 1976;133(suppl):192-198. The Medial Medullary Syndrome \s=b\ In a 55-year-old woman, the medial medullary syndrome developed owing to infarction of the left medullary pyramid, ventromedial portion of the inferior olivary nucleus, medial lemniscus, and hypoglossal nerve. The previously reported 14 cases of the medial medullary syndrome are reviewed, and their clinical features and topography of the medullary lesions are discussed. Like the lateral medullary syndrome, the medial medullary syndrome is closely associated with hyper- 5. Vidarabine for herpes simplex encephalitis. Med Lett Drugs Ther 1979;21:17-18. 6. Fahn S: Differential diagnosis of tremors. Med Clin North Am 1972;56:1363-1375. 7. Holmes G: Introduction to Clinical Neurology. Edinburgh, E & S Livingstone, 1946, pp involve the right leg. She did not have impairment of consciousness, convulsions, paresthesias, vertigo, diplopia, or visual defect. The blood pressure was 170/100 mm Hg, and the pulse rate, 80 beats per minute. Examination of the heart showed no abnor¬ mality, and the ECG was normal. She was alert, cooperative, and oriented. The visual fields were intact and ocular movements full. The eye grounds showed some thicken¬ ing and tortuosity of the arterioles. There was no nystagmus. There was right facial paralysis. The gag reflex was impaired. The tongue moved normally, though there was slurring of speech. The patient had a flaccid right hemiplegia with only a trace of movement in the leg. Plantar response was extensor on the right. The muscle stretch reflexes were symmetrical. There was no sensory deficit to pinprick, touch, vibration, and position sense. During the first 48 hours, there was some intermittent resurgence of the motor power in the right arm and leg. However, after the second day the paralysis of the arm and leg became complete. In the mean¬ time, the slurring of speech disappeared, but the right-sided facial paralysis re¬ mained minimal. She was soon able to walk with assistance. Neurologic evaluation at two weeks revealed slight spasticity of the right limbs with hyperactive reflexes. She was discharged three weeks after admis¬ sion. Her final admission was in 1980, at the age of 70 years, because of septic shock due to staphylococcal septicemia. She died on the second hospital day. PATHOLOGIC FINDINGS There were moderately severe athero¬ sclerosis of the aorta and its branches, cardiomegaly with old myocardial infarc¬ tion of the left ventricle, and petechial hemorrhages in various organs. There were no notable pathologic changes in the cere¬ brum and cerebellum except for a small lacunar infarct in the right putamen. The brainstem was sectioned horizontal¬ ly at 2- to 4-mm intervals. In the lower half of the pons, the basis pontis was slightly small on the left as compared with the right side. In the rostral two thirds of the medulla, the left pyramid was shrunken and replaced by a collapsed cystic lesion (Fig 1). The cystic destruction gradually disappeared rostrally at the medullopon- Downloaded from jamanetwork.com by Midwestern University user on 01/27/2019 tine junction and caudally at the lower medulla (Fig 2). The left pyramid in the caudal third of the medulla and the right lateral column of the entire spinal cord were shrunken and tan-brown as compared with the other side. Microscopically, the cystic lesion of the left pyramid was that of a lacunar infarct within which were macrophages, reactive astrocytes with glial fibers, and small ves¬ sels. The ventromedial portion of the left inferior olivary nucleus was destroyed with a marked astrocytosis of the remaining nucleus. The infarction extended dorsally to involve the lateral most portion of the medial lemniscus and hypoglossal nerve (Fig 2). The medial longitudinal fasciculus appeared to be uninvolved. Loss of axis cylinders and myelin sheaths with moder¬ ate astrogliosis were present in the lesion. Although the left hypoglossal nucleus was not involved by the infarction, there was a marked loss of nerve cells as compared with the right (Fig 3). In the caudal medul¬ la, the left hypoglossal nucleus and its fibers retained their normal appearance. There were no lesions in the lateral medul¬ lary region or on the right side of the medulla. Wallerian degeneration was seen in the left pyramid of the caudal medulla and the right corticospinal tract of the spinal cord. The basis pontis on the left contained scattered macrophages and reac¬ tive astrocytes. Its small size probablyresulted from retrograde degeneration of the pyramidal lesion. There were no infarcts or notable lesions in the rest of the brainstem, cerebrum, or cerebellum. The vessels of Willis' circle showed mod¬ erate atherosclerosis. Both vertebral arter¬ ies and the basilar artery were patent, despite patchy areas of calcified atheroma¬ tous change with narrowing of the lumen. At the point during dissection when the infarct of the pyramid was found, the relationship of small branches from the vertebral arteries to the region of the pyramid could no longer be reconstructed. However, microscopic examination reveal¬ ed several arterioles with thickened walls and narrowed lumens in the leptomeninges ventral to the right pyramid (Fig 4). COMMENT There are, to our knowledge, 15 clinically and pathologically verified cases of the medial medullary syn¬ drome reported in the literature. Although Spiller' and Dejerine1 pre¬ dicted and outlined the clinical syn¬ drome of the medial medulla, their case reports leave doubt about the nature and location of the lesions. The occluded vessel was not anatomically identified. The long period between the ictus and autopsy precluded a def¬ inite conclusion about the pathogenesis of the infarction. The lateral medullary syndrome is closely associated with hypertension and atherosclerosis."1" The same inti¬ mate association is also observed in the present review of the medial medullary syndrome. Of the 15 re¬ ported cases, ten had a history of hypertension. As in the lateral medul¬ lary syndrome, severe atherosclerosis with thrombus formation appears to be the main cause of vascular occlu¬ sion leading to the medial medullary syndrome. Moreover, the medullary infarct seems to reflect part of a more for inremote sev- infarct of left pyra¬ 1.—Section atherosclerosis, of midmedulla shows Figgeneralized midal region with cystic degeneration (hematoxylin-eosin, 4). Fig 3.—Section of hypoglossal nuclei reveals marked loss of nerve cells on left side. Medial longitudinal fasciculi are intact (hema¬ toxylin-eosin, x30). by Currier3 had clinical features of the medial medullary syn¬ drome, but pathologic confirmation was lacking. Recently, in a detailed topographic study of 49 cases of medullary infarction, Hauw et als described ten cases with a lesion involving the medial medulla but without clinical data. The blood supply to the paramedian area of the medulla is derived from small arterial branches coursing me¬ case described dially from the ipsilateral vertebral artery and coursing laterally from the anterior spinal artery in the median fissure."7 The majority of the re¬ ported cases of the medial medullary syndrome were due to occlusion of the vertebral artery or the anterior spinal artery. In the present case, an Fig 2—Section of caudal third of medulla shows gradual disap¬ pearance of cystic lesion. Infarct extends to involve ventromedial portion of inferior olivary nucleus, lateral most portion of medial lemniscus, and hypoglossal nerve (hematoxylin-eosin, 8). Fig 4.—Section of lower medulla shows atrophy of left pyramid and arterioles with thickened walls and narrowed lumens in leptomeninges (hematoxylin-eosin, occluded vessel was not anatomically identified. The long period between the ictus and autopsy precluded a def¬ inite conclusion about the pathogenesis of the infarction. The lateral medullary syndrome is closely associated with hypertension and atherosclerosis."1" The same inti¬ mate association is also observed in the present review of the medial medullary syndrome. Of the 15 re¬ ported cases, ten had a history of hypertension. As in the lateral medul¬ lary syndrome, severe atherosclerosis with thrombus formation appears to be the main cause of vascular occlu¬ sion leading to the medial medullary syndrome. Moreover, the medullary infarct seems to reflect part of a more generalized atherosclerosis, for in sev- Downloaded from jamanetwork.com by Midwestern University user on 01/27/2019 8). eral instances there were multiple infarcts in the cerebrum and cerebel¬ lum as well."-'4 At least three patients with the medial medullary syndrome died of acute myocardial infarct.7-11·" The medial medullary vascular area extends dorsally from the pyramid and ventromedial portion of the infe¬ rior olivary nucleus to the medial lem¬ niscus, tectospinal tract, medial longi¬ tudinal fasciculus, the hypoglossal nucleus, and its fibers. The clinical signs and symptoms of the medial medullary syndrome depend on the extent of the lesion. Nevertheless, the pyramidal signs are constantly pres¬ ent in the acute stage and in most cases persist thereafter. In six cases,713"1' patients were initially ob¬ served as having pure motor hemiple- già, an entity defined by Fisher and Curry.17 Among these six cases, only the case reported by Ropper et al13 had a lesion strictly confined to the pyramid. It should be noted that in the cases of Chokroverty et al" and Leestma and Noronha,7 although there were no peripyramidal symptoms or signs, the infarct extended from the pyra¬ mid to involve the inferior olivary nucleus and the medial lemniscus. The pathophysiologic question, "Is the paralysis that resulted from involvement of the pyramid spastic or flaccid?" has occasionally been raised. From the present review of the reported cases of the medial medulla¬ ry syndrome, it is clear that pyramidal infarction will result in spasticity after an interval of flaccidity of one to six weeks. Moreover, from clinicopathologic studies of patients with infarc¬ tion of the internal capsule and basis pontis,17"' it seems reasonable to state that all the lesions involving the corti- cospinal pathway eventually produce spasticity. Facial weakness, usually mild and transitory, was present in seven cases. As in the lateral medullary syndrome, it is suggested that a lesion in the medullary pyramid may interrupt the corticobulbar fibers that leave the pyramid in the medulla and cross to the opposite facial nucleus and pro¬ duce a central facial weakness contralateral to the infarct. The occasional presence of vertical nystagmus on for¬ ward gaze3'"1-1""' is probably caused by the involvement of ipsilateral medial longitudinal fasciculus, which, as elu¬ cidated by Crosby et al,-" is one of the pathways involved in vertical gaze. In the present case, the medial longitudi- nal fasciculus was intact and the patient did not have nystagmus. Paralysis of the tongue was ob¬ served in seven cases. In the cases reported by Meyer and Herndon,1" Nardelli et al,J1 and Mizutani et al,"' the patients had bilateral tongue involvement. Tongue weakness is due either to involvement of the fibers of the hypoglossal nerve, which are located just lateral to the medial lem¬ niscus and the pyramid, or to involve¬ ment of the nucleus. In our case, de¬ spite involvement of intramedullary fibers of the right hypoglossal nerve with a marked secondary neuronal loss in the hypoglossal nucleus at the level of the infarct, there was no paralysis of the tongue. This probably was due to the preservation of the nerve and nucleus in the caudal medulla. Although the inferior olivary nu¬ cleus is commonly involved in the medial medullary syndrome, the le¬ sion is usually confined to the ven1 tromedial portion of the nucleus and is not accompanied by clinical findings. In the case of Leestma and Noronha,7 there was hypertrophy of the inferior olivary nucleus but no palatal myoclo¬ nus. Impairment of the posterior col¬ umn function was observed in five cases,11·"-'"'-1" and all had a rather extensive lesion in the medial lemnis¬ cus. In the cases reported by Meyer and Herndon,1" Trelles et al,-' Chokroverty et al," Leestma and Noron¬ ha,7 and in the present case, the medial lemniscus was involved by infarction but there was no posterior column sensory loss. The lack of clinicopathologic correlation in these cases is probably due to less severe involve- ment of the medial lemniscus and to subtle clinical changes that might eas¬ ily be overlooked during the sensory examination. Bilateral medial medullary syn¬ drome occurred in seven of the 15 cases (46%). This is in sharp contrast to the rare occurrence of bilateral involvement of the lateral medullary syndrome."'" Of these seven cases, three were due to occlusion of the anterior spinal artery.1--- In six cases, both lesions occurred almost simulta¬ neously, but in the case of Trelles et al,2' the two lesions apparently had occurred in separate episodes. Of the 15 patients with medial medullary syndrome, seven died with¬ in two months,'-"1"'7'2'--3 and only three survived five years after the onset of the syndrome."' '"' This is in contrast to the lateral medullary syn¬ drome, which has at least a 50% fiveyear survival rate.'-"-4 As would be expected, patients with bilateral me¬ dial medullary infarction were more seriously ill and died in the early postinfarction period.'-''" -'"-'- There are reports of combined later¬ al and medial medullary syn¬ dromes.'-' · "'·"·-' "' In the case of the medial medullary syndrome reported by Fisher and Curry,17 there were clini¬ cally silent lesions in the lateral medullary region. In all the pathologi¬ cally verified cases of combined later¬ al and medial medullary syndrome, there was occlusion of the vertebral artery," which was also true for the case of Fisher and Curry. This investigation was supported in part by the research corporation of Detroit Receiving Hospi¬ tal. References 1. Spiller WG: The symptom-complex of a lesion of the uppermost portion of the anterior spinal and adjoining portion of the vertebral arteries. J Nerv Ment Dis 1908;35:775-782. 2. Currier RD: Syndromes of the medulla oblongata, in Vinken PJ, Bruyn GW (eds): Hand-$ book of Clinical Neurology. New York, Elsevier North Holland Inc, 1969, vol 2, pp 217-237. 3. Currier RD: The medial medullary syndrome. J Univ Mich Med Cen 1976;42:96-104. 4. Dejerine J: Semiologie des affections du systeme nervoeux. Paris, Masson & Cie, 1914. 5. Hauw JJ, Agopian PD, Trelles L, et al: Les infarctus bulbaires. J Neurol Sci 1976;28:83-102. Theanatomy and pathology of 6. Fisher CM: the cerebral vasculature, in Meyer JS (ed): Modern Concepts of Cerebrovascular Disease. New York, Halsted Press, 1975, pp 1-41. 7. Leestma JE, Noronha A: Pure motor hemiplegia, medullary pyramid lesion, and olivary hypertrophy. J Neurol Neurosurg Psychiatry 1976;39:877-884. 8. Peterman AF, Siekert RG: The lateral medullary (Wallenberg) syndrome: Clinical features and prognosis. Med 1960;44:887-896. Clin North Am 9. Fisher CM, Karnes WE, Kubik CS: Lateral medullary infarction: The pattern of vascular occlusion. J Neuropathol Exp Neurol 1961;20:323\x=req-\ 379. 10. Currier RD, Giles CL, Dejong RN: Some comments on Wallenberg's lateral medullary syndrome. Neurology 1961;11:778-791. 11. Davison C: Syndrome of the anterior spinal artery of the medulla oblongata. Arch Neurol1937;37:91-107. 12. Davison C: Syndrome of the anterior spinal artery of the medulla oblongata. J Neuropathol Exp Neurol 1944;3:73-80. 13. Ropper AH, Fisher CM, Kleinman GM: Pyramidal infarction in the medulla: A cause of pure motor hemiplegia sparing the face. Neurolo- gia of vascular origin. Arch Neurol 1965;13:30\x=req-\ 44. 18. Fisher CM: Capsular infarcts: The underlying vascular lesions. Arch Neurol 1979;36:65-73. 19. Mizutani T, Lewis RA, Gonatas NK: Medial medullary syndrome in a drug abuser. Arch Neurol 1980;37:425-428. 20. Crosby EC, Humphrey T, Lauer EW: Correlative Anatomy of the Nervous System. New York, Macmillan Publishing Co Inc, 1962. 21. Nardelli E, Iannucci A, Rizzuto N: Bilateral infarction of pyramidal tracts. Acta Neurol 1978;33:130-136. 22. O'Brien FH, Bender MB: Localizing value of vertical nystagmus. Arch Neurol 1945;54:378\x=req-\ gy 1979;29:91-95. 380. 23. Trelles JO, Trelles L, Urquiaga C: Le ramollissement median du bulbe. Rev Neurol Arch Neurol 1975;32:647-648. 15. Brown WJ, Fang HCH: Spastic hemiplegia in man associated with unilateral infarct of the corticospinal tract at the pontomedullary juncture. Trans Am Neurol Assoc 1956;81:22-26. 16. Meyer JS, Herndon RM: Bilateral infarction of the pyramidal tract in man. Neurology 1973;129:91-104. 24. Currier RD, Giles CL, Westerberg MR: The 14. Chokroverty S, Rubino FA, Haller C: Pure motor hemiplegia due to pyramidal infarction. 1962;12:637-642. 17. Fisher CM, Curry HB: Pure motor hemiple- Downloaded from jamanetwork.com by Midwestern University user on 01/27/2019 prognosis of some brain stem vascular syndromes. Neurology 1958;8:664-668. 25. Harris TH, Hauser A: Occlusion of the right posterior inferior cerebellar artery and right vertebral artery. Arch Neurol 1931;26:396\x=req-\ 400.