tation of mtDNA in the oocyte or in the zygote. In contrast, MELAS is often familial; maternal inheritance has been suspected and is in accord with the recent demonstration of a mtDNA point mutation [7}. Our patients had no affected relatives, and a muscle biopsy specimen from the mother of Patient 1 showed no RRF and no detectable mtDNA deletion. Direct analysis of mtDNA excluded the presence of the point mutation in the tRNALeU(UUR) gene recently described {7]. The prominent ocular signs (PEO and pigmentary retinopathy), lack of family history, evidence of widespread mtDNA deletions, and lack of the point mutagene support the diagnosis of tion in the tRNALeu(UUR) KSS rather than MELAS. How, then, can we explain the stroke-like episodes? The stroke-like episodes in MELAS may not be the result of classical vascular problems because the cerebral “infarcts” often are not in the distribution of major vessels and there is usually no evidence of thromboembolisrn. It has been suggested that the smooth muscle cells of small and medium arterioles of the brain contain excessive numbers of abnormal mitochondria, resulting in intermittent abnormalities of autonomic vascular control [12, 131. If this hypothesis is correct, it is imaginable that an especially high number of deleted mtDNAs in the smooth muscle of the cerebral microvasculaturc could cause stroke-like episodes in patients with otherwise typical

KSS. We think that molecular genetic analysis will confirm rather than confuse the distinction of the three major syndromes initially suggested by clinical criteria. It is, however, difficult to explain how genetic lesions of the mtDNA, which ought to have similar physiological consequences, usually cause dissimilar clinical pictures. Detailed study of overlap patients may help us understand the pathogenesis of those clinical differences that, in typical patients, separate KSS, M E W , and MELAS.

References 1. DiMauro S, Bonilla E, Zeviani M, et al. Mitochondrial myopathies. Ann Neurol 1985;17:521-538 2. Pavlakis SG, Rowland LP, DeVivo DC, et al. Mitochondrial myopathies and encephalomyopathies. In: Plum F, ed. Advances in contemporary neurology. Philadelphia: Davis, 1988:95-133 3. Petty RKH, Harding AE, Morgan-Hughes JA. The clinical features of mitochondrial myopathy. Brain 1986;109:915-938 4. Moraes CT,DiMauo S, Zeviani M, et al. Mitochondrial DNA deletions in progressive external ophthalmoplegia and KearnsSayre syndrome. N Engl J Med 1989;320:1293-1299 5. ShoffnerJM, htt MT, Lezza AM, et al. Myoclonic epilepsy and r e e d red fiber disease (MERRF)is associated with a mitochondrial DNA tRNALysmutation. Cell 1990;61:931-937 6. Mita S, Rizzuto R, Moraes CT,et al. Recombination via flanking direct repeats is a major cause of large-scale deletions of human mitochondrial DNA. Nucleic Acid Res 1990;18:561-567 7. Goto Y,Nonaka I, Horai S. A mutation in the tRNALu‘UUR’ gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. N a m e 1990;348:651-653 8. Pavlakis SG, Phillips PC, DiMauro S, et al. Mitochondrial myop-

athy, encephalopathy, lactic acidosis, and stroke-like episodes: a distinctive clinical syndrome. Ann Neurol 1984;16:481-488 9. Montagna P, Gallassi R, Medori R, et al. MELAS syndrome: characteristic migrainous and epileptic features and maternal transmission. Neurology 1988;38:7 5 1-7 54 10. Shanske S, Moraes CT, h m b e s A, et al. Wide-spread tissue distribution of rnitochondrial DNA deletions in Kearns-Sayre syndrome. Neurology 1990;40:24-28 11. Zeviani M, Gellera C, Pannacci M, et al. Tissue distribution and transmission of rnitochondrial DNA deletions in mitochondrial myopathies. Ann Neurol 1990;28:94-97 12. Sakuta R, Nonaka I. Vascular involvement in mitochondrial myopathy. Ann Neurol 1989;25:594-601 13. Ohama E, Ohara SA, Tanaka K, et al. Mitochondrial angiopathy in cerebral blood vessels of mitochondrial encephalomyopathy. Acta Neuropathol 1987 ;?4:226-2 33

Fatal Disseminated Hemorrhagc Toxoplasmic EnceDhalitis As the-Initial Man;festation of AIDS Eelco F. M. Wijdicks, MD,*Jan C. C. Borleffs, MD,? Andy I. M. Hoepelman, MD,? and Gerard H. Jansen, MDS

A 28-year-old woman presented with progressive coma after being asymptomatic for 1 year after the demonstration of seropositivity for human immunodeficiency virus and high serum immunoglobulin G toxoplasma titers. Computed tomographic scanning showed multiple rounded cerebral hemorrhages and massive cerebral edema. Postmortem examination disclosed Toxoplasma gondii cysts scattered throughout the brain. An overwhelming fatal toxoplasmosis associated with multiple cerebral hemorrhages may be the first presentation of the acquired immunodeficiency syndrome. We raise the possibility that frequent neuroradiological monitoring may be indicated in asymptomatic human immunodeficiency virus-infected patients with high immunoglobulin G toxoplasma titers. Wijdicks EFM, Borleffs JCC, Hoepelman AIM, Jansen GH. Fatal disseminated hemorrhagic toxoplasmic encephalitis as the initial manifestation of AIDS. Ann Neurol 1991;29:683-686

Central nervous system (CNS) toxoplasmosis as the initial manifestation of the acquired immunodeficiency From the Departments of *Neurology, +Internal Medicine, Section Immunology and Infection, and SNeuropathology, University Hospital Utrecht, Utrecht, The Netherlands. Received Oct 15, 1990, and in revised form Dec 18. Accepted for publication Dec 22, 1990. Address correspondence to D r Wijdicks, Department of Neurology, University Hospital Uuecht, Heidelberglaan 100,3584 CX Utrecht, The Netherlands.

Copyright 0 1991 by the American Neurological Association 683

syndrome (AIDS) may occur in patients infected with the human immunodeficiency virus (HIV) 11-31. Focal neurological signs tend to dominate the clinical picture and usually are accompanied by ring-enhancing lesions on contrast computed tomographic (CT) scanning 147. Few patients with fulminant lethal evolution of toxoplasmosis are reported in patients with AIDS and only occasionally are petechial hemorrhages seen in toxoplasmic abscesses on CT scanning 14-61. Herein, we describe a fulminant clinical course in an HIVseropositive woman with multiple cerebral hemorrhages due to Toxophsm gondii infection as the first AIDS-defining condition.

Patient Report A 28-year-old woman with a previous history of parented drug abuse was found comatose on the day of admission to the hospital. There was a history of fever and headache 3 weeks before entry. She was seen 1 year earlier in the clinic with vague complaints of fatigue after a nonspecific salpingitis. On physical examination then she appeared well. A generalized nontender lymphadenopathy and a hairy leukoplakia was noted. Neurological examination was normal. Laboratory findings yielded an erythrocyte sedimentation rate of 53 mm and slightly elevated liver function tests. She had serological evidence of a past infection with hepatitis B, Leishmania, and cytomegalovirus. Immunoglobulin G (IgG) antibody titer to T. gondii, measured with enzyme-linked immunosorbent assay (ELISA) (Toxonostika, Organon Technika, Boxtel, The Netherlands), was very high ( > l :1,600), but specific IgM titer was negative. Antibodies against HIV were found in both ELISA and immunoblot assay. Phenotyping of peripheral blood lymphocytes demonstrated 62 x lo6 CD4positive cells per liter with a CD4+/CD8+ ratio of 0.1. The test for p24 antigen was negative. She remained asymptomatic and was only occasionally seen in the clinic. On arrival at the hospital, she was comatose. Her temperature was 38.8"C, her blood pressure was 120 mm Hgi70 mm Hg, and her pulse was 93 beatdmin. Petechiae and ecchymoses were absent. Respiration was irregular and shallow. Occasionally, ventricular tachycardia was noted. She moaned in response to deep pain, and spontaneous extensor motor responses were noted. Pupils were fixed and dilated. Corneal and oculocephalic reflexes were absent. Laboratory examination revealed anemia (hemoglobin, 5.8 mmol/L), a slightly decreased platelet count (127 Y. 109/L), and a normal number of leukocytes (6.1 x 109/L). Arterial Po, and Pco, were 73 and 21 mm Hg, respectively. Kidney and liver function tests were normal. Again, serum IgG toxoplasma antibodies but no IgM antibodies were found. Circulating toxoplasma antigen and immune complexes could not be detected. CT scanning showed multiple rounded hemorrhages in both cerebral hemispheres, brainstem, and cerebellum associated with massive edema (Fig 1). She was treated with a multiple drug regimen for toxoplasmosis, cryptococcosis,and tuberculosis. Despite aggressive treatment with mannitol and hyperventilation to decrease intracranial pressure, she deteriorated progressively within several hours to deep unresponsive coma with absent brainstem reflexes and apnea. She devel-

684 Annals of Neurology Vol 29 No 6 June 1991

Fig I. Noncontrast enhanced computed tomographic scan obtained on admission demonstrating m u l t ~ l ehyperdense masses dae to hemorrhage, with surrounding and di'jj.use edema in the white matter of both cerebral hemispheres.

oped severe diabetes insipidus and fulfilled all clinical criteria for brain death approximately 10 hours after admission. Mechanical ventilation was discontinued after unchanged clinical examination and electrocerebral silence on two electroencephalographic recordings. At autopsy, the brain was diffusely swollen and weighed 1,540 gm. The uncinate processes were bilaterally grooved. Coronal sections of the brain showed multiple hemorrhagic masses throughout the brain, predominantly located at the junction of gray and white matter (Fig 2). The white matter of both cerebral hemispheres was diffusely edematous. A brown yellowish necrotic mass (18 X 12 mm) was noted in the left globus pallidus and anterior commissure. Microscopic examination revealed a mixed inflammatory infiltrate, microglial cells, and macrophages in areas of necrosis and hemorrhage. A few vessels located in the necrotic area in the basal ganglia showed characteristic occlusive hypertrophic changes as previously described [7]. In the hemorrhagic areas, some perivascular infiltration was seen, but frank vasculitis was absent. Numerous T . gondii cysts and some endozoites, immunoreactive to specific peroxidase-antiperoxidase { S ] , were identified in these areas (Fig 3). Histopathological examination of other organs also revealed myocardial fibers replete with T. gondii endozoites, presumably related to the paroxysms of ventricular tachycardia.

Fig 2. Coronal sections through the brain showing rounded hemorrhagic areas a n d a lefr basal ganglia necrotic masJ corresponding with the appearance on computed tomographic scanning.

Fig 3. Nwnerous toxoplarma cyst5 i n w h i t e matter with in$ammatory reaction ( x 1,200, before 38% reduction).

Discussion Invasion of the CNS with T . gondii has emerged as one of the most prevalent AIDS-related opportunistic infections [2, 41. Most of the patients who are diagnosed with toxoplasmic encephalitis follow a subacute clinical course that manifests as headache, fever, mild hemiparesis, confusional state, or focal seizures. Movement disorders are rare despite the presence of basal ganglia lesions in many instances C1-3, 31. This patient report presents a very unusual course of toxoplasmosis in an HIV-infected woman. Although a fulminant fatal CNS toxoplasma infection has been described in some patients as the initial manifestation of AIDS, massive subcortical hemorrhages seldom complicate the pathological picture [ S , 61. Only a few patients with small

petechial cerebral hemorrhages or hemorrhagic infarction have been reported in large neuroradiological series [4]. The neuropathological counterpart usually consists of a coagulation necrosis together with an extensive vasculitis surrounded by white matter edema P, 3, 71. AIDS-related strokes are well recognized in large series, but little is known about the actual risk. It has been estimated that clinical significant cerebrovascular complications occur in approximately 3 to 4% of patients with established AIDS 12, lo]. Yet Mizusawa and colleagues [ll] claimed a stroke percentage of 34% in 83 patients with AIDS, after careful postmortem examination. Most cerebrovascular lesions in AIDS are due to cerebral infarction often secondary to nonbacterial thrombotic endocarditis or disseminated inrravascular coaguiopathy 110, 111. A few patients with frank vasculitis are on record [12, 131. In contrast, intracerebral hemorrhage is an uncommon condition in HIV infection C4, 10, 111. One recent series of 1,338 patients with asymptomatic HIV infection and low CD4 counts did not report 1 single patient with intracerebral hemorrhage or cerebral infarction after a maximum follow-up of 2 years (mean, 55 weeks) [14J Nevertheless, parenchymal cerebral hemorrhage in patients with AIDS may occur as a result of thrombocytopenia, bleeding in CNS neoplasms, and perhaps also in association with abuse of drugs such as amphetamines or cocaine Y2, 15, 161. It is not clear whether alternative management in this woman at the time of detection of high serum toxoplasma IgG titers would have prevented the fatal outcome. One recent report demonstrated a significant association between high IgG toxoplasma titers, determined by immunofluorescence and later development of toxoplasmic encephalitis [17]. It is, however, undecided whether prophylactic treatment for toxoplasmosis in indicated in HIV-infected patients selected on the basis of low CD4 counts and high serum IgG toxoplasma titers. In addition, the role of neuroradiological monitoring in HIV-seropositive patients with high IgG toxoplasma titers is not established, but we raise the possibility that it may detect clinically silent lesions that should be treated [ 2 , IS]. References 1. Handler M, Ho V, Whelm M, Budzilovick G. Intracerebral toxoplasmosis in patients with acquired immune deficiency syndrome. J Neurosurg 1983;59:994-1001 2. Levy RM, Bredesen DE. Central nervous system dysfunction in acquired immunodeficiency syndrome. In: Rosenblum ML, Levy RM, Bredesen DE, eds. AIDS and the nervous system. New York: Raven Press, 1988:29-63 3. Navia BA, Pedto CK, Gold JWM, er al. Cerebral roxoplasmosis complicating the acquired immune deficiency syndrome: clinical and neuropathological finding in 27 patients. Ann Neurol 1986;19:224-238

Brief Communication: Wijdicks et

al: Hemorrhagic Toxoplasmic Encephalitis

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4. Levy RM, Rosenbloom S, Perrett LV. Neuroradiologic findings

in AIDS: a review of 200 cases. AJNR 1988;7:833-839 5. Casado-Naranjo I, Lopez-Trigo J, Ferrandiz A, et al. Hemorrhagic abscess in a patient with the acquired immunodeficiency syndrome. Neuroradiology l989;3 1:289 6. Chaudhari AB, Singh A, Jindal S, Poon TF'.Haemorrhage in cerebral toxoplasmosis. A report on a patient with the acquired immunodeficiency syndrome. S Afr Med J 1989;76:272-274 7. Huang TE, Chou SM. Occlusive hypertrophic arteritis as the cause of discrete necrosis in CNS toxoplasmosis in the acquired immunodeficiency syndrome. Hum Pathol1988;19:12 10-12 14 8. Conley FK, Jenkins KA, Remington JS. Toxoplasma gondii infection of the central nervous system: use of the peroxidaseantiperoxidase method to demonstrate toxoplasma in formalin fixed, paraffin embedded tissue sections. Hum Pathol 1981; 121690-698 9. Wong B, Gold JWM, Brown AE, et al. Central nervous system toxoplasmosis in homosexual men and parented drug abusers. Ann Intern Med 1984;100:36-42 10. Vincers HV, Anders KH. Vascular complications in AIDS. In: Vinters HV, Anders KH, eds. Neuropathology in AIDS. Boca Raton, Florida: CRC Press, 1990 11. Mizusawa H, Hirano A, Llena JF, Shintaku M. Cerebrovascular lesions in acquired immunodeficiency syndrome (AIDS). Acta Neuropathal 1988;7645 1-457

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12. Schwartz hTD,So YT, Hollander H, et al. Eosinophilic vasculitis leading to amaurosis fugax in a patient with acquired immunodeficiency syndrome. Arch Intern Med 1986;146:2059-2060 13. Yankner BA, Skolnik PR, Shoukimas GM, et al. Cerebral granulomatous angiitis associated with isolation of human T-lymphotropic virus type I11 from the central nervous system. Ann Neurol 1986;20:362-364 4. Volberding PA, Lagakos SW, Koch MA, et al. Zidovudine in asymptomatic human immunodeficiency virus infection: a controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. N Engl J Med 1990;322:941-949 5. Levine SR, Brust JCM, Futrell N , et al. Cerebrovascular complications of the use of the "crack" form of alkaloidal cocaine. N Engl J Med 1990;323:699-704 16. Citron BP, Halpem M, McCarron M, et al. Necrotizing angiitis associated with drug abuse. N EnglJ Med 1970;283:1003-101 1 17. Grant IH, Gold J W M ,Rosenblum M, et al. Toxoplasma gondii serology in HIV-infected patients: the development of central nervous system toxoplasmosis in AIDS. AIDS 1990;4:5 19-52 1 18. Roue R, Debora T, Denamur E, et al. Diagnosis of toxoplasma encephalitis in absence of neurological signs by early computerized tomographic scanning in patients with AIDS. Lancet 1984; 2:1472