Acute

Hemorrhagic Leukoencephalitis

A Successful

Recovery

David Seales, MD, PhD, Melvin Greer, MD

\s=b\ A 50-year-old woman developed acute hemorrhagic leukoencephalitis approximately 7 days after the onset of a benign respiratory infection. Mycoplasmal pneumonia was suspected because of Coomb's positive hemolysis, cold agglutinins, and sensitivity to erythromycin base but was not proved. Acute hemorrhagic leukoencephalitis was demonstrated by brain biopsy 24 hours after admission. The patient recovered without lasting sequelae following reduction of increased intracranial pressure by mannitol, hyperventilation, and phenobarbital and prolonged immunosuppression by plasmapheresis, steroids, and cyclophosphamide. (Arch Neurol. 1991 ;48:1086-1088)

"^

cute

hemorrhagic leukoencephalitis

(AHL) was established as a patho¬

logic entity in 1941.! This fulminant, myelinoclastic disease of the central nervous system is characterized by the development over hours to days of se¬ vere neurologic symptoms of confusion, dysarthria and/or aphasia, hemiparesis, seizures (focal or generalized), and, oc¬ casionally, acute myelitis. Fever, often remarkably high, may be present. Coma and death usually follow within a week. A prodromal illness (usually a vi¬ ral upper respiratory infection) usually occurs days to 3 weeks before the onset of AHL, with apparent recovery.2 Acute hemorrhagic leukoencephalitis was considered uniformly fatal, al¬ though survival has occurred in isolated cases treated with surgical decompres¬ sion, corticosteroids, or plasma ex¬ change.3' The patient described herein was treated aggressively with plasma¬ pheresis, corticosteroids, and cyclo¬ phosphamide and had intracranial pres¬ sure (ICP) monitoring. The patient recovered without residua.

REPORT OF A CASE

For 1 week, a previously healthy, righthanded, 50-year-old white woman had a cough and low-grade fever. Chest roentgen¬ ography revealed a diffuse interstitial infil¬ trate. The cough improved with oral erythro-

Accepted for publication May 7, 1991. From the Department of Neurology, University of Florida College of Medicine, Gainesville. Reprint requests to Box J-236, JHMHC, Gainesville, FL 32610-0236 (Dr Greer).

mycin base therapy (500 mg every 6 hours). Seven days after the onset of her illness, the patient developed severe neck pain, occipital headache, and slurred speech. When discov¬ ered 8 hours later by her husband, she was

lethargic

and left-sided weakness

was

apparent.

In the emergency department 2 hours lat¬ er, her blood pressure was 150/100 mm Hg; pulse rate, 92 beats per minute; respiration rate, 24 breaths per minute; and tempera¬

ture, 37.8°C rectally. There

was no

nuchal

rigidity. She picked aimlessly in the air. In¬ termittently, she would squeeze the examin¬ er's hand in response to command; she squeezed with the right hand only. She opened her eyes to painful stimulation but did not speak. Her pupils were pinpoint (1.5 mm) but briskly reactive to light. Rov¬ ing, conjugate, horizontal eye movements were present but alternated with a right gaze preference. Her mouth was held rigidly closed. She perceived pinprick diffusely as assessed by withdrawal and facial response. Strength (assessed during spontaneous movements) was reduced diffusely in the left hemibody (4/5 upper extremity; 4 + /5 lower extremity). Tone was increased in the left upper extremity. Deep tendon reflexes were symmetrical and hyperactive diffusely. A Babinski's sign was present on the left. A chest roentgenogram revealed a resolv¬ ing left midlung field infiltrate. Computed tomography ofthe head before and after per¬ fusion with contrast (Hypacque, 100 mL in¬ travenous 60%

solution) revealed

a nonen¬

hancing low-density area in the right frontal and parietal lobes, with a slight mass effect. Arterial blood gas analysis disclosed the fol¬ lowing values: pH, 7.38; PC02, 44 mm Hg, P02, 45 mm Hg; bicarbonate, 25.3 mEq/L; and oxygen saturation, 77%. The white blood cell count was 23.2 107L. The differential cell count was 0.76 polymorphonuclear leu¬ kocytes, 0.11 band cells, 0.06 lymphocytes, and 0.07 monocytes. Samples ofthe patient's blood held at bedside agglutinated at room temperature. Coomb's positive reactivity was noted with a cold agglutinin (titer 1:640). The agglutinin was not directed against the anti-I antigen on the red blood cell sur¬ face. Sedimentation rate (Westergren) was

25 mm/h.

Acyclovir sodium (loading dose, 1 g; main¬ hours), penicil¬ lin G potassium (2 million U every 4 hours), chloramphenicol sodium succinate (500 mg every 6 hours), and phenytoin sodium (load¬ ing dose, 500 mg; maintenance dose, 100 mg tenance dose, 700 mg every 8

every 8

hours)

were

administered intra¬

venously.

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At 12 hours after admission, a nasal airway placed because of increased upper air¬ way obstruction with trachéal retraction. At 14 hours, there was coffee grounds emesis. At 15 hours, after experiencing difficulty with nasogastric tube placement, the patient was in respiratory distress (pH, 7.04; PC02, 71 mm Hg; Po2, 30 mm Hg; bicarbonate, 19 mEq/L; and oxygen saturation, 34%. Endotracheal intubation was performed. Arter¬ ial blood gases returned to pH, 7.46; PC02, 28 mm Hg; Po2, 158 mm Hg; and oxygen saturation, 99% (intermittent mandatory ventilation, 12 breaths per minute; positive end-expiratory pressure, 5 cm H20; and 50% was

oxygen).

Seventeen hours after admission, decerebrate posturing was evident in response to stimulation. The right pupil dilated (6 mm) and became nonreactive to light; the left pu¬ pil dilated to 3 mm and was sluggishly reac¬ tive to light. Ankle clonus and Babinski's

signs

were

present bilaterally. Hyperventi¬

lation was begun. Mannitol (50 mg per intra¬ venous dose), phénobarbital sodium (loading dose, 550 mg; maintenance dose, 250 mg/d), and dexamethasone sodium phosphate (Decadron, 6 mg per nasogastric tube every 6 hours) were administered. Twenty-two hours after admission, erythromycin base (1 g administered intravenous¬ ly every 6 hours) and ceftriaxone sodium (loading dose, 2 g; maintenance dose, 2 g administered intravenously every 24 hours) therapy was begun. Penicillin and chloramphenicol therapy was discontinued. Brain biopsy was performed at the right frontal region 24 hours after admission. In white matter, there were microhemorrhages and focal acute fibrinoid necrosis of small vessels; the cortex was completely spared.

Vacuolization, lymphocytes, polymorphonu¬ clear leukocytes, and erythrocytes were pre¬ sent in perivascular white matter spaces. No

inclusion bodies were seen, and stains for bacteria, acid-fast bacilli, India ink, Toxo¬ plasma, herpes simplex, and fungi were neg¬ ative. Acyclovir and ceftriaxone therapy was discontinued. At the time of biopsy, an ICP monitor was inserted anterior to the site of the biopsy. The ICP remained elevated (16 to 19 mm Hg) for the second hours of hospitalization. Thereafter, the ICP could be held between 10 and 15 mm Hg by the intravenous adminis¬ tration of mannitol (50 mg) when the ICP increased to 15 to 20 mm Hg. Arterial pH was maintained at 7.45 to 7.50 with the PC02 at 30 mm Hg. The patient's neurologic status showed gradual improvement after 32 hours. Her

pupils were 1.5 to 2.0 mm bilaterally; her left pupil showed minimal response to light. Her oculocephalic reflex and corneal reflexes were still depressed. She was still hyperreflexic but no longer had ankle clonus. At 35 hours, a sternal rub elicited posture.

extensor

The hematocrit dropped from 0.35 at ad¬ mission to 0.16 thirty-six hours after admis¬ sion. The drop in hematocrit was thought to be secondary to hemolysis (corrected reticulocyte count, 2.1%; total bilirubin, 32.3 µ /L; direct bilirubin, 3.4 µ /L). Packed red blood cells (2 U) were given. Intravenous methylprednisolone sodium succinate (Solu-Medrol) therapy (60 mg ev¬ ery 6 hours) was initiated. At 36 hours, plasmapheresis (3 L exchange with a solution of 1500 mL of 5% albumin per 1500 mL of normal saline) was begun daily for 5 days. Electroencephalography revealed diffuse slowing in the anterior hemisphere (more pronounced on the left than on the right) consistent with encephalopathy. By 49 hours, the patient's pupils were 3 mm and reactive to light with presence ofthe oculoce¬ phalic response and bilateral corneal reflex¬ es. The pharyngeal reflex was intact. Exten¬ sor posturing was still noted in response to pain. By 96 hours, extensor tone occurred in the extremities at rest. By 110 hours, eye movements fluctuated from oculocephalic re¬ flex only to spontaneous, conjugate, roving eye movements. Ventilatory assistance was still required; spontaneous respirations were present only when the patient was stimulat¬ ed. She still demonstrated extensor tone at rest but withdrew all four extremities to painful stimulation. She opened her eyes to sternal rub. By days 6 and 7, the presence of corneal reflexes was variable. Plasmaphere¬ sis was concluded on hospital day 7. By day 8, her eyes were deviated downward (left eye more than right). Her pupils were small and unreactive. Tone alternated between flaccid and rigid. On hospital day 8, cyclophosphamide ther¬ apy (180 mg/d) was begun. Erythromycin therapy was discontinued. By hospital day 9, spontaneous respirations had returned, and the patient underwent extubation. Her neu¬

rologic status gradually improved. Purpose¬

ful eye movements occurred in response to verbal inquiry. Spontaneous movements of the body and then meaningful speech re¬ turned. Left-sided weakness resolved to a large extent. A lumbar puncture on day 28 revealed the following values: opening pressure, 220 mm of cerebrospinal fluid with no red or white blood cells; glucose, 4.1 mmol/L; and protein, 0.28 g/L. Cerebrospinal fluid stains (India ink, acid-fast bacilli, and bacterial) and cul¬ tures (tuberculin, fungal, bacterial, and vi¬ ral) showed no growth. Serologie tests were negative for cerebrospinal fluid, VDRL, and

cryptococcal antigens. Thirty-two days after admission, the pa¬ tient was discharged. Mild recent memory impairment was evident. There were no defi¬ cits in immediate

or

remote memory. Orien¬

tation, judgment, content, affect, speech, reading, writing, naming, comprehension, left-right orientation, finger naming, calcula¬ tion, buccofacial and appendicular praxis,

figure drawing, mapping, stereognosis, and graphesthesia were intact. There was no ne¬ glect or perseveration. There was vertical diplopia (most marked with gaze to the lower left visual field) and mild weakness in the left hip flexors. Tone was increased in the left lower extremity. Cyclophosphamide had been given intravenously for 23 days (180 mg/d on days 8 through 10 and 12 through 24, tapered over the next 7 hospital days. The patient had received methyl¬ prednisolone sodium succinate (60 mg every 6 hours) on days 3 through 10 and oral predni¬ sone (60 mg/d) on days 13 through 17 with tapering over days 18 through 39. Follow-up computed tomographic scans of the head on hospital days 15 and 39 revealed reduced edema without cystic degeneration in the right frontoparietal regions. Acute and convalescent titers of mycoplasmal pneumo¬ nia, herpes simplex, rubella, influenza A and B, Epstein-Barr virus, parainfluenza III, equine encephalomyelitis, St Louis encepha¬ litis, cytomegalovirus, and legionnaire's dis¬ ease were negative for current infection. Tests were negative for human immunodefi¬ ciency virus. Six months after the onset of her illness, the patient resumed her previous employment. Four years later, the findings of her examination remained normal. COMMENT

Approximately 70 cases of AHL are documented in the English language lit¬ erature.6" Both sexes are affected equally, with an age range of 2.5 to 60 years.' The lack of reported cases before approximately 3 years of age may relate to the incomplete myelinization of cere¬ bral white matter before this age. A temporal relationship has been noted between certain common illnesses, such as upper respiratory infections, varicel¬ la, and bronchial pneumonia, and the subsequent development of AHL in the following days or weeks.0 Acute hemor¬ rhagic leukoencephalitis has also been noted following or in association with processes as diverse as removal of tooth stumps, herniorrhaphy, injection of pertussis vaccine, herpes simplex, thrombotic thrombocytopenic purpura, and application of arsphenamine to the

gums.3,9

The incidence of AHL complicating is probably less than 0.1%.10 Coomb's positive hemolysis and cold agglutinins are seen, especially in relation to Mycoplasma pneumoniae

atypical pneumonia infection.u In the

M

present

pneumoniae

case, infection with was

suspected, but

acute and convalescent titers were neg¬

ative. Furthermore, the cold aggluti¬ nins did not react with polysaccharide antigen expressed on the surface of adult erythrocytes as is noted in myco¬ plasmal pneumonia. No other viral ti¬ ters were positive for current infection. Thus, the precise nature of the atypical pneumonia in the present case is

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unknown. The differentiation of AHL from her¬ pes simplex encephalitis can be difficult. Fever, headache, hallucinations, focality of neurologic abnormalities, and acuteness do not differentiate the two diseases. Examination of cerebrospinal fluid may exclude bacterial, fungal, and mycobacterial infection but will not dif¬ ferentiate AHL from herpes simplex. Thus, early brain biopsy is advocated. In AHL, necrotizing angiitis of venules and capillaries of white matter is noted microscopically. Gray matter and sub¬ cortical U-shaped fibers are usually spared as opposed to the gray and white matter damage observed in herpes sim¬ plex encephalitis. In AHL, ball-andring hemorrhages form around affected vessels, with fibrinoid necrosis and polymorphonuclear leukocytes evident in vessel walls. Later, lymphocytes re¬ place the polymorphonuclear leuko¬ cytes; lipid phagocytosis is seen if sur¬ vival is several days. Grossly, the lesions are usually unilateral in the pari¬ etal or posterior frontal regions, but may be bilaterally symmetrical. Le¬ sions can occur in other regions as well, including the brain stem and spinal

cord.2,3

The lesions of AHL can be demon¬ strated by computed tomography.12 Furthermore, it has been proposed that with computed tomography one may be able to distinguish between AHL and herpes simplex encephalitis.11 This is based on the findings that in AHL the computed tomographic findings arise earlier (in 1.5 days as opposed to 3 to 11 days for herpes simplex), are restricted to white matter, and do not enhance with contrast. The pathogenesis of AHL is un¬ known. An immunoreactive basis is supported by (1) the latent period be¬ tween preceding illness and onset of AHL, (2) the lack of identification of an infecting organism, (3) the relation to immunization, (4) the atopy observed in many patients with AHL, and (5) the similarity to a fulminant form of experi¬ mental allergic encephalitis.2 In ani¬

mals, experimental allergic encephalitis is

a

model of acute disseminated leu¬

koencephalitis; it is also a white matter myelinoclastic process but of less acute course

than AHL.14 In

addition, DNA-

synthesizing lymphoblasts have been observed in the peripheral blood of a patient with AHL, as well as in animals with experimental allergic encephali¬ tis.15

Success in the treatment of AHL has been modest. Two of five proved cases survived following surgical decompres¬ sion.11' High-dose steroids (10 mg of dexamethasone administered intrave-

nously, then 6 mg every 6 hours) have been thought to aid in the survival of patients with AHL.3,4 More recently, plasma exchange was used successfully in one patient with neurologic sequelae of mycoplasmal pneumonia.1' Until now, to our knowledge the use cyclophospha¬ mide has not been reported in the treat¬ ment of AHL. Its effect in this patient

remains uncertain. Effective treatment probably consists of a combination of early diagnosis based on clinical suspi¬ cion, neuroimaging, brain biopsy, life support with reduction of elevated ICP in the critical stage, and early, sus¬ tained treatment with appropriate

immunosuppressants.

References 1. Hurst EW. Acute

hemorrhagic leukoencephalitis: a previously undefined entity. Med J Aust. 1941;2:1-6.

2. Beham PO, Moore MJ, Lamarche JB. Acute

necrotizing hemorrhagic encephalopathy. Postgrad Med. 1973;54:154-160. 3. Byers RK. Acute hemorrhagic leukoencepha-

litis: report of three cases and review of the literature. Pediatrics. 1975;56:727-735. 4. Foley JM, Kane CA. Clinical pathologic conference. Neurology. 1957;7:135-141. 5. Coxe WS, Luse SA. Acute hemorrhagic leukoencephalitis: a clinical and electron-microscopic report of two patients treated with surgical decompression. J Neurosurg. 1963;20:584-596. 6. Gosztonyi G. Acute hemorrhagic leukoencephalitis (Hurst's disease). In: Vinken PJ, Brun GW, eds. Handbook of Clinical Neurology. Amsterdam, the Netherlands: Elsevier Science Publishers;

1978;3(pt 2):587-604.

7. Lander H. Acute hemorrhagic leukoencephalitis. Australas Ann Med. 1958;7:55-68. 8. Kulich SA. Acute hemorrhagic leukoencephalitis: report of a case and review of the literature. Boston Med Q. 1960;11:120-130. 9. Martins AN, Kempe LG, Harp GJ. Acute hemorrhagic leukoencephalitis with a concurrent primary herpes simplex infection. J Neurol Neurosurg Psychiatry. 1964;27:493-501. 10. Yesnick L. Central nervous system compli-

cations of primary atypical pneumonia. Arch Intern Med. 1956;97:93-98. 11. Fisher RS, Clark AW, Wolinsky JS, Parhad IM, Moses H, Mardiney MR. Postinfectious leukoencephalitis complicating Mycoplasma pneumoniae infection. Arch Neurol. 1983;40:109-113. 12. Rothstein TL, Shaw CM. Computerized tomography as a diagnostic aid in acute hemorrhagic leukoencephalitis. Ann Neurol. 1983;13:331-333. 13. Watson RT, Ballinger WE, Quisling RG. Acute hemorrhagic leukoencephalitis: diagnosis by computed tomography. Ann Neurol. 1984;15:611\x=req-\ 612. 14. Levine S, Wenk EJ. A hyperacute form of allergic encephalomyelitis. Am J Pathol. 1965; 47:61-88. 15. Lamarche JB, Behan PO, Segarra JM, Feldman RG. Recurrent acute necrotizing hemorrhagic encephalopathy. Acta Neuropathol(Berl). 1972; 22:79-87. 16. Kristianson K, Harkmark W, Cohen MM. Acute hemorrhagic encephalitis. Neurology (Min-

neap). 1956;6:503-509. 17. Cotter FE, Bainbridge D, Newland AC. Neurological deficit associated with Mycoplasma pneumonia reversed by plasma exchange. BMJ. 1983;286:22.

Isolated Congenital Hemianopia Caused by Prenatal Injury to the Optic Radiation Nicola K. Ragge, MRCP FCOphth; A. James Barkovich, William F. Hoyt, MD; Scott R. Lambert, MD

\s=b\ Isolated

congenital hemianopias

REPORT OF CASES

are

typically

caused by developmental abnormalities of the occipital lobe cortex. We describe two patients with an incidental partial hemianopia associated with unilateral periventricular leukomalacia that was acquired

prenatally. Magnetic scans suggest a late

MD;

imaging early third

resonance

second or trimester unilateral cerebral ischemic event. (Arch Neurol. 1991 ;48:1088-1091)

Tsolated congenital occipital lesions

with accompanying hemianopia usu¬ ally involve gray and white matter. Ex¬ amples include porencephaly1"3; vascular malformations, either isolated or in as¬ sociation with Sturge-Weber-type mal¬

formation without cutaneous signs4; colpocephaly'; and polymicrogyria of the striate cortex.'' ' This report documents two cases of congenital hemianopia caused by prenatal injury to the peri¬ ventricular white matter.

Case l.—A

drantanopia

healthy 21-year-old

white

found to have an inferior quadrantic field defect during a routine eye ex¬ amination. She had a history of herpetic kerwoman was

atitis in her right eye. There was no history of prenatal or postnatal illness or neurologic disorder. Her visual acuities were 20/50 in the right eye and 20/20 in the left eye. There were no abnormalities of color vision. Her pupil reflexes were equal bilaterally. Both Goldmann and computerized visual field test¬ ing showed a right inferior homonymous qua-

Fig 1. —Patient perimetry.

1.

Right

inferior

with minor incongruity along the horizontal meridian (Fig 1). There were signs in both retinas of nerve fiber loss corre¬ sponding to that seen in homonymous hemioptic atrophy. Both discs were small in diameter. The right disc showed band atro¬ phy, with loss of nerve fiber layer especially prominent at the nasal disc edge, where the pigment epithelial edge could be seen. The superior and inferior arcuate bundles were well preserved. On the left disc, a full com¬ plement of nasal nerve fiber layer could be seen, but temporal pallor and relative loss of the superior and inferior arcuate bundles

homonymous quadrantic

Accepted for publication April 18,1991. From the Departments of Neurology, Neurosurgery, and Ophthalmology (Drs Ragge and Hoyt) and Radiology (Dr Barkovich), School of Medicine, University of California, San Francisco, and the Department of Ophthalmology, Emory University School of Medicine, Atlanta, Ga (Dr Lambert).

Reprint requests to Neuro-ophthalmology Unit, Department of Neurosurgery, 126 UC, University of California Medical Center, San Francisco, CA 94143 (Dr Hoyt).

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defect demonstrated

by Goldmann