Fulminant form of acute disseminated encephalomyelitis: successful treatment with hypothermia

Journal of the Neurological Sciences 165 (1999) 94–97

Fulminant form of acute disseminated encephalomyelitis: successful treatment with hypothermia T. Takata*, M. Hirakawa, M. Sakurai, I. Kanazawa Department of Neurology, Division of Neuroscience, Graduate School of Medicine, University of Tokyo, 7 -3 -1, Hongo, Bunkyo-ku, Tokyo 113 -8655, Japan Received 8 July 1998; received in revised form 31 March 1999; accepted 2 April 1999

Abstract We described herein a case of the fulminant form of acute disseminated encephalomyelitis (ADEM) that developed after mycoplasma pneumonia. A 28-year-old man who presented with fever, headache, and writing difficulty was admitted to our hospital in August 1997. He developed hernia on the 3rd hospital day. Surgical decompression and intravenous prednisolone failed to halt his progressive deterioration. We introduced systemic hypothermia and he has shown marked recovery; despite having Broca’s type aphasia, he could comprehend spoken language and communicate with others by gesture. Head MRI demonstrated diffuse high signals over the white matter on fluid attenuated inversion recovery (FLAIR) images, which suggested extensive demyelination. The clinical course, imaging studies and presence of polymorphonuclear dominant leucocytosis in the blood and CSF in the patient are somewhat similar to findings in acute hemorrhagic leukoencephalitis, however, the result of a brain biopsy was inconclusive. The fulminant form of ADEM is usually fatal. Treatments such as corticosteroids, intravenous immunoglobulin, and surgical decompression have been performed to improve the prognosis. Our case results indicate that hypothermia, which suppresses both brain edema and immune response, may be included in the repertoire of treatment for the fulminant form of ADEM.  1999 Published by Elsevier Science B.V. All rights reserved. Keywords: Acute disseminated encephalomyelitis (ADEM); Acute hemorrhagic leukoencephalitis; Hypothermia; Mycoplasma pneumonia

1. Introduction Acute disseminated encephalomyelitis (ADEM) is an immune-mediated disorder of the central nervous system that is a complication of infection or vaccination. ADEM ranges across a broad spectrum of clinical severity, and the outcome of the fulminant form has been poor except for a few reports cases of recovery. Acute hemorrhagic leukoencephalitis (AHL) is also considered to be an immune-mediated disease with poor prognosis, and its pathogenetic similarity to ADEM has been reported [1]. The rapid clinical course, imaging studies, and polymorphonuclear dominant leucocytosis in the blood and CSF in *Corresponding author. Present address: Department of Geriatric Medicine, University of Kobe, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Tel.: 181-78-382-5901; fax: 181-78-382-5919.

this case resembled those of AHL cases. Various approaches have been tried in combination to improve the prognosis of the fulminant form of ADEM: immunosuppressants, corticosteroids, surgical decompression, and plasmapheresis [2–4]. We experienced a case of the fulminant form of ADEM subsequent to mycoplasma pneumonia, and treated this patient successfully with hypothermia in combination with surgical decompression and steroid therapy.

2. Case report A 28-year-old man developed cough and low grade fever 3 weeks prior to admission to our institution. One week before admission, he suffered headache and 388C fever. Chest roentogenogram at a neighborhood clinic

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T. Takata et al. / Journal of the Neurological Sciences 165 (1999) 94 – 97

showed interstitial shadows in the right lower lung, and antibiotics were prescribed. Fever at 388C level continued and he experienced writing difficulty during the next 2 weeks. An examination at another hospital showed a temperature of 38.68C, nuchal rigidity, right upper hemianopsia, right facial palsy, and accelerated tendon reflex of the bilateral lower extremities. He was referred to our hospital on the same day. On admission, he was a slender right-handed man (height 170 cm, body weight 45 kg) and disoriented and complained of headache. Neurological examination showed paraphasia, dysarthria, and right hemiparesis involving the right side of the face, as well as findings similar to those reported at the other hospital. Laboratory studies showed a WBC of 20.7310 3 / ml (band forms 2.0%, neutrophils 86.0%, monocytes 3.0%, lymphocytes 9.0%), CRP 7.6 mg / dl (normal ,0.3), CK 2410 IU / l (MM pattern, normal: 55–210), creatinine 1.7 mg / dl (normal: 0.5–1.3) and blood sugar 135 mg / dl. Lumbar puncture showed that opening pressure was 230 cmH 2 O, cell count was 1429 / mm 3 (87% polymorphonuclear cells, no RBC), glucose was 66 mg / dl, and protein was 113 mg / dl. The head CT performed at the other hospital showed diffuse brain swelling in the left frontal lobe with low density areas with enhancement. Cefotaxime, piperacillin, acyclovir, and hyperosmolarity fluid were administered, but his consciousness level worsened progressively to a semicomatose state, and complete left hemiplegia developed on the 3rd hospital day. A head CT showed impending left uncal herniation (Fig. 1A,B). Emergency left craniectomy was performed, and a biopsy specimen was taken from the temporal lobe. High-dose prednisolone (2.5 mg / kg / day) was administered intravenously, but his consciousness level deteriorated to a deep coma state, and Cheyne–Stokes respiration pattern appeared despite the decompression surgery. To prevent further damage to the brain, mild hypothermia at 358C was introduced 15 h after decompression surgery. After the introduction of hypothermia, his vital signs became stable, and there were no signs of high intracranial pressure, such as high blood pressure or bradycardia. On the 5th hospital day, during the early stage of rewarming, high blood pressure and bradycardia emerged, and the left pupil tended to dilate. Rewarming therefore was stopped. An intracranial pressure monitor was inserted on the surface of the left frontal lobe, and the opening pressure showed 40 mmHg (¯178 cmH 2 O). Hypothermia was reinstituted at 338C. Intracranial pressure could then be controlled to under 25 mmHg, and his vital signs became stable again. On the 11th hospital day, pneumonia developed, which was complicated by the prolonged hypothermia state. Elevation of serum amylase and a decrease in platelet count were noted, but there were no major clinical signs of pancreatitis or bleeding tendency. Rewarming was started to avoid further complications. Despite the rewarming process, ICP could be suppressed to under 20 mmHg using 10% glycerin and 20% mannitol.

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Methylprednisolone pulse therapy (1 g / day33 days) was started to prevent the brain swelling accompanied by the elevation of body temperature. The serum sampled earlier at the initial clinic showed a high antibody titer (3640; passive agglutinin method) to mycoplasma, and the titer had increased to 35120 at the time of admission to our hospital. Anti-galactocerebroside antibody was negative, and no significant increases in the titers of viral antibodies were found. Routine blood and CSF cultures and CSF PCR for herpes simplex virus were negative. PCR findings for the mycoplasma DNA from the pharynx, the CSF and the brain biopsy specimen were all negative. The brain biopsy specimen showed only such non-specific changes as interstitial edema, nuclear degeneration of cortical neurons, and minor cell infiltration (polymorphonuclear cell type) around a single small artery. No information was obtained on the white matter changes because the biopsy site was not sufficiently deep. On the 15th hospital day, lumbar puncture showed an opening pressure of 150 cmH 2 O, cell count 3 / mm 3 , glucose 63 mg / dl, and protein 88 mg / dl. He could open his eyes but could neither speak nor follow the directions. Neurological examination showed bilateral spasticity with complete right hemiplegia. Head MRI (Fig. 1C,D) on the 21st day showed diffuse high signals over the white matter on FLAIR and T2-weighted images, and on T1-weighted images with no enhanced lesion. His consciousness level gradually improved thereafter, and he became capable of following brief commands by day 150. On 270 hospital day, he still has remained hospitalised due to secondary hydrocephalus and cranioplasty surgery. He has Broca’s type aphasia and right hemiplegia, but can enjoy TV programs and communicate with medical staffs by gesture.

3. Discussion Diagnosis of the fulminant form of ADEM subsequent to mycoplasma pneumonia was most likely based on the hyperacute clinical course subsequent to mycoplasma infection, and the results of imaging studies, which indicated extensive demyelination of the white matter [5]. CSF analysis and brain biopsy examination revealed a prominent increase in cells in CSF and minor polymorphonuclear cell infiltration around a single small artery, which may suggest meningoencephalitis. However, since he experienced writing difficulty early in the clinical course and since right upper hemianopsia and hemiparesis were revealed on admission, we concluded that he suffered primary from a severe left cerebral damage. Cultures were negative, and in paired sera antibody titers for viruses did not show any significant abnormalities. Meningoencephalitis was unlikely given the clinical course and laboratory data. The CT images of our patient showed low attenuation of the left frontal lobe that progressed over the white matter

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T. Takata et al. / Journal of the Neurological Sciences 165 (1999) 94 – 97

Fig. 1. Panels A and B show the plain head CT scan on the 3rd hospital day. Left hemisphere edema with mass effect and a midline shift are evident (A). Low density is prominent in the white matter of both hemispheres. The left inferior horn of the lateral ventricle and the left basal cistern are compressed by the left temporal lobe, indicating impending uncal hernia (B). Panels C and D show the FLAIR image of the head MRI on the day 21. The FLAIR image demonstrates the peri-ventricular area more clearly than can be done with conventional T1 or T2-weighted image. The white matter in both hemispheres shows diffuse high signals, and part of the left frontal lobe is herniated from the craniectomy site (D).

of both hemispheres with an extensive mass effect that led to uncal herniation within a few days. The MRI demonstrated high signals over the white matter of both hemispheres, indicating extensive demyelination. AHL was considered because of the rapidly deteriorating clinical course and imaging studies. The typical CT images reported in AHL cases are a low density area in the white matter with mass effect and mostly asymmetrical in-

volvement [3,4,6,7]. MRI findings in cases of AHL have rarely been reported. Only one case of a 6-year-old girl has been published, in which multiple non-enhancing white matter lesions, involved the centrum semiovale, cerebral peduncle, tectum, internal capsule, and putamen [8]. The distribution of the affected regions in this previous patient were quite different from those in ours, and there were apparently no hemorrhagic findings on MRI in the girl’s

T. Takata et al. / Journal of the Neurological Sciences 165 (1999) 94 – 97

case [8]. Our patient showed no evidence of CNS necrosis or hemorrhage. However, these negative findings can not rule out AHL because of the low rate of erythrocyte detection from CSF in AHL cases [8], no detection of hemorrhage by imaging studies in several histology-proven AHL cases [3,4,6,7], and possible sampling error in our patient. Hypothermia has been shown to have a prominent protective effect against severe head trauma, which have been ascribed to the maintenance of the blood–brain barrier, the inhibition of the release of excitatory amino acids or cytokines, and the reduction of brain edema [9]. On the 3rd hospital day, our patient showed impending uncal hernia because of severe brain swelling. Immediately after introducing hypothermia, the swelling decreased dramatically, which we considered to be the primary reason his life was saved. In addition to the ameliorative effect on edema, we speculate that the immunosuppresssive and anti-inflammatory effects of hypothermia were beneficial to our patient. Hypothermia attenuates the production of cytokines and subsequent inflammation, and thereby prevents the progression of cerebral edema or ischemia [10]. Further, in vitro experiment showed that neutrophil function, including phagocytosis or migration, was suppressed under moderate hypothermia [11]. In fact, in our patient, CSF analysis done after rewarming showed normalization of cell count and IgG index. Infections are common complications associated with prolonged hypothermia and are considered to be due to the general suppression of immune system [12]. Eight days after the introduction of hypothermia, this patient also developed pneumonia that was unresponsive to antibiotics. This pneumonia had improved a few days after the warming, suggesting that pneumonia was probably related to the hypothermia. The first rewarming after 48 h of hypothermia at 358C had to be stopped because of the reappearance of high ICP signs. This failure probably was due to insufficient cooling and to beginning rewarming too early. We used methylprednisolone pulse therapy only after the second re-warming, but earlier usage may have been appropriate. No therapeutic trials using hypothermia to ADEM or AHL case have been published, and only one encephalitis case of uncertain etiology before the advent of CT with successful recovery was reported [13]. Ours is the first

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reported case of fulminant form of ADEM in which hypothermia was used successfully. Further investigation to obtain the most appropriate strategy for the introduction, maintenance, and discontinuance of hypothermia, as well as measures required to prevent complications during hypothermia are needed. This case report shows that the clinical application of hypothermia has a beneficial effect on fulminant ADEM and that hypothermia should be considered in the repertoire of therapy for fulminant ADEM.

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