Journal of Clinical Apheresis 7: 173-179 (1992)

Role of Plasmapheresis in Acute Disseminated (Postinfectious) Encephalomyelitis Raphael B. Stricker, Robert G. Miller, and Dobri D. Kiprov Divisions of lmmunotherapy and Neurology, Department of Medicine, California Pacific Medical Center, San Francisco, California Acute disseminated encephalomyelitis (ADEM) is a demyelinating central nervous system disease that is associated with high morbidity and mortality. Although the recognition of ADEM may be facilitated by newer imaging techniques, the optimal treatment of this disease remains uncertain. We describe 4 patients with severe ADEM who responded to treatment that included intensive plasmapheresis. Two of the patients were in coma at the time that plasmapheresis was instituted, and all 4 patients made an excellent recovery. Immunologic studies revealed increased serum IgA levels, increased circulating immune complex levels as measured by the Raji cell assay, and decreased numbers of T and B cells prior to treatment of ADEM. These abnormalities improved following plasma exchange. Plasmapheresis appears to be effective in reversing the neuropathologic process in ADEM. The role of this treatment modality in ADEM requires further evaluation in controlled clinical trials. 6 I992 Wiley-Liss, Inc.

Key words: plasma exchange, central nervous system disease, ADEM.

INTRODUCTION

Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the central nervous system (CNS) that occurs following infection or immunization [l-91. ADEM accounts for one third of all cases of encephalomyelitis diagnosed in the United States, and it has a mortality of up to 30% [ 1-31. Neurologic deficits may occur in 19% of patients following ADEM, and recurrences have been reported in 28% of patients [6]. Although ADEM is thought to be an infection-induced autoimmune disease of the CNS, its pathogenesis is poorly understood [4-61. In the past, the diagnosis of ADEM has been based on clinical findings [ 1,2]. Although computerized tomographic (CT) scanning may be helpful, the CT scan is frequently normal in this disease [10,11]. In contrast, magnetic resonance imaging (MRI) reportedly provides a highly sensitive test for ADEM [12-141. With wider availability of this imaging technique, ADEM may be diagnosed more rapidly and accurately in the future. Thus, it is essential that effective treatment for this disease should be available. Corticosteroid therapy may lead to improvement in up to 64% of cases, but relapse on tapering the medication is common [3]. In severe cases of ADEM, the optimal therapy for the disease is unclear. We describe 4 patients with severe ADEM who responded to treatment with plasma exchange. Our report represents the largest group of patients with ADEM ever to be treated with plasmapheresis. 0 1992 Wiley-Liss, Inc.

CASE REPORTS Patient 1

A 25-year-old woman was admitted to the hospital because of confusion. She was well until 2 weeks prior to admission, when she developed low-grade fever, headache, and myalgias. A complete blood count was normal, and she responded to symptomatic treatment. She remained well until 2 days prior to admission, when she became progressively confused and disoriented. There was no history of alcohol abuse, and she took no medications. Physical examination revealed that the patient was afebrile. There was no lymphadenopathy or hepatosplenomegaly . Neurologic examination revealed disorientation to time and place. She did not recognize her family. The motor and sensory examination was nonfocal. Reflexes were increased symmetrically. Laboratory evaluation showed white blood cells (WBC) 7,6001pl, hematocrit 41.5%, and platelets 347,OOO/pl. Tests of liver and renal function were normal. Examination of cerebrospinal fluid (CSF) showed 150 WBC/pl (96% lymphocytes), protein 41 mg/dl, and glucose 72 mg/dl. The CSF contained 3 oligoclonal bands, and myelin ba-

Received for publication May 16, 1992; accepted September, I , 1992. Address reprint requests to Raphael B. Stricker, M.D., California Pacific Medical Center, California Campus, P.O. Box 7999. San Francisco, CA 94120.

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sic protein was undetectable. Cultures of CSF were negative. A CT scan of the brain was negative. Over the next 5 days, the patient became progressively obtunded. An MRI scan was reported to be normal. An electroencephalogram (EEG) showed marked generalized slowing without focal or paroxysmal features. The patient became comatose with respiratory insufficiency. She was intubated and maintained on a ventilator. Cultures of blood, urine, and sputum were negative. Tests for syphilis, Epstein-Ban- virus, mycoplasma, herpes simplex virus, influenza virus, and leptospirosis were all negative. Because of the patient’s deteriorating clinical state, plasmapheresis was instituted. A single-volume plasma exchange was performed daily using the IBM 2997 cell separator, as previously described [ 151. Each exchange was performed using 5% albumin as the replacement fluid. After 3 treatments, the patient became responsive to verbal stimuli. She was gradually weaned from the ventilator. She received a total of 10 treatments, after which she became oriented to place and could recognize her family. Corticosteroids were instituted in an attempt to decrease further inflammation of the CNS. She was discharged to a rehabilitation facility and her mental status returned to normal over the next 2 months. She has no residual neurologic deficits, and she remains well 3 years after her acute illness. Patient 2

A 31-year-old woman was admitted to the hospital because of headache, nausea, vomiting, and photophobia. She had undergone cesarean section with delivery of twins 10 weeks prior to admission. One week prior to admission she developed headache, myalgias, and malaise. The headache became severe and did not respond to acetaminophen and codeine. The patient denied alcohol abuse or ingestion of other medications. On physical examination, the patient was afebrile. There was shotty left cervical lymphadenopathy and mild nuchal rigidity. There was no organomegaly . Neurologic examination revealed that the patient was alert and oriented without focal deficits. Laboratory evaluation showed WBC 13,40O/pl, hematocrit 40.7%, and platelets 327,00O/pl. Tests of renal and liver function were normal. Examination of CSF revealed 137 WBC/ pl (82% lymphocytes), protein 86 mg/dl, and glucose 84 mg/dl. Oligoclonal bands were present, and cultures of CSF were negative. A CT scan of the brain was negative. The patient was treated with intravenous antibiotics for possible bacterial meningitis. However, 3 days after admission she was found on the floor of her room in a confused state. Subsequently, she developed paraplegia, incontinence, left IV cranial nerve palsy, a visual field defect, and sensory loss below the level of T I . A repeat

CT scan of the brain was negative, but an MRI scan of the thoracic spine was consistent with myelitis. Over the next 3 days, the patient developed respiratory insufficiency and coma. She was intubated and maintained on a ventilator. Cultures of blood, urine, and sputum were negative, and all viral studies were negative. Because of the patient’s deteriorating clinical status, plasmapheresis was instituted using the IBM 2997 cell separator. A single-volume plasma exchange was performed daily with 5% albumin as the replacement fluid. After 2 treatments, the patient became responsive and could be weaned from the ventilator. She received a total of 5 plasmapheresis treatments, with gradual improvement in her muscle strength and resolution of her bulbar palsy and visual field deficit. Her sensory deficit decreased to the level of T10. Antimyelin antibody was reported to be present in serum, as measured by Dr. D. Griffin at Johns Hopkins Medical Center. The patient subsequently was placed on corticosteroids. She was discharged to a rehabilitation facility, where she continued to recover from her paraplegia and sensory deficit. After 3 months she could walk with a cane, and her sensory deficit had resolved. She remains well with only a minimal motor deficit 3 years after her acute illness. Patient 3

A 5-year-old boy was admitted to the hospital because of agitation, weakness, and ataxia. He was well until 3 weeks prior to admission, when his parents noted 2 episodes of lethargy and leg weakness that resolved spontaneously. Examination by a private physician was unrevealing. The child was then well until 6 days prior to admission, when he developed abdominal pain and a WBC count of 36,OOO/pl. A barium enema was negative. He was treated with intravenous hydration and his abdominal symptoms resolved. However, on the day of admission, he had several episodes of agitation with crying, shouting, and screaming. His mother also noted unsteady gait. He was admitted to a local hospital, where he continued to have periods of combative behavior over 3 days with 1 episode of unfocused gaze. He was transferred to the intensive care unit. Physical examination revealed no fever, lymphadenopathy, or hepatosplenomegaly . Neurologic examination showed decreased strength in the right arm, falling to the left, and an upgoing toe on the left. There was a slight left facial droop. Deep tendon reflexes were brisk. Laboratory examination showed WBC 25,900/ p1, hematocrit 35.5.%, and platelets 408 ,OOO/ pl. Tests of liver and renal function were normal. Examination of CSF revealed 90 WBC/pl with 46% lymphocytes, protein 41 mg/dl, and glucose 64 mg/dl. Bacterial and viral cultures of CSF were negative. A test for measles antibody

Plasmapheresis in Encephalomyelitis

was positive in the midrange. Antibodies against arboviruses, herpes simplex virus I and 11, Epstein-Barr virus, and Borrelia burgdorferi were undetectable. Tests for hepatitis B surface antigen and anti-core IgM were negative, while tests for hepatitis B surface antibody and anti-core IgG were positive. Antinuclear antibody and anti-DNA antibody titers were negative. A CT scan of the brain was normal. However, an MRI scan revealed multiple foci of white matter abnormalities in the left peritrigone and the right brachium pontis consistent with demyelination. The patient was treated with intravenous acyclovir. Over the next 24 hours he continued to be irritable, ataxic, and weaker in his arms. He also refused to eat. Because of the progression of his clinical symptoms, plasmapheresis was instituted using the Cobe Spectra cell separator. A single-volume plasma exchange was performed daily for 3 days using 5% albumin as the replacement fluid. After the first exchange, the patient became more coherent and began to eat. He had an episode of agitation and hallucinations after the second treatment. By the third treatment, his arm weakness and ataxia had markedly improved. Plasmapheresis was discontinued, and the child was placed on corticosteroids. He was discharged home with physical therapy for his weakness. By 1 month after discharge, his motor deficit had almost completely resolved, and he was symptom free at 6 months. Patient 4

A 27-year-old man was admitted to the hospital because of diplopia, ataxia, and headache. He was in good health until 2 weeks prior to admission, when he developed fever to 104"F, oral mucosal ulceration, and diarrhea. He was treated with amoxicillin and his symptoms resolved. One day prior to admission he noted the onset of unsteady gait and visual abnormalities. There were no fevers, chills, or weakness, and he was taking no medication. Physical examination on admission revealed no adenopathy on organomegaly. There was horizontal and rotatory nystagmus, incomplete abduction of the left eye, and mild ataxia. Motor strength in the extremities was normal, and deep tendon reflexes were intact. Laboratory evaluation revealed WBC 12,30O/pl, hematocrit 42.9%, and platelets 255,0001pl. Tests of liver and renal function were normal. CSF examination showed 3 WBC (all lymphocytes), protein 42 mg/dl, and glucose 66 mg/dl. Oligoclonal bands and myelin basic protein were not detected. Tests for hepatitis B virus, Epstein-Barr virus, syphilis, Borrelia burgdorferi, cryoglobulins, antinuclear antibody, and heavy metals were all negative. Cultures of blood, urine, and CSF were also negative.

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TABLE I. Clinical Features of Patients with ADEM Patient

Prodromal illness Time to ADEM (days) Features of ADEM Confusionlagitation Weakness Coma Sensory loss Bulbar deficits Ataxia Respiratory failure Seizures CT scan MRI scan Number of pheresis treatments

1

2

3

4

25 F

27 F

5 M

27 M

14

7

6

14

+ + +

+ + + + + +

+ +

-

+

-

+

+

+

-

+ +

-

+ +

+ + +

-

-

-

-

-

(+)

-

-

-

-

-

-

+

+

-

10

5

3

8

CT, computerized tomographic brain scan; MRI, magnetic resonance imaging.

Over the next 3 days, the patient's condition worsened with more pronounced ataxia, progressive intranuclear ophthalmoplegia, lethargy, intermittent confusion, dysarthria, and facial paresthesias. He was unable to walk because of the ataxia. Electrophysiologic studies demonstrated slowing and desynchronization of somatosensory and visual evoked potentials, consistent with a demyelinating encephalomyelitis. An electromyographic study of peripheral nerve function was normal. CT and MRI scans of the brain were both negative. Because of the patient's progressive clinical deterioration, plasmapheresis was instituted using the Cobe Spectra cell separator. A single-volume plasma exchange was performed daily for 4 days using 5% albumin replacement. During this treatment the patient became more alert, his speech improved, and his facial signs resolved. He was started on corticosteroids and he received 4 additional plasma exchanges over the next 7 days. His vision and ataxia improved, and his speech became clear. He was discharged to a rehabilitation facility, where he made a complete recovery over the next 2 months. METHODS AND RESULTS

Oligoclonal bands in CSF were detected by isoelectric focusing [ 161. Serum immunoglobulin levels were determined by rate nephelometry [ 171. Serum immune complex levels were measured using the C l q binding and Raji cell assays [ 18,191, Lymphocyte subsets were determined in peripheral blood using flow cytometry, as previously described [20]. The clinical features of the 4 patients with ADEM are shown in Table I. Each patient had a prodromal viral-

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TABLE 11. Cerebrospinal Fluid Findings at Diagnosis in Patients With ADEM Patient White blood cells Lymphocytes Protein Glucose Oligoclonal bands Myelin basic protein

TABLE 111. Serum Immunoglobulin Levels in Patients With ADEM Before and After PlasmaDheresis

I

2

3

4

Normal

150 144 41 72

137 112 86 84

90 41 41 64

+

3 3 42 66

-

O-IOpl 0-10 pI 15-45 mg/dl 40-75 mgidl

-

ND

ND

-

+

+

-

ND, not done

type illness 1-2 weeks prior to the onset of neurologic disease. Subsequently each patient developed signs of severe encephalomyelitis. The 2 women were in coma with respiratory failure at the time that plasmapheresis was instituted. The boy had ataxia, bulbar signs, and seizure-like activity, while the man had severe ataxia, bulbar signs, and lethargy. In each case, steroid therapy was withheld because of the possibility of infectious encephalomyelitis. Culture studies were repeatedly negative in all 4 patients, however. CT scans of the brain were negative in all patients, while MRI scans were positive in 2 of the 4 cases. The number of plasma exchanges varied from 3 to 10 in each case. CSF findings are shown in Table 11. Patients 1-3 had pleocytosis with increased numbers of lymphocytes, These patients also had oligoclonal bands present in CSF. In contrast, patient 4 did not have pleocytosis or oligoclonal bands in his CSF. The CSF protein level was elevated in only 1 of the 4 patients, and free myelin basic protein was not detected in the 2 patients who were tested. Thus CSF abnormalities were variable in these patients. Serum immunoglobulin levels were measured in patients 1-3 (Table 111). All 3 patients had increased levels of serum IgA at the time of diagnosis of ADEM. Serum IgG and IgM levels were normal. The IgA levels returned to the normal range after plasmapheresis. Patient 3 also had circulating immune complex levels measured by the C l q binding and Raji cell assays (Table IV). Immune complexes were not detected using the C l q assay. In contrast, extremely high levels of immune complexes were detected by the Raji cell assay. These levels returned to normal following plasma exchange (over a period of 5 days). Serum complement levels were normal (data not shown).

Normal range (mg/dl) Patient 1 Prepheresis Postpheresis Patient 2 Prepheresis Postpheresis Patient 3 Prepheresis PostDheresis

IgA

IgG

IgM

35-220

660- 1,500

60-280

422 ND

1,300 ND

215 ND

415 223

1,260 1,100

21 1 265

436 204

1,230 1,320

225 108

ND, not done.

Lymphocyte subsets were determined before and after plasmapheresis in patients 1, 3, and 4 (Figs. 1-4). During the acute illness, each patient demonstrated a decrease in CD8 (suppressor/cytotoxic) T-cells (Fig. 1). CD4' (helperiinducer) T-cell numbers were normal or slightly decreased in each patient (Fig. 2). Following plasmapheresis, the number of CD8 T-cells returned to normal (Fig. 1). CD4+ T-cell numbers also increased following plasma exchange (Fig. 2). The total number of T-cells more than tripled in each patient following plasmapheresis (Fig. 3). B-cell numbers also increased 2- to 3-fold in each case (Fig. 4). +

+

DISCUSSION

ADEM is an acute demyelinating disease of the CNS. The disease has been reported following infections with measles, mumps, influenza virus, Epstein-Barr virus, rubella, varicella, and Mycoplasma [ 1-91. In addition, ADEM has been associated with immunization against vaccinia and rabies [1,2]. In many cases, however, no specific infectious agent can be identified, and the diagnosis is made on clinical grounds. Although ADEM may be mild and reversible within 4-6 weeks [1,2], some patients develop severe neurologic impairment, including respiratory failure and coma. Since the pathogenesis of ADEM is poorly understood, identification of patients at risk for severe disease is difficult, and the availability of effective treatment for severe neurologic impairment is important. It has been postulated that ADEM is the CNS equiva-

TABLE IV. Immune Complex Assays in Patient 3 Before and After Plasmapheresis Assay 1. ClQ binding 2. Raji cell

Prepheresis

Postpheresis

Normal

Role of plasmapheresis in acute disseminated (postinfectious) encephalomyelitis.

Acute disseminated encephalomyelitis (ADEM) is a demyelinating central nervous system disease that is associated with high morbidity and mortality. Al...
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