Fatal acute disseminated encephalomyelitis associated with cytomegalovirus infection

Abstract

We present the case of a young man with recent cytomegalovirus (CMV) infection who was admitted with generalised seizure and coma. Computed tomography scan and magnetic resonance imaging (MRI) on admission were normal. Despite transient initial improvement he rapidly deteriorated leading to repeated MRI that revealed findings highly suggestive of acute haemorrhagic leucoencephalitis (AHLE). The patient died despite treatment with pulse methylprednisolone and intravenous immunoglobulin. Acute disseminated encephalomyelitis (ADEM)/AHLE should be considered in the differential diagnosis of rapid neurological deterioration even when initial imaging is normal. This case report underscores the importance of early diagnosis as early aggressive treatment may improve outcome.

BACKGROUND

Acute disseminated encephalomyelitis (ADEM) is an acute inflammatory demyelinating disease affecting the central nervous system which usually follows a vaccination or infection of the respiratory or gastrointestinal systems.¹ An abnormal autoimmune reaction directed against normal brain tissue has been proposed as the primary pathogenesis. Hence, high dose corticosteroids are most commonly used for treatment of ADEM, but several immunosuppressive drugs and other therapies have been also used.^1–5 Prognosis is reported to be favourable,^6,7 except for the more fulminant variant, acute haemorrhagic leucoencephalitis (AHLE). Varying degree of demyelination can occur anywhere in the brain, accounting for the wide spectrum of clinical manifestations and disease severity. Thus, diagnosis may be difficult and therefore treatment is sometimes delayed. Here, we report the case of a patient in whom the diagnosis was not made until the second magnetic resonance imaging (MRI) scan had been performed revealing extensive bilateral white matter changes compatible with this rare entity.

CASE PRESENTATION

A 33-year-old previously healthy man was admitted to our hospital with a prolonged complex seizure. He had a 1 week history of fever, cough and mild sore throat, but no headache or photophobia.

On physical examination, the patient was unconscious. His heart rate was 126/min, his temperature was 36.1°C, and blood pressure was 124/82 mm Hg. There were no meningeal signs. Neurological examination revealed reflexes to be diminished bilaterally with no pathological plantar extensor response. The remaining physical examination was within normal limits.

A cranial computed tomography (CT) scan without contrast was normal. Laboratory tests performed at admission revealed no leucocytosis. Haemoglobin, platelets count, liver and kidney function tests and electrolytes were normal. T3 and T4 were within normal range. Electrocardiogram (ECG) and chest radiography were also normal.

A lumbar puncture was performed. Opening pressure was 80 mm Hg, cerebrospinal fluid (CSF) was bloody (hence, interpretation of its findings is limited) and showed 99 mg/dl protein, 82 mg/dl glucose and 95 cells/mm³ (88% polymorphonuclears). Gram staining showed no organisms and culture of CSF was sterile. Polymerase chain reaction (PCR) testing for herpes simplex viruses and enzyme linked immunosorbent assay (ELISA) testing for West Nile virus performed on CSF sample were both negative. Myelin based products (MBP) and CSF antibodies for other viruses were not measured.

The patient was admitted to the medical intensive care unit sedated and intubated. Brain MRI done on the same day was normal. An electroencephalogram (EEG) showed generalised slow activity, with occasional epileptiform activity, mainly in the fronto-temporal regions bilaterally. Antinuclear antibody titres, C3, C4, C-ANCA, P-ANCA and rheumatoid factor were all within normal limits. Values of ammonia and lactate were normal. Serologic evaluation for Brucella, Mycoplasma pneumonia, Rickettsia typhi and Rickettsia conorii and Epstein–Barr virus (EBV) were negative, as well as tests for hepatitis viruses and HIV infection. Recent cytomegalovirus (CMV) infection was determined by positive IgM and IgG, but quantitative titre was not performed nor was PCR for CMV.

Anticonvulsant treatment with sodium valproate was started, along with sedation, acyclovir and antibiotic treatment with ceftriaxone, ampicillin and doxycyclin. Ampicillin and doxycyclin were stopped later based on negative results of serology tests. The patient had no additional seizures and he partially regained consciousness to the point that he could be extubated 4 days after his admission. Over the next 24 h his condition gradually deteriorated, culminating in a generalized seizure. The patient was re-intubated and intravenous phenytoin was added.

INVESTIGATIONS

Repeat CT scan and MRI performed 6 days after admission were significantly different, revealing extensive bilateral white matter lesions which were hypointense on T1 weighted images (fig 1A) and hyperintense on T2 WI (SE-EPI) weighted images (fig 1B). Some of the lesions extended to the adjacent subcortical regions. Low diffusivity areas were identified using DWI (fig 1C). After contrast administration minimal leptomeningeal enhancement was noted (fig 1D). There was no evidence of arterial or venous occlusion. These findings were highly suggestive of AHLE, the fulminant variant of ADEM. A repeat EEG at that time showed mixed theta-delta activity, but ruled out non-convulsive status epilepticus.

Figure 1.

Magnetic resonance images of the second study (A: sagittal T1 WI; B: T2 WI(SE-EPI); C: axial DWI; and D: axial T1 post-contrast) reveal diffuse white matter changes (A+B) without signs of haemorrhage but with restriction in DWI (C). Minimal leptomeningeal enhancement is noted after contrast was given (D).

DIFFERENTIAL DIAGNOSIS

The abrupt onset of neurologic symptoms preceded by a febrile illness had led to an initial working diagnosis of infectious viral encephalitis. However, MRI images consistent with AHLE had raised this rare entity as it suited the clinical presentation as well. Since ADEM/AHLE is a diagnosis of exclusion, differential diagnosis at that time included first uncommon presentation of multiple sclerosis (MS), syndrome of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), and atypical presentation of lupus cerebritis.

TREATMENT

Pulse therapy with steroids (intravenous methylprednisolone, 15 mg/kg/day, for 3 days) was initiated. Thiamine was also given even though MELAS was rather unlikely. Intravenous immunoglobulin (IVIG), 0.4 g/kg/day, was administered for five consecutive days.

OUTCOME AND FOLLOW-UP

Despite treatment no improvement was observed. The EEG was consistent with deep coma showing low amplitude activity. A follow-up MRI done on day 13 revealed diffuse brain oedema and changes in white matter as described in the last scan; however, this MRI also demonstrated involvement of the grey matter and the cerebellum. Brain stem and cerebellum were in a low position, and tonsils protruded into the foramen magnum. There was no significant arterial perfusion and no flow in venous sinuses.

These complex findings reflected the primary disease process accompanied by secondary ischaemic changes resulting in a picture consistent with brain death.

The patient never regained consciousness and died on the 16th day after his initial presentation.

DISCUSSION

The clinical features and imaging studies of our patient are consistent with ADEM. However, the rapid fatal course that was unresponsive to conventional therapy is highly suggestive of AHLE. The case under discussion illustrates the following important clinical issues: (1) association with CMV infection; (2) symmetric findings in MRI and biphasic course; (3) ADEM has a broad spectrum of severity and should be considered in the differential diagnosis of unexplained seizures even when initial imaging is normal. Early diagnosis is of importance as therapeutic response may depend on timing of immunosuppressive therapy.

CMV association

Primary infection with human CMV is usually either subclinical or self limited in the immunocompetent host. The diagnosis of acute CMV infection in our patient was based on the history of fever associated with pharyngitis (primary infection site) and the detection of specific IgM antibodies and by an increase in specific IgG antibody concentrations. Since IgM may be detected for many months following primary infection,⁸ an additional confirmation was obtained by commercial automated VIDAS CMV IgG avidity assay (bioMérieux, France) that further supported the notion of a recent primary infection. In short, VIDAS CMV IgG assay is an automated enzyme linked fluorescent immunoassay that enables quantitative measurement of CMV specific IgG. An index >0.80 excludes recent primary infection since the antibody response matures from low to high avidity antibody production over a period of several weeks to several months. Afterwards, IgG avidity remains characteristically high. In this case, the avidity index of anti-CMV IgG was low (0.64), which is diagnostic of recent infection.

To our knowledge this is only the second reported case of fulminant ADEM associated with CMV infection. Kanzaki et al described a 60-year-old woman with severe acute neurological deficits, in whom CSF examination yielded increased level of CMV antibodies and MRI images of brain and cervical spinal cord showed diffuse lesions that are characteristic of ADEM.⁹ Moreover, it has been shown that the human CMV major capsid protein shares sequence similarity with an encephalitogenic myelin/oligodendrocyte glycoprotein (MOG 34–56). This structural homology provides the foundation for a putative autoimmune mechanism linking CMV infection to ADEM.¹⁰

Symmetric findings in MRI and biphasic course

MRI is the imaging modality of choice for demonstrating the lesions of demyelinating diseases. Characteristic MRI findings of extensive lesions located predominantly in the parieto-occipital white matter bilaterally suggest ADEM.¹¹ However, appearances of brain lesions related to ADEM including solitary lesion with ring enhancement or mass effect have been described.¹² The distribution of these lesions ranges from fairly symmetrical to very asymmetrical. Since there are no pathognomonic MRI findings, the diagnosis of ADEM should always rest on clinical grounds combined with consistent imaging.

The distinction between ADEM and AHLE is difficult. Typically, the lesions of AHLE tend to be larger, associated with more oedema and frequently show foci of haemorrhage.¹³ Nonetheless, there are several histology proven AHLE cases in which imaging studies showed no evidence of central nervous system (CNS) haemorrhage.⁵ Thus, the fact that in our patient no haemorrhage was detected by MRI does not rule out AHLE.

In most patients ADEM is a monophasic disease lasting from 2–4 weeks, but recurrent attacks have been reported.¹⁴ Indeed, it is a difficult diagnostic challenge to differentiate MS from ADEM when neurological disturbances recur. Tenembaum et al¹⁵ suggested the term “biphasic disseminated encephalomyelitis” to describe a variant of ADEM in which patients manifest a biphasic course with a second attack observed at an interval of at least 1 month from initial event. It is doubtful whether our patient’s course was truly biphasic since clinical course and concomitant imaging evolved over a very short time frame. We believe that the findings in the later MRI scans reflected the disease progression that had started earlier. His brief transient improvement was probably related to the natural course of his illness that was unaffected by any intervention that was attempted. Alternatively, it could be suggested that during the first phase he recovered from primary encephalitis caused by CMV, and later deteriorated secondary to the autoimmune AHLE. Both scenarios may be equally plausible, but this distinction has no practical implications.

Clinical spectrum of ADEM and importance of early diagnosis

ADEM is probably more frequent than previously reported. It has a broad clinical spectrum and differentiating ADEM/AHLE from other causes of neurological impairment which are more common may be difficult. Radiographic studies and other laboratory tests are especially valuable in excluding alternative diagnoses. Patients with ADEM may have normal findings on MRI on initial presentation but become characteristically abnormal at a later stage, with a coincident progression of clinical symptoms. Thus, ADEM should be included in the differential diagnosis of unexplained seizures and coma in young adults. Persistent neurological deficit and failure to respond to conventional therapy should entertain this possibility. As with other rare clinical entities, high index of suspicion may lead to earlier diagnosis.

As already mentioned, ADEM is generally considered a benign condition, despite dramatic clinical and radiological presentation. However, the severe form of ADEM, AHLE, has a high mortality rate and requires early diagnosis resulting in early institution of appropriate therapy. Although the management of ADEM has not been subjected to controlled trials, intravenous high dose corticosteroids is the most frequently employed therapy, with good response in most patients. Even though the case under discussion was refractory to standard treatment and despite the lack of evidence that early treatment changes survival rates, it is reasonable to assume that early treatment should be associated with better outcome.

LEARNING POINTS

• Acute disseminated encephalomyelitis (ADEM) is an acute inflammatory demyelinating disease affecting the central nervous system typically associated with characteristic findings on MRI.

• Initial imaging in ADEM may be normal.

• ADEM may be associated with CMV infection.

• ADEM has a broad spectrum of severity and should be considered in the differential diagnosis of unexplained seizures in the young.

• Early diagnosis is important as therapeutic response may depend on timing of immunosuppressive therapy.