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Abstract
We describe a patient who died from a fulminant presentation of encephalitis. After an exhaustive search, we found no treatable cause. Postmortem PCR analysis of brain tissue led to a diagnosis of eastern equine encephalitis. We have identified several clinical pearls that may assist others in making the diagnosis earlier in the disease course.
- infectious diseases
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CASE
A 55-year-old man presented to the emergency room in October with 2 days of fever, 1 day of intractable vomiting, frontal headache, and 12 hours of diplopia. In the emergency room, he developed dysarthria and a left facial droop. He was receiving monthly rituximab infusions for Waldenström’s macroglobulinaemia. He had been hiking in a wooded area of northern New Jersey, USA, several weeks before presentation and had sustained multiple mosquito bites.
On examination, he had a fever of 39.4°C but with otherwise normal vital signs. His mental status was normal and there was no nuchal rigidity. He had left-sided lower motor neurone facial weakness. His knee reflexes were brisk and there was ankle clonus. Investigations included a peripheral white blood cell count of 15.8×109/L (4.5×109/L–10.5×109/L) with a neutrophilia. His erythrocyte sedimentation rate was 5 mm per first hour (<15). Urine analysis and chest radiograph were normal. Blood cultures were sent. CT scan of head without contrast was normal except for a probable small arachnoid cyst in the high left cerebral convexity. We empirically started him on ceftriaxone, vancomycin, ampicillin and acyclovir to cover community-acquired causes of bacterial and viral meningoencephalitis. An urgent lumbar puncture showed 1.523×106/L (1523/uL) white cells (normal ≤5) (63% neutrophils), 0 red cells, glucose 4.1 mmol/L (serum 9.7) and protein 1.46 g/L. Gram stain was negative and bacterial culture was sent. We also sent a cerebrospinal fluid (CSF) multiplex PCR panel, including selected viral causes of meningoencephalitis.
Three hours after his presentation, he remained alert but became more dysarthric, with a new left gaze preference and left arm weakness (grade 4+/5). Several hours thereafter, he became comatose and required intubation for airway protection. An MR scan of brain with and without contrast on the day of admission showed extensive T2 signal abnormality within the basal ganglia, thalamus, midbrain and pons. There were also scattered areas of cortical T2 hyperintensity. Additionally, there was an unusually prominent region of T2 prolongation within the external capsule that hooked around the putamen and extended into the posterior limb of the internal capsule on both sides (figure 1). Video-electroencephalography monitoring for 72 hours showed only moderate-to-marked generalised background slowing without epileptiform activity.
T2 fluid-attenuated inversion recovery showing T2 prolongation in the basal ganglia, thalami and cortex. In addition, there is a strikingly hyperintense T2 signal noted in the external capsule that wraps around the putamen and involves the posterior limb of the internal capsule on both sides (parenthesis sign).
During his hospitalisation, he remained intubated on full ventilatory support, comatose with intact pupillary and corneal responses, but absent vestibulo-ocular reflex and gag reflex, and no motor response to noxious stimulus. CSF bacterial culture, blood cultures, paraneoplastic panel testing, HIV testing (fourth-generation antibody/antigen assay) and PCR testing were negative for the following: Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, Listeria monocytogenes, herpes simplex virus 1 and 2, varicella zoster virus, West Nile virus, Epstein–Barr virus, cytomegalovirus, enterovirus and Cryptococcus neoformans. A CSF arbovirus IgM and IgG panel (including testing for eastern equine encephalitis, western equine encephalitis, St. Louis encephalitis and La Crosse encephalitis) was negative. The leading diagnosis remained an unidentified fulminant viral meningoencephalitis.
Following discussion with his family, we obtained a brain biopsy during his illness to exclude a treatable cause of encephalitis. A right frontal lobe biopsy including both cerebral cortex and adjacent white matter showed patchy necrosis with associated macrophages, suggesting viral encephalitis. After there was no clinical change for 2 weeks, we treated him palliatively and he died shortly thereafter. We requested a brain autopsy and sent frozen brain tissue for further molecular analysis. Total nucleic acid was obtained from a 10% suspension of brain tissue in phosphate-buffered saline using bioMérieux easyMAG and run in a PCR assay for viral causes of encephalitis. All targets were negative except for eastern equine encephalitis, which was several logs stronger than the positive control.
Neuropathological findings
The brain weighed 1540 g (normal 1410±10 g).1 The brain was immersed in 10% normal buffered formalin solution for 3 weeks. Gross examination after fixation showed mild diffuse cerebral oedema (figure 2). There was no gross evidence of haemorrhage, necrosis or infarction, aside from prior treatment. Sections stained with H&E and luxol fast blue showed patchy parenchymal necrosis with microglial nodules and chronic inflammation with reactive gliosis consistent with panencephalitis (figure 3). The patchy necrosis was predominantly in the substantia nigra, basal ganglia, basal forebrain, thalamus and cerebellar dentate nucleus, but also in the region of the claustrum and external capsule. The leptomeninges showed only slight focal chronic inflammation. There was variable moderate-to-marked neuronal loss throughout the brain with focal loss of the laminar and columnar architecture within the cerebral cortex.
Gross examination of the brain showed mild oedema: (A) superior cerebral surface with biopsy site at the right frontal lobe; (B) left lateral surface with mild gyral flattening and narrowing of sulci; (C and D) coronal sections showing marked narrowing of the lateral ventricles with haemorrhagic biopsy site and intraventricular shunt tract (right frontal lobe and corpus callosum, respectively). Scale bar represents 2 cm.
(A) H&E, 4× with patchy white matter pallor and rarefaction; (B) H&E, 10× with microglial nodule (arrow); (C) combination H&E and luxol fast blue (myelin stain), 20× with loosely defined collection of microglia associated with vacuolation of the surrounding neurophil (microglial nodule) in the area of the external capsule; (D) H&E, 10× of parenchymal blood vessel with slight perivascular chronic inflammation (arrow); (E and F) combination H&E and luxol fast blue (4× and 20×, respectively) of linear necrosis of the substantia nigra (arrows) with marked neuronal loss and macrophages containing pigmented neurone debris (arrow heads).
Discussion
In a recent large retrospective review of encephalitis, the most common causes were viral (48%) and autoimmune (22%)2; in 30%, there was no identifiable cause.2 Our patient’s fulminant presentation with high fever and focal neurological signs supported an infective process. Although he was urgently started on empirical antibiotics, we found no treatable infection after an exhaustive search. The rapidity and severity of his neurological decline raised the suspicion of eastern equine virus as the cause.
Eastern equine encephalitis is a rare mosquito-borne viral infection found mainly along the East and Gulf coasts of the USA. There are an average of eight human cases of neuroinvasive disease reported annually in the USA, with most cases presenting between June and October.3 Although most infections are clinically asymptomatic, a minority develop neuroinvasive disease with a mortality of 33% and severe brain injury in many survivors.3 Although we do not know the risk factors for developing neuroinvasive disease, our patient’s long-term rituximab treatment may have lowered his ability to mount a robust B-cell-mediated immune response and contributed to his rapid decline. His serum IgG concentration on presentation was low at 4.68 g/L (6.0–13.0 g/L). Rituximab treatment has been previously associated with a more severe disease course and diminished humoural response in transplant patients with West Nile virus meningoencephalitis.4
This patient’s neuropathological examination findings were similar to those previously reported (table 1) with an inflammatory response comprising microglial nodules with lymphocytes, primarily T-cell lymphocytes, and only a few neutrophils. However, unusually, the substantia nigra showed the most severe neuronal loss and inflammation. This distribution has not previously reported in eastern equine encephalitis, but can occur in encephalitis lethargica and in West Nile encephalitis.
Neuropathological findings in eastern equine encephalitis: review of selected literature
Our report underscores the limitations of early CSF antibody testing for eastern equine encephalitis. Possible reasons for the negative IgM and IgG antibody tests include blunting of the B-cell response by rituximab and testing early in the disease course before an antibody response could be mounted. His dramatic white cell pleocytosis (predominantly neutrophils), elevated protein and absence of hypoglycorrhachia are consistent with previous cases.5 Among a series of patients with eastern equine encephalitis, 77% of those with CSF white cell counts of >5×105/L (>500/uL) had an unfavourable outcome compared with 28% of those with fewer CSF white cells.5 His MR scan of brain showed oedema in the basal ganglia, thalamus and midbrain, although these are non-specific and can occur in encephalitis caused by members of the togavirus family.6 The more remarkable finding was of an unusually prominent region of T2 prolongation in the external capsule that hooked around the putamen and extended into the posterior limb of the internal capsule: this has been recently reported in patients with eastern equine encephalitis and labelled the ‘parenthesis sign’.7 Neuronophagia with microglia and macrophages around dead neurones is a hallmark of viral encephalitis.8 However, the innumerable scattered microglial nodules throughout this patient’s parenchyma suggest prior neurone destruction with subsequent resorption of the necrotic neurones over time. The finding of pigmented neurone debris within macrophages of the substantia nigra and necrosis confined to this linear region further supports widespread neuronophagia. The parenthesis sign seen on radiology likely relates to this patchy necrosis and associated microglial nodules seen in the claustrum and external capsule.
This patient had several features suggesting a poor prognosis, including his age, rapid clinical decline and pronounced inflammatory response in the CSF. We emphasise the importance of testing CSF PCR for eastern equine encephalitis when the sample is drawn early in the disease course, as an antibody response may not yet have mounted, particularly in an immunosuppressed patient. In addition, his MR scan finding of the parenthesis sign further suggested eastern equine encephalitis.
Key points
Eastern equine encephalitis predominantly occurs along the Gulf and East coasts of the USA and can result in severe neuroinvasive disease with high mortality.
Characteristic MR scan findings are prominent T2 hyperintensity in the basal ganglia and thalamus together with the ‘parenthesis sign’.
When a lumbar puncture is performed early in the course of eastern equine encephalitis, cerebrospinal fluid PCR testing is probably more sensitive than antibody testing.
Acknowledgments
We thank Dr Simon Tsiouris for his review of the manuscript.
Footnotes
Contributors The authors contributed equally to the conception, writing and revision of the manuscript.
Competing interests None declared.
Patient consent Obtained.
Ethics approval None declared.
Provenance and peer review Not commissioned; externally peer reviewed. This paper was reviewed by Nicholas Davies, London, UK.
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