key: cord-0799514-gdg75l37
authors: Kakoullis, Loukas; Yalcin, Arman; AbdelRazek, Mahmoud A.; Sasson, Jacques Pierre; Behlau, Irmgard
title: Powassan virus infection presenting as acute encephalitis in a patient from the New England area: a case report
date: 2022-04-25
journal: Neurol Sci
DOI: 10.1007/s10072-022-06058-z
sha: 32ad5ed900e7db1e9596ea02d8b3d22f08860f83
doc_id: 799514
cord_uid: gdg75l37

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Basic laboratory parameters on presentation were nonrevealing, apart from a mild hyponatremia with a sodium of 131. Cerebrospinal fluid (CSF) evaluation revealed lymphocytic pleocytosis and normal levels of protein and glucose (Table 1) .

Imaging studies at presentation, including chest X-ray, head CT, and brain MRI, did not reveal any significant findings. However, a follow up MRI 1 week later revealed increased T2 signal present within the basal ganglia including the caudate nuclei, globus pallidus, and putamen bilaterally, as well as subcortical T2 hyperintensity in the bilateral posterior parietal lobes and in the cerebellum (Fig. 1) .

A wide range of microbiology and immunology investigations were carried out (Table 2) , including titers for VZV, babesiosis, tularemia, CSF VDRL, eastern equine encephalitis virus, West Nile virus, enterovirus, and CSF cryptococcal antigen, but all were negative. Serum HSV 1&2 IgG were positive, but both serum IgM and CSF PCR were negative. A tick-borne disease panel was notable for past infection (IgG only) with Borrelia burgdorferi and Anaplasma spp. EBV antibody titers were positive, but serum EBV PCR was negative. EBV convalescent titers obtained 21 days later showed a change in titers but given that the IgM titer did not change by a fourfold and the PCR was negative, it was unlikely that this represented an acute EBV infection. Finally, an autoimmune encephalitis panel did not reveal any findings.

The patient's presentation, which consisted of subacute onset of confusion, lymphocytic pleocytosis in the CSF, and findings of inflammation in the basal ganglia, parietal lobes, and cerebellum on MRI were suggestive of encephalitis. The differential diagnosis included autoimmune encephalitis, acute disseminated encephalomyelitis (ADEM), viral encephalitis, and tick-borne associated encephalitis. Given that the patient resided in Martha's Vineyard, an island off the coast of Massachusetts, USA, which suffers from a heavy burden of tick-borne infections, such as Lyme disease, West Nile Virus, and Anaplasma encephalitis were evaluated for.

Laboratory testing was negative for common viral causes of encephalitis, autoimmune encephalitis, and acute tick-borne illnesses, including West Nile Virus; notably, patient had remote past infection for Anaplasmosis and Lyme disease.

Specifically, the involvement of the basal ganglia made Powassan virus encephalitis a possible diagnosis, as this finding has been associated with infections by Flaviviridae [1] . Therefore, after 9 days of hospitalization, a CSF sample was submitted to the CDC for antibody titers against Powassan virus.

Based on the initial CSF finding of lymphocytic pleocytosis, the patient was started on an empiric 10-day acyclovir course; her CSF PCR for HSV 1 & 2 resulted as negative. She completed a course of ceftriaxone for empiric coverage of central nervous system bacterial infections and received a 28-day course of doxycycline, in the event that she had Lyme meningitis. She also received a 6-day course of Prednisone 60 mg daily with tapering, which was associated with a slight improvement of her symptomsshe could ambulate to the bathroom, was more conversant, and had a slight improvement in her short-term memory.

She subsequently also received a 4-day course of IVIG, without any further improvement of her symptoms.

The patient's neurological function improved slightly, as she was more conversant after corticosteroid administration, but she remained oriented only to self. She was discharged after a total of 33 days of hospitalization. Two weeks postdischarge, the CDC reported that her CSF was positive for Powassan virus IgM antibodies. On follow-up examination 7 weeks post-discharge, her cognitive function remained impaired, which was supported by her scoring 13/30 on a Mini Mental State Exam, but she was otherwise physically doing well. Unfortunately, 4 months later, she continues to be cognitively impaired and her MRI remains unchanged.

Between 2010 and 2019, there have been 181 documented cases of Powassan virus encephalitis in the USA. The vast majority have been identified in four states, namely Minnesota, Wisconsin, Massachusetts, and New York, which when combined, make up 74% of cases. Of these 181 cases, 166 had neuroinvasive disease (91.7%) and 21 (11.6%) resulted in death. Of note, death occurred only in patients with neuroinvasive disease [2] .

Rates of Powassan virus infections have been increasing, likely due to the increased awareness for arboviral encephalitides secondary to the West Nile Virus outbreaks, as well as the territorial expansion of one of the vectors of Powassan virus, Ixodes scapularis [2, 3] . Indeed, 85% of Powassan virus infections reported by the CDC between 2010 and 2015 included patients with encephalitis or meningitis, while only 15% of patients had non-neuroinvasive disease, suggesting that patients without CNS involvement are less likely to be tested for Powassan virus [3] .

The 2 variants of Powassan virus are transmitted by different vectors. Lineage I is transmitted by Ixodes cookei, while Lineage II is transmitted by I. scapularis, the tick vector for Borrelia burgdorferi, Babesia microti, and Anaplasma phagocytophilum [3] . However, whereas the transmission of other tick-borne diseases requires prolonged tick attachment (48 h for Lyme disease and 24 h for babesiosis), Powassan virus can be transmitted to a new host within 15 min. What sets it apart is that the virus is located in the salivary glands of the tick prior to the tick bite, allowing it to rapidly infect the new host [4] . Regarding its clinical presentation, after an incubation period of 8 to 34 days, the disease initially manifests with malaise, nausea, and sore throat. Patients who develop neuroinvasive disease go on to manifest high fever, headache, and disorientation 1 to 3 days later. Other findings include cranial nerve palsies, convulsions, obtundation, tremors, twitching, nystagmus, hallucinations, hemiparesis, quadriplegia, and respiratory failure [3, 5] .

Imaging findings of Powassan virus neuroinvasive disease are most commonly appreciated using MRI with T2-weighted fluid-attenuated inversion recovery (T2/ FLAIR) sequences. Similar to other arboviruses, such as West Nile Virus, Powassan virus has a predilection for the deep foci in the basal ganglia, thalamus and brainstem. In addition, it may affect the cerebellum and cortex [1, 3] . Pathology findings include necrotizing inflammation with a lymphocytic infiltrate primarily in the gray matter, as well as reactive gliosis [3] .

The diagnosis of Powassan virus encephalitis is established through the identification of the virus, either directly through PCR in serum or CSF samples during the prodromal phase, or indirectly, either through identification of IgM neutralizing antibodies in the serum or CSF during the acute illness phase or through serum IgG in later phases [2, 3] .

Neuroinvasive disease can have devastating long-term complications, including cognitive deficits, memory loss, hearing impairment, aphasia, muscle wasting, dysarthria, apnea, psychosis, and spastic hemiplegia, which develop in about 50% of patients, while approximately 10% of cases result in death. There is no specific treatment for Powassan virus disease; therefore, prevention of the disease through the avoidance of tick bites is of utmost importance [3, 5] .

In conclusion, Powassan virus encephalitis is a severe tick-borne infection that can lead to devastating long-term complications or even death. The diagnosis requires a high degree of clinical suspicion and is based on epidemiologic evidence of tick exposure in patients with symptoms and signs of central nervous system infection. In general, the combination of findings of encephalitis, history of recent travel to an endemic region, and T2/FLAIR hyperintensities in the basal ganglia should suggest Powassan virus encephalitis as a probable cause. As treatment remains supportive, prevention of tick bites is critical in limiting occurrence of disease in the population. 

Flavivirus encephalitis

Tick-borne flaviviruses, with a focus on Powassan virus

Short report: duration of tick attachment required for transmission of Powassan virus by deer ticks

Underrecognized tickborne illnesses: Borrelia miyamotoi and Powassan virus

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The authors would like to thank Dr. Adam Basiago for selecting the pertinent MRI slides and Mr. Mehdi Bandali for his critical review of the manuscript.

Ethical approval This work is in accordance with the requirements of the authors' institution regarding research involving human participants, as well as with the 1964 Helsinki Declaration and its later amendments.