WNV is a member of the Japanese encephalitis antigenic sero-complex, belonging to the family of Flaviviridae, which also includes Japanese encephalitis virus, St Louis encephalitis virus, Dengue Virus, Yellow Fever Virus and the emerging Zika Virus (5, 6). It was first identified in the West Nile province of Uganda in 1937 (7). Since the initial communication, several WNV outbreaks were reported in Africa and in the Middle East, but significant disease activity was identified in Europe and North-America only after 1990 (8). The first major outbreak in Europe was described in south-east Romania in 1996 (9). Nowadays, cases of WNV infection are reported in many European countries, but the incidence is higher in the central and southern regions (10).

In nature, WNV is maintained in a bird-mosquito-bird transmission cycle. Birds develop sustained viremia and are considered amplifier hosts while humans usually develop transient low-level serum viremia and are unlikely to act as a reservoir for the virus. Transmission to humans commonly occurs through the Culex Mosquito spp. but transmission by blood transfusion, organ donation, pregnancy, and lactation have also been identified or postulated (5).

WNV infections usually start in summer and peak in early fall due to the natural life cycle of the mosquitos (9, 11). Local risk factors that might contribute to WNV amplification in the environment include elevated ambient temperature, heavy rains, stagnant water sources and immunologically naive avian host reservoirs (12). The onset of symptoms of our patient and of two other reported cases of OMS associated with WNV infection was in the typical early fall period. Although there are no reported details about the season of disease onset for the other similar published cases, WNV infection should probably be highly considered and searched for in all cases of OMS of undetermined etiology with onset during early fall.

Up to 70% of the individuals infected with WNV will remain asymptomatic or will develop only minor, non-specific symptoms while one third will present with West Nile fever or other rare forms of the disease (13, 14). The clinical picture of West Nile fever is indistinguishable from other flu-like illnesses and includes: fever, headache, malaise, myalgia, nausea, vomiting, abdominal pain, and a morbilliform or maculopapular rash (13, 15). Although symptoms are usually self-limited, some patients develop persistent complaints such as fatigue, memory impairment or headache (16, 17).

Neuroinvasive disease occurs in <1% of patients who develop clinical manifestations of WNV infection and can manifest as one of the following three clinical entities: WNV meningitis, WNV encephalitis or acute flaccid paralysis (18). Established risk factors for neuroinvasive disease include: advanced age, history of cardiovascular disease, chronic kidney disease, hepatitis C infection, immunosuppression, and particular genomic determinants involving adaptive and innate immune response pathways (12).

Neuroinvasive mechanisms for WNV are not yet clarified with both haematogenous and trans-neural pathways being proposed (19). The most likely hypothesis suggests a trans-endothelial route of entry whereby the virus is trafficked through an altered blood brain barrier by infected leucokytes (20, 21). The different clinical phenotypes reported in neuroinvasive WNV infection might be explained by the innate differences in antiviral cytokines and interferon stimulated-genes expressed in different neural subtypes (22). Recent studies on experimental animal models identified a mutation in the interferon stimulated-gene Ifi27l2a which promotes location specific neuronal cell death. In Ifi27l2a^−/− and WNV infected mice, neurons in the cerebellum, brainstem, and possibly spinal cord live longer and harbor higher WNV burden in the active phase of the disease (23).

The acute development of a rash during the initial phase of the disease is thought to be significantly more rare in patients who further develop WNV encephalitis (24), but the mechanisms underlying this finding are yet unknown. However, two of the reported cases of OMS associated with WNV infection developed rash over the neck and trunk during the early course of the disease. Our patient did not show any skin changes prior to or during hospitalization.

Patients with West Nile encephalitis most commonly present with altered mental status of different severity, ranging from mild confusion to severe encephalopathy and coma. Extrapyramidal disorders are commonly observed, myoclonus, and tremor being the most frequently described (11, 25, 26). Ataxia and various ocular motility disorders, including nystagmus and opsoclonus are also consistently reported (27–30). Although West Nile infection was reported as a cause of rhombencephalitis (31), only 13 cases of OMS were described so far in the literature (see Table 2), the first case being published in 2004 (11). However, since many authors report cases of West Nile virus encephalitis in which myoclonus is accompanied by abnormal nystagmoid eye movements, the true incidence of OMS in WNV infection is probably underestimated (11, 27, 40).

OMS is a rare disease in adults. A literature search regarding adult-onset OMS performed in 2012 identified <150 reported cases over a nearly 50-year period.(2) When the syndrome is not considered idiopathic, the most frequent identified etiologies are either paraneoplastic, or para-infectious, but the exact mechanisms of the disease and the neural structures involved are still not completely elucidated, due to the small number of cases and the absence of comprehensive pre-clinical and clinical studies. Several hypotheses regarding the affected neurons and neurotransmitters in this disease have been proposed. The first hypothesis postulates that alterations in the membrane properties of the saccadic burst neurons reduce the efficacy of omnipause neurons in the nucleus raphe interpositus of the pons either through excessive postinhibitory rebound or through a malfunction of the glycine receptors. However, to date, no autopsy study showed any histological changes of the omnipause cells. The second hypothesis states that the malfunction of the Purkinje and granular cells in the dorsal vermis might lead to deafferentation of the fastigial nucleus and further on to a reduced inhibitory effect of the omnipause neurons, rendering saccadic neurons free to oscillate (41, 42). Several PET and fMRI studies have confirmed the hypermetabolism of the fastigial area in OMS patients, supporting this theory (43, 44). However, in WNV associated OMS the neuronal dysfunction probably extends to more widespread areas including the brainstem and the cerebellum, thus causing abnormally occurring discharges of saccadic generators in the lower pons. Furthermore, the acute dysfunction of the cerebellum could lead to a phenomenon of cerebello-cortical diaschisis which might explain the associated encephalopathy and the cognitive sequelae seen in some OMS patients (45, 46).

The main characteristics of all reported cases of WNV associated OMS are summarized in Table 2. Three of the patients had a history of cancer and underwent prior chemotherapy, one suffered liver transplantation 6 years before and received immunosuppressive treatment. Three other patients, all aged more than 50 years, had a history of arterial hypertension and two of them also had diabetes mellitus. With the exception of one case with a very severe and rapidly progressing clinical course, all other patients developed symptoms suggestive of West Nile fever 5 to 14 days before the occurrence of neurological signs. Altered mental status, which was not predictive of unfavorable outcome, was reported in 4 patients and usually developed after hospital admission. Of the two patients with deep coma, one made a full recovery whereas details about the long-term outcome of the other patient were not available.

Since the majority of reported patients with WNV associated OMS showed no supratentorial lesions on MRI, altered mental status and EEG changes could be interpreted either in the context of a diffuse gray matter dysfunction induced by the viral infection, or in the context of a secondary cerebello-cortical network impairment. Previous research on this topic has shown that focal brainstem lesions can cause widespread cortical hypoperfusion with secondary dysfunction (45).

Details about brain MRI findings performed during the acute phase of the disease were available for 11 of the 13 reported cases of WNV associated OMS. No imaging findings consistent with brainstem involvement were identified. The most frequent reported findings were stigmata of small vessel disease in older individuals. Details about imaging findings on follow-up brain MRI scans performed weeks or months after the acute illness were not available. However, a recent small study comparing brain volumetry of healthy controls and patients with previous ocular flutter or opsoclonus showed a decrease of the cerebellar cortex volume with preservation of the cerebellar white matter volume and a subsequent decrease in both cortical and subcortical gray matter of the cerebral hemispheres despite the fact that most of the patients made a complete recovery (47). EEG findings were reported in few patients and showed a non-specific diffuse slow rhythm. Lumbar puncture changes were non-specific, most patients presenting mildly elevated white blood cell counts and CSF proteins with normal CSF glucose levels.

Although several therapeutic agents were used for the treatment of WNV infection, none was proven to be efficient in a randomized controlled trial. The mainstay of therapy is primarily supportive. Reported therapeutic options that have been tried for WNV encephalitis include: immune γ-globulin (IVIG), plasmapheresis, WNV–specific neutralizing monoclonal antibodies, corticosteroids, ribavirin, interferon α-2b and antisense oligomers (5). The rationale for immunoglobulin administration in WNV neuroinvasive disease is based on pre-clinical studies and individual case reports. However, one phase I/II randomized controlled trial in patients with WNV encephalitis which evaluated immunoglobulin therapy compared with placebo found no significant differences in outcome between groups (48). The lack of efficacy of immunoglobulin treatment might be explained by the fact that human patients already have IgM antibodies at the time of diagnosis and have cleared systemic viremia (49).

Two of the reported patients with WNV associated OMS were treated with IVIG and steroids, one with IVIG and Rituximab and one with plasmapheresis. The rest of the patients received treatment with corticosteroids or only supportive care. There was no significant difference in terms of speed and degree of neurologic improvement or persisting disability between patients.

Serious sequelae in WNV infection are usually encountered only in patients with neuroinvasive disease. Fatality rates reach 10–30% in WNV encephalitis, older age and immunocompromised state being both consistently associated with poor outcome (50, 51). Significant improvement in WNV encephalitis survivors is usually seen during the first year after the acute disease but patient—reported clinical sequelae persist in up to 70% of WNV-encephalitis patients even at 5 years after the initial event (52). Most patients complain of persistent fatigue, cognitive deficits, and muscle aches (51).

Data derived from the reported cases of WNV associated OMS suggest that this form of WNV infection has a more benign course compared to the classical WNV encephalitis. Out of the 13 reported cases in the literature till now, one patient died 4 weeks after onset but other 10 showed almost complete neurologic recovery several months after the acute illness. For two patients long term follow up was not available. Although male sex was reported to be associated with more severe illness and death (50), none of the reported male cases of WNV associated OMS died and the clinical course seems to have been similar in women and men.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.