“Clock dial pattern”, a radiologic clue to neuro-chikungunya diagnosis: a case series

Background  Chikungunya is a mosquito-borne disease caused by the chikungunya virus (CHIKV) and can lead to neurological complications in severe cases. Objective  This study examined neuroimaging patterns in chikungunya cases during two outbreaks in Brazil to identify specific patterns for diagnosis and treatment of neuro-chikungunya. Methods  Eight patients with confirmed chikungunya and neurological involvement were included. Clinical examinations and MRI scans were performed, and findings were analyzed by neuroradiologists. Data on age, sex, neurological symptoms, diagnostic tests, MRI findings, and clinical outcomes were recorded. Results  Patients showed different neuroimaging patterns. Six patients exhibited a “clock dial pattern” with hyperintense dotted lesions in the spinal cord periphery. One patient had thickening and enhancement of anterior nerve roots. Brain MRI revealed multiple hyperintense lesions in the white matter, particularly in the medulla oblongata, in six patients. One patient had a normal brain MRI. Conclusion  The “clock dial pattern” observed in spinal cord MRI may be indicative of chikungunya-related nervous system lesions. Isolated involvement of spinal cord white matter in chikungunya can help differentiate it from other viral infections. Additionally, distinct brainstem involvement in chikungunya-associated encephalitis, particularly in the rostral region, sets it apart from other arboviral infections. Recognizing these neuroimaging patterns can contribute to early diagnosis and appropriate management of neuro-chikungunya.


INTRODUCTION
Chikungunya is a mosquito-borne disease caused by the chikungunya virus (CHIKV).Among epidemic outbreaks of CHIKV, rare neurological manifestations were described in some severe patients. 1Neuroimaging is frequently normal in most patients, but abnormalities could be seen especially in those diagnosed with encephalitis and myelitis. 1ur study presents a case series of neuroimaging patterns during two epidemic outbreaks in 2016 and 2019 in the state of Rio Grande do Norte, Brazil.These patients developed new and more specific patterns.The recognition of these patterns might help to narrow differential diagnosis in neural-infectious diseases and guide early diagnosis and treatment of neuro-chikungunya.

METHODS
We conducted a case study and included 8 patients from one center, admitted to a tertiary care hospital during two epidemics of chikungunya outbreaks in 2016 and 2019.All subjects had confirmed diagnosis of chikungunya through serological or molecular tests (performed by the Rio Grande do Norte state secretariat of public health, ►Table 1), had fulfilled 2015 CDC criteria of neuroinvasive infection by arboviruses 2 and underwent clinical examination by a neurologist.Patients were not included if had vaccination one month before the onset of symptoms; if presented a previous diagnosis of neurologic diseases; or if they had a concomitant infection with dengue or Zika virus.Patients had MRI studies performed in 1.5 Tesla scanners (GE HDxt and Siemens MAGNETOM Avanto) using sagittal and axial images of cervical, thoracic, and/or lumbar spine in T1WI, T2WI, and STIR sequences, with and without paramagnetic contrast agent (gadolinium).Additionally, six patients underwent brain MRI studies when symptoms suggested encephalitis.Images were analyzed by an experienced neuroradiology team.
Clinical measures were recorded by interrogation and relevant information was obtained in the medical records, including age, sex, neurological presentation, diagnostic test, MRI findings, and clinical outcome at discharge.This case study was approved by the local ethics committee (Ethics Committee in Research, Universidade Federal do Rio Grande do Norte, 09144819.1.0000.5292).Free and informed consent was given by all patients.

RESULTS
We included 8 patients (50%, male), with a mean age of 59 years old (standard deviation AE 13,9 years; range: 36 to 75-year-old), a median time at imaging exam from the
Conclusão O "padrão de mostrador de relógio" observado na RM da medula espinhal pode ser indicativo de lesões do sistema nervoso relacionadas à chikungunya.O envolvimento isolado da substância branca da medula espinhal na chikungunya pode ajudar a diferenciá-la de outras infecções virais.Além disso, o envolvimento distinto do tronco cerebral na encefalite associada à chikungunya, especialmente na região rostral, a distingue de outras infecções por arbovírus.O reconhecimento desses padrões de neuroimagem pode contribuir para o diagnóstico precoce e manejo adequado da neurochikungunya.In six cases (patients 1, 2, 3, 5, 7, and 8), spinal cord MRI presented a singular pattern of T2WI hyperintense small dotted lesions in multiple segments, mainly on the periphery of the spinal cord (►Figure 1).There is no mass effect or enhancement by paramagnetic contrast media in most cases in patient 3, however, there was enhancement after Gadolinium mainly in the cervical (►Figure 1 G, H) and thoracic lesions.This pattern of multiple peripheral lesions resembles a "clock dial" configuration when observed in axial sections.One of the patients (patient 4) has shown thickening and enhancement by the contrast in the anterior nerve roots of the cauda equina (►Figure 1 I-K).

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Six patients underwent brain MRI (►Figure 2).Three cases (patients 1, 6, and 7) have shown T2WI hyperintense small multiple spotlights and randomly distributed lesions in supratentorial white matter and brainstem, especially in the anterior medulla (►Figure 2 D-F).The lesions in patient 7 have shown abnormal restricted diffusion in DWI sequence (►Figure 2 C).One of the brain MRIs was normal (patient 8).Their imaging findings are in ►Table 1.

DISCUSSION
Herein, we describe a case series of Neuro-Chikungunya during two epidemic outbreaks in 2016 and 2019.We suggest that T2 hypertense small peripheral white matter dotted or linear lesions, with or without contrast enhancement, in the spinal cord MRI, the here-named "clock dial pattern," could be a radiological clue to distinguish Chikungunya virus-associated nervous system lesions from those caused by other neurotropic arboviruses.
CHIKV is an arbovirus of the Togaviridae family that is recognized for its neurovirulence and neurological complications. 3 These neurological complications are not specific to CHIKV infection among arboviruses, they are also reported in dengue and zika virus infections, other arboviruses that cocirculate with and share the same vector of CHIKV.
Among patients that show neurological complications in CHIKV infection, neuroimaging abnormalities are variable.The abnormalities in the spinal cord range from findings suggestive of demyelinating pathology to hyperintensity in FLAIR sequences, suggestive of extensive longitudinal myelitis. 1There is a case report, during the Brazilian epidemic, of predilection for the anterior horn of the spinal cord in a case of chikungunya and dengue coinfection, associated with acute transverse myelitis. 4The neuroimaging findings of patients with clinical signs of encephalitis or encephalopathy are also unspecific and variable.][7] The patients in our series who had neurological manifestations compatible with myelitis displayed the "clock dial pattern."In most patients, the "clock dial pattern" is observed without enhancement after contrast (only one of the patients displayed lesions enhancement after contrast).These peripheral lesions in the white matter could be associated with direct virus injury through retrograde dissemination due to nerve root involvement.This pattern of lesions resembles "clock dials" due to the peripheral distribution of lesions in the white matter of the spinal cord when seen in axial sections (►Figure 1 A-I).Among other viral infections, dengue myelitis shows a pattern of gray matter preferential involvement, mainly in the anterior horn of the spinal cord, including cases of longitudinally extensive transverse myelitis. 8,9This pattern of anterior horn involvement is also seen in enterovirus infections. 8Therefore, the particular involvement of the spinal cord white matter might be a helpful feature suggestive of differential diagnosis of neurochikungunya from other viral infections in the central nervous system.
Other findings also found in the spinal cord MRIs were the thickening and enhancement by the contrast of the anterior nerve roots of the cauda equina (►Figure 1, J-K).This patient has a clinical presentation compatible with Guillain-Barré Syndrome, which explains this different morphological pattern of the nerve roots and peripheral nerves. 10This pattern is not particular to CHIKV infections, it is also seen in dengue, zika, and other viruses related to Guillain-Barré Syndrome manifestations. 8,10mong patients with clinical signs of encephalitis, brain MRI has shown multiple and scattered white matter hyperintense lesions on T2WI sequences, without enhancement after contrast or mass effect.Brainstem involvement has presented a predilection for the medulla oblongata region, regarding a similar pattern of multiple dotted and linear hyperintensities on T2WI sequences, as seen in the spinal cord, mainly in the rostral region, particularly in medullary pyramids (►Figure 2, A-H).In dengue virus-associated encephalitis, the main differential diagnosis of CHIKV-associated encephalitis, brainstem involvement is not common and usually spares the rostral region, preferentially affecting the substantia nigra of the midbrain. 8We need to consider that the overlapping between gliosis related to microangiopathy and CHIKV-related lesions is a limitation in elderly patients.In young patients, however, these findings must be considered as secondary to CHIKV.
Limitations of this study include that it is retrospective and thus dependent on the accuracy of existing medical records.We were limited by the observational nature of the study, including analysis of patients at different times of their disease course, as well as missing data.These limitations are inherent to the study design.The number of cases is small, and a larger number of patients is needed to better estimate the frequency of the occurrence of the "clock dial pattern" in neuro-chikungunya cases.Nevertheless, the strength of our study involves describing an imaging pattern reproducible in two different epidemic settings (►Table 1), which helps to narrow the differential diagnosis of a rare but severe complication of a common disease, thus possibly decreasing morbidity and mortality and improving the outcome of these patients.
In general, neurological complications are rare in chikungunya but have high morbidity and mortality.Additionally, it is possible that the "clock dial pattern" is an early manifestation of the disease.Then, clinicians, neurologists, and radiologists should be aware of and recognize this pattern to support an early correct diagnosis.

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Clock dial pattern": a clue to neuro-chikungunya Fraiman et al. 3 beginning of symptoms of 4 weeks (range: 1 to 6 weeks).Their clinical and laboratory data are shown in ►Table 1.

Figure 1
Figure 1 Spinal cord magnetic MRI features of patients with CHIKV-associated encephalomyelitis.(A, B) patient 7 -Axial FSE T2WI images demonstrating small dotted lesions (arrowheads) with high signal in the periphery of the spinal cord (the "clock dial pattern").(C-E) patient 1 -Axial T2-WI images showing multiple small dotted or linear lesions (arrowheads) with high signal in the periphery of the cervical and thoracic spinal cord (features of the "clock dial pattern").(F) patient 7 -Sagittal FSE T2WI image demonstrating small dotted lesions (arrowhead) with high signal in the periphery of the spinal cord (features of the "clock dial pattern").(G, H) patient 3 -Sagittal STIR and FSE post-contrast T1WI images of the cervical spine, demonstrating small multiple T2 high signal lesions with post-contrast enhancement in the periphery of the spinal cord (arrowhead).Similar features are seen in the thoracic spinal cord of this patient (not shown).(I, J, K) patient 4 -Sagittal and axial post-contrast T1WI images, demonstrating thickening and post-contrast enhancement (arrowheads) of the anterior cauda equina roots, a pattern usually seen in Guillain-Barré Syndrome.

Figure 2
Figure 2 Brain MRI features of patients with CHIKV-associated encephalomyelitis.(A-F) patient 7 -(A, B) Axial T2WI FLAIR images showing multiple small and scattered punctiform (white arrowhead) or linear lesions (black arrowhead), with high signal in T2WI, no mass effect, enhancement, or restriction on diffusion sequence in the white matter of both brain hemispheres.Axial DWI images (C) revealed restriction to the diffusion of water in some of these lesions (arrowheads).Axial T2WI (D), Axial (E) and Sagittal (F) FLAIR images showing small lesions with high signal (arrowheads), no mass effect or enhancement, in the anterior regions of the medulla oblongata.(G, H) patient 6 -Axial images in FSE T2WI (G, H) showing small dotted or linear lesions (arrowheads) with high signal in T2WI, no mass effect, enhancement, or restriction on diffusion sequence, in the medulla oblongata.

Table 1
Patients and their neuroimaging characteristics.