Ischemic Cerebellar Infarct During Recovery from Secondary Dengue Fever—A Case Report and Literature Review

Abstract

Background: Dengue fever is a global health problem and is endemic in Singapore, with a high economic burden. Neurological manifestations of dengue fever, although rare, are being increasingly reported. Ischemic stroke as a complication of dengue fever has rarely been reported. Methods: This case report describes a case of ischemic cerebellar infarct during the recovery phase of secondary dengue fever with a review of similar cases previously described in the literature. Results: This is the first known case report of cerebellar ischemic stroke in Singapore following dengue fever, where Magnetic Resonance Angiography (MRA) demonstrated a possible occlusion or severe stenosis of a cerebral artery as the underlying pathophysiology of dengue-associated stroke. Dengue fever has been shown to increase the incidence of stroke. Conclusions: Physicians in dengue-endemic areas need to have a high index of suspicion to consider this diagnosis, especially in patients with dengue fever who present with neurologic deficits.

1. Introduction

The tropical illness of dengue fever is a global health problem and the most common mosquito-borne viral disease worldwide, with an estimated 390 million cases occurring annually in more than 100 countries [1]. It is endemic in Singapore, with the incidence rate showing considerable variability and a peak of 621.1 cases per 100,000 person-years in 2020 [2]. Four different serotypes (DEN 1–4) can cause dengue fever, with a variety of presentations ranging from asymptomatic to severe hemorrhagic fever.

Neurological manifestations of dengue fever are being increasingly reported, with an estimated incidence rate of 0.5 to 20% depending on the clinical setting and population studied [3,4,5,6]. Intracranial hemorrhage due to thrombocytopenia in dengue fever has been reported, but ischemic stroke secondary to dengue fever is rare. Due to the rarity of these complications, they are prone to under-recognition and misdiagnosis. Adding to this diagnostic challenge, there are a variety of neurological manifestations such as altered mental status, encephalitis, and dengue seizures that overlap with symptoms of ischemic stroke. This makes exact diagnosis of the underlying cause of symptoms challenging. We report a rare case of a patient with an ischemic cerebellar infarct during the recovery phase of secondary dengue fever and present a literature review on this.

2. Case Report

A 62-year-old male presented to the Emergency Department (ED) with the sudden onset of vertiginous giddiness that started in the morning. He denied headache, weakness or numbness of limbs, slurred speech, blurred vision, nausea, or vomiting. He was admitted to our hospital 10 days prior for dengue fever. His serological test was positive for dengue IgG and dengue NS1 antigen, while his IgM was negative. He was discharged 3 days after with an uneventful recovery. He had been asymptomatic since discharge, until the morning of his re-visit when he developed acute vertigo. He had no past medical history or any risk factors for stroke such as diabetes mellitus, hypertension, or dyslipidemia. He did not have any prior smoking or alcohol use.

Upon arrival, his vital signs showed a temperature of 35.9 °C, heart rate of 57 beats per minute, blood pressure of 122/75 mmHg, and oxygen saturation of 100% in room air. He was alert and had horizontal nystagmus on the left gaze. His neurological examination did not reveal any weakness or numbness of limbs, slurring of speech, dysmetria, or dysdiadochokinesia. His gait was not assessed initially due to postural giddiness while attempting to sit up in bed.

Apart from a platelet count of 134 × 10⁹/L, the rest of the patient’s blood tests (renal panel and full blood count) were normal. His resting electrocardiogram showed normal sinus rhythm with no signs of ischemia. There was no postural drop in blood pressure. He was administered intravenous fluids, treated symptomatically for vertiginous giddiness with intramuscular prochlorperazine, and admitted to the Extended Diagnostic and Treatment Unit in the ED for further monitoring. Despite the above treatment and a further 12 h of observation, he remained giddy and was unable to ambulate steadily.

A Computed Tomography (CT) scan of the brain demonstrated a recent non-hemorrhagic infarct in the left cerebellar hemisphere and vermis (Figure 1).

The patient was thus admitted, and a subsequent Magnetic Resonance Imaging (MRI) of the brain showed a left cerebellar acute, non-hemorrhagic infarct in the Posterior Inferior Cerebellar Artery (PICA) territory, accounting for his symptoms and signs. Magnetic Resonance Angiography (MRA) of the brain showed a possible occlusion or severe stenosis of the left distal PICA with no large vessel occlusion (Figure 2).

A transthoracic echocardiography of his heart showed normal heart valves and ejection fraction. Ultrasound of his carotid arteries did not reveal any arterial stenosis. He received oral aspirin upon admission. He underwent physiotherapy and rehabilitation during his inpatient stay. He made an uneventful recovery and was discharged after five days with an outpatient follow-up appointment with a neurologist and an outpatient physiotherapist. He was followed up at a 3-month interval and continued on lifelong aspirin. He did not exhibit significant residual neurological deficits in the long term. In summary, the patient was diagnosed with dengue fever on day 3 of symptom onset, discharged on day 10, and re-presented to the hospital again on day 13 with acute giddiness. He was diagnosed with cerebellar stroke on day 15, for which he was admitted for treatment and made a subsequent recovery before being discharged on day 20.

3. Discussion

As of 30 April 2024, over 7.6 million dengue cases have been reported to the World Health Organization (WHO), including 3.4 million confirmed cases, over 16,000 severe cases, and over 3000 deaths [7]. Dengue fever is a systemic and dynamic disease presenting a wide range of clinical manifestations. After an incubation period of about 3–10 days, the illness has three phases, including the febrile phase, critical phase (day 3–7 of illness), and recovery phase (1–2 days after critical phase). In 2009, the WHO added central nervous system (CNS) involvement as a criterion for severe dengue fever due to increasing recognition of neurological manifestations of dengue fever arising from clinical observations and studies.

The neurological complications of dengue fever include encephalopathy, encephalitis, transverse myelitis, Guillain–Barré syndrome, myositis, cerebellar syndromes, and dengue-associated cerebrovascular events [4,5,8]. Cerebrovascular events are rare compared to other neurological complications. We used the following keywords for our search strategy: (Dengue or “dengue fever” or “Dengue hemorrhagic fever” or DHF or DENV) AND (stroke or “cerebrovascular accident” or CVA or “cerebral infarction” or “intracranial hemorrhage” or “subarachnoid hemorrhage” or “ischemic stroke” or “hemorrhagic Stroke”) in Pubmed, from 1 January 1980 up to 31 April 2025. We only included studies on adult patients and full papers. The abstracts were reviewed by two independent reviewers for inclusion, and the full text of the included papers was further reviewed for overlap and exclusion. There were seven identified papers. A study on dengue fever patients in Taiwan found the overall incidence rate of stroke to be 5.33 per 1000 person-years for dengue fever [9]. while another study found the incidence of dengue encephalitis to occur in around 4–5% of dengue cases. Stroke in a dengue patient is usually due to thrombocytopenia-related intracranial hemorrhage [10,11]. Ischemic stroke as a complication of dengue fever has rarely been reported [12,13,14].

The exact pathophysiology of ischemic stroke in dengue fever remains unclear. One such proposed mechanism includes plasma leakage secondary to endothelial dysfunction [15]. Various immune mediators released during dengue fever, such as cytokines, chemokines, and complement, cause breakdown of the blood–brain barrier and local inflammation, leading to vasoconstriction, vasculitis, thromboembolism, cerebral edema, ischemia, and hemorrhage [16,17]. Another possible mechanism is the development of a transient hypercoagulable state when platelet levels recover rapidly during the recovery phase of dengue fever, leading to ischemic stroke [18]. Direct viral invasion of the CNS, as well as autoimmune reactions and metabolic changes from host–viral interactions, have also been described as possible mechanisms [19].

In our patient, this was likely the case, with MRA showing a possible occlusion of the left distal PICA without any large vessel occlusion. We think that vasculitis and severe inflammation from an immune-mediated response may explain the severe stenosis of the left distal PICA. In our experience, this is the first case report with MRA imaging studies demonstrating severe stenosis of the left distal PICA as the underlying pathophysiology of dengue-associated strokes. Although isolated case reports have described ischemic strokes in various territories in dengue patients, an explicitly MRA-documented PICA occlusion, to our knowledge, represents a novel contribution to the existing literature and emphasizes the critical need for clinicians to consider dengue fever in the differential diagnosis of acute ischemic stroke, even with precise vascular territory involvement, to ensure timely diagnosis and appropriate management.

During previous hospitalizations for dengue fever, our patient’s serological testing showed a positive IgG, negative IgM, and a positive NS1. A positive IgG denotes prior dengue fever and positive NS1 reveals repeated dengue fever in an acute setting. Thus, our patient was diagnosed with secondary dengue fever. Among the various dengue serotypes, “Asian” genotypes of DEN-2 and DEN-3 are frequently associated with severe disease accompanying secondary dengue fever.

A retrospective cohort study suggested that dengue fever is associated with a 2.49 times increased risk of hemorrhagic and ischemic stroke in the first 2 months after the diagnosis of dengue, with the risk declining as the follow-up period increases. The highest incidence of stroke was seen in patients with dengue hemorrhagic fever, followed by patients with repeated dengue fever. Dengue fever was noted to be an independent risk factor for stroke, along with male sex, age > 62 years, and other comorbidities [9]. Another population-based cohort study in laboratory-confirmed dengue diagnoses showed that the infection was associated with an increased risk of both hemorrhagic and ischemic stroke within 30 days. Among these patients, those aged >/= 65 were found to have an increased risk of overall stroke. No increased risk was observed after 30 days [20]. Our patient did not have any other predisposing vascular risk factors for ischemic stroke except for his age. Moreover, repeated dengue fever and the time trend of symptom onset on the 10th day after the emergence of fever (the recovery phase of dengue fever) led to dengue fever being the likely cause of acute ischemic stroke in the case of our patient.

One of the differential diagnoses of acute ischemic stroke in dengue patients is cerebellar syndrome (dengue cerebellitis). This condition is also rare, and the patient can present with similar clinical manifestations like horizontal nystagmus, dysmetria, dysdiadochokinesia, and ataxic gait. The onset of symptoms can range from 2 days to 2 weeks after dengue fever [21]. Compared to ischemic stroke, cerebellitis is more often bilateral, resulting in generalized ataxia. Patients with cerebellitis also usually have a gradual onset of symptoms, compared to an abrupt and maximal onset of symptoms in stroke. The pathogenesis of cerebellitis following dengue fever is not fully understood, but it may involve direct viral invasion or immune-mediated mechanisms causing inflammation. A brain MRI can aid in differentiating this condition from acute ischemic stroke, as the MRIs of these patients will usually show symmetrical and diffuse cerebellar involvement with areas of susceptibility, diffusion restriction, and patchy post-contrast enhancement without signs of infarction or vessel occlusion [22]. Most patients have a self-limiting course with complete recovery, with the resolution of symptoms within 2–3 weeks after dengue fever [23,24].

It is challenging to treat ischemic stroke in patients with dengue fever, as the administration of thrombolytic therapy or anti-platelet drugs to patients with thrombocytopenia could result in an increased risk of bleeding. They should be used with close monitoring of platelet counts and bleeding risk. Intravenous fluid therapy should also be administered judiciously to avoid the risk of cerebral edema in stroke patients. Early supportive therapy, close monitoring, physiotherapy, and rehabilitation can help improve clinical outcomes. The duration of rehabilitation ranges from several weeks to several months, depending on the severity of the stroke. Rehabilitation involves gait training such as parallel bar walking and balance exercises, including tandem walking and single-leg balance. In cases of severe thrombocytopenia or bleeding, platelet transfusions may be considered, although prophylactic platelet transfusions are generally not recommended unless there is active bleeding or a very low platelet count [25]. Corticosteroids are not routinely recommended for dengue fever by the WHO or CDC but may be used in specific cases of stroke secondary to immune-mediated vasculitis, particularly in the pediatric population where the pathology is clearly defined [13,26].

4. Limitations

Dengue DEN-2 and DEN-3 serotypes have been associated with severe disease accompanying secondary dengue fever, including neurological manifestations. Our hospital does not routinely perform serotype testing, and the serotype of our patient is not definitively known. Without serotype testing, we are unable to confirm if our patient’s disease severity is linked to a particular serotype or simply due to a secondary infection. Obtaining information about the serotype would be helpful to deepen understanding of the association between serotypes and disease severity and shed light on a patient’s prognosis.

5. Conclusions

Cerebellar ischemic strokes, although rare, can occur during the course of dengue fever. Its incidence is relatively higher in patients with secondary dengue fever, and patients can present with subtle clinical findings. Physicians in dengue-endemic areas need to have a high index of suspicion to consider this diagnosis, especially in patients with dengue fever who present with neurologic deficits. Advanced imaging with brain MRIs can confirm the diagnosis and help provide appropriate and timely care to improve clinical outcomes.