A Scoping Review Of Neurological Manifestations Of Dengue Virus Infection Besides Cerebrovascular Disorders

1. Introduction

Arboviruses are viral diseases transmitted mainly by mosquitoes and other hematophagous arthropods. Several arboviruses are transmitted by mosquitoes, such as Zika virus, dengue, malaria, yellow fever and chikungunya, accounting for millions of deaths each year, especially in third world countries with tropical climates [1]. Unfortunately, due to global warming, the prevalence of these viruses which was previously limited to tropical areas, has been rising significantly even in temperate nations due to unusually higher temperatures in those areas. In this context, arboviruses have posed significant challenges for health systems worldwide.

In 2023, there were more than five million individuals infected with dengue virus, and dengue-related deaths were reported in more than five thousand cases. Noteworthy, these numbers are likely under-reported because most individuals will have minor symptoms or be asymptomatic [2]. Furthermore, there are a rising number of reports of dengue worldwide, and some specialists believe that this can be related to climate changes, since the environmental factors can lead to expansion of the geographical area and population of the vectors [3].

There are four serotypes of the dengue virus (DENV 1–4), which share genetic similarity but are antigenically distinct [4]. Dengue syndrome can be caused by any of the four DENV serotypes. DENV is a member of the Flaviviridae family, which includes other notable arboviruses such as Zika, West Nile, and yellow fever viruses. It is a small, spherical virus approximately 50 nm in diameter. The virus is encased in a lipid bilayer envelope, which is derived from the host cell membrane during viral budding. Embedded in this envelope are the E (envelope) and M (membrane) proteins, which play crucial roles in viral entry into host cells and immune response evasion. DENV’s genome consists of approximately 10.7 kilobases of single-stranded, positive-sense RNA. This RNA encodes a single polyprotein, which is subsequently cleaved into three structural proteins—C (capsid), prM (precursor membrane), and E (envelope)—and seven non-structural proteins, including NS1, NS3, and NS5, which are critical for viral replication and immune modulation. The E protein, in particular, mediates host cell attachment and fusion, while the NS5 protein contains RNA-dependent RNA polymerase and methyltransferase activities essential for viral replication and capping of the RNA genome. This genetic organization allows efficient replication and adaptation in mosquito vectors and human hosts, contributing to the virus’s persistence and widespread transmission. The primary vector of dengue is the female Aedes aegypti mosquito, predominantly found in tropical and subtropical regions. However, due to climate changes associated with global warming, the Aedes albopictus mosquito, another potential vector, has increasingly been identified in temperate regions. [5].

The clinical manifestations caused by DENV infection vary greatly (Table 1). Some patients may only present with a flu-like syndrome also known as dengue fever (DF). However, dengue fever (DF) can sometimes progress to a life-threatening condition known as dengue hemorrhagic fever (DHF), characterized by plasma leakage, severe bleeding, and organ involvement. In severe cases, it may lead to dengue shock syndrome (DSS), marked by circulatory collapse, profound hypotension, and multi-organ failure. These complications result from an exaggerated immune response, increased vascular permeability, and disruption of the coagulation system [6]. Dengue fever typically presents with a sudden onset of acute fever accompanied by a variety of symptoms, including severe headaches, muscle pain (myalgia), joint pain (often referred to as “breakbone fever”), nausea, vomiting, abdominal pain, and skin rashes. Gastrointestinal symptoms such as diarrhea or loss of appetite may also occur. The characteristic rash often appears 2–5 days after the fever onset and can range from a maculopapular to a petechial rash, contributing to the disease’s diagnostic features [5]. Less than 5% of dengue patients develop severe, life-threatening manifestations, such as DHF or DSS. These severe outcomes are more commonly observed in individuals with prior exposure to a different DENV serotype, a phenomenon linked to antibody-dependent enhancement (ADE), where non-neutralizing antibodies from the previous infection facilitate increased viral replication [7]. The clinical outcome of dengue infection is influenced by a combination of factors involving the host (patient), the vector, and the virus. Patient-related factors include age, genetic predisposition, immune status, pre-existing conditions, and prior dengue infections, which may contribute to either protective immunity or severe disease through antibody-dependent enhancement (ADE). Vector-related factors, such as the mosquito species (Aedes aegypti or Aedes albopictus), mosquito density, and feeding behavior, affect the transmission efficiency. Viral factors include the infecting dengue serotype (DENV-1 to DENV-4), virulence, and the genetic diversity of the virus, which can impact replication rates and immune evasion. Together, these factors interact to determine the severity of the disease and clinical progression.

Interestingly, recent evidence has shown that DENV can also affect the central nervous system (CNS), leading to a wide range of neurological manifestations. These manifestations are variable, with reported incidence rates ranging from 0.5% to 21% across different studies. Neurological complications can include encephalitis, encephalopathy, seizures, Guillain-Barré syndrome, myelitis, and other peripheral neuropathies. The underlying mechanisms for these CNS involvement include direct viral invasion of neural tissues, immune-mediated responses, and metabolic disturbances associated with severe dengue. These neurological manifestations can complicate the clinical course and may result in long-term neurological deficits in some patients [8]. The most common DENV serotype associated with neurological disorders appears to be DENV-3. This serotype’s increased association with CNS involvement could be due to factors such as its ability to more effectively invade neural tissues or its propensity to trigger stronger immune responses that may lead to neuroinflammation. However, it is important to note that neurological manifestations can occur with any of the four dengue serotypes, with varying frequencies [9]. In this context, the hemorrhagic manifestations of dengue in the central nervous system (CNS) are among the most well-known and frequently reported neurological complications. These can include subarachnoid hemorrhage, intracerebral hemorrhage, and cerebral venous thrombosis, which are typically seen in severe cases of dengue, such as DHF. The bleeding within the CNS is thought to result from the increased vascular permeability and coagulation abnormalities associated with severe dengue infection. The presence of hemorrhagic manifestations in the CNS is a serious clinical concern and often correlates with poor outcomes, including neurological deficits or even death [10]. However, herein we will describe neurological manifestations that are not related with hemorrhagic or ischemic events.

2. Search Methods

We searched PubMed for articles published until December 2024 without language restriction. We used the term “dengue fever,” “myelitis,” “encephalitis,” “ADEM,” “new daily persistent headache,” “guillain barre syndrome,” “neurological complications.” In this review, we focus on clinical studies, case reports, systematic reviews (with or without meta-analysis), and relevant narrative reviews to examine neurological complications of dengue that are not associated with hemorrhagic or thromboembolic events (Table 2).

3. Discussion

Neurological events in dengue are relatively uncommon, but an increasing number of reports have emerged in recent years, highlighting the growing recognition of these complications. These neurological manifestations can range from mild symptoms such as headaches and dizziness to more severe conditions like encephalitis, encephalopathy, and Guillain-Barré syndrome. In a study conducted by Sahu et al., which enrolled 486 dengue fever patients, the incidence rate of neurological complications was found to be 9.26%. This study reported a variety of neurological manifestations, with the most common being seizures, altered mental status, and focal neurological deficits. The study also emphasized that these complications were more likely to occur in severe cases of dengue and in individuals with previous dengue exposure. The findings underscore the need for heightened clinical awareness and the importance of monitoring neurological symptoms in dengue-endemic areas, especially as more cases with neurological involvement are being reported globally [9]. Nonetheless, a prospective study involving 116 patients revealed a significantly higher incidence of neurological complications, with 79% of the patients presenting with neurological manifestations. Among these, 34% exhibited encephalitis or encephalopathy, characterized by altered mental status, confusion, or seizures, while 45% experienced muscular symptoms, including myalgia, muscle weakness, and even acute flaccid paralysis. This study highlights the broad spectrum of neurological involvement in dengue and underscores the importance of recognizing and managing these complications, particularly in severe cases [11]. Bhushan et al. identified that 4.86% of 1,627 patients DENV infection experienced immune-mediated neurological complications. These complications included conditions such as Guillain-Barré syndrome, acute disseminated encephalomyelitis (ADEM), and other peripheral neuropathies, suggesting that immune responses triggered by DENV infection can contribute to neurological damage. This study highlights the potential for immune-mediated mechanisms in the pathogenesis of neurological complications in dengue, emphasizing the need for early recognition and appropriate management to reduce long-term neurological sequelae [12]. In a study involving 71 confirmed cases of dengue in children, it was found that 28.17% of the patients had central nervous system (CNS) involvement [13]. For a complete understanding of the prevalence of neurological manifestations in patients with DENV infection, read Table 3.

The mechanisms by which dengue affects the central nervous system are yet to be elucidated [8]. Several potential mechanisms have been proposed, including direct viral invasion of neural tissues, immune-mediated damage, and systemic effects such as metabolic disturbances and hypoxia. The virus may enter the CNS via the bloodstream or through the olfactory nerves, potentially leading to encephalitis or encephalopathy. Immune responses triggered by dengue infection, such as antibody-dependent enhancement (ADE), may also contribute to neuroinflammation and neuronal injury. Additionally, alterations in the blood-brain barrier, resulting from increased vascular permeability during severe dengue, may facilitate viral entry into the CNS or exacerbate neurological damage. Further studies are needed to clarify these mechanisms and improve our understanding of how dengue leads to CNS involvement [7].

There are three main mechanisms to explain the neurological manifestations of dengue (Figure 1). The first is related to direct viral invasion of the CNS structures, which can be observed in encephalitis, meningitis, and myelitis. It has also been hypothesized that DENV may cause a systemic infection resulting in ultimately in encephalopathy and stroke. The third proposed mechanism is an immune-mediated infection, which likely results in acute disseminated encephalomyelitis, Guillain-Barre syndrome, and optic neuritis that present after DENV infection [17].

Experimental in vitro and in vivo studies suggest that glial cells and the innate immune response play a significant role in DENV infection of the CNS. Glial cells, including microglia and astrocytes, may serve as both targets and mediators of the immune response to DENV. These cells can become activated during infection, releasing pro-inflammatory cytokines and chemokines that contribute to neuroinflammation. The innate immune response, particularly the activation of pattern recognition receptors such as toll-like receptors (TLRs), can also trigger an inflammatory cascade that may lead to neuronal injury. Additionally, the activation of glial cells can influence the blood-brain barrier’s integrity, potentially facilitating viral entry into the CNS and exacerbating neurological damage. These findings highlight the complex interplay between viral infection, immune response, and glial cell function in the pathogenesis of dengue-related neurological complications [18]. In a study involving rhesus monkeys, no apparent brain histological alterations were observed; however, the study did report a series of virus-induced changes in astrocytes. Specifically, there was a decrease in the number of astrocytes, along with signs of their activation. These alterations suggest that while overt structural damage may not always be evident, DENV infection can still affect glial cell function, leading to a disruption in the normal homeostasis of the central nervous system. Astrocyte activation is often associated with neuroinflammation, which could contribute to the neurological complications observed in dengue infection [19]. There is also evidence of DENV presence in the CSF of infected patients. Studies have detected viral RNA or antigens in CSF samples from individuals with neurological complications associated with dengue infection, such as encephalitis and encephalopathy. The detection of the virus in CSF supports the hypothesis of direct viral invasion of the CNS, which may contribute to the development of neurological symptoms. However, the exact mechanism by which the virus crosses the blood-brain barrier remains unclear, and further research is needed to better understand how DENV affects the CNS [20].

Regarding the immune response, a study found similarities between the cytokine release in dengue infection and that of Japanese encephalitis virus. Several cytokines were detected in the CSF of dengue-infected patients, indicating that an inflammatory response is likely playing a key role in dengue’s CNS involvement. The accumulation of these cytokines in the CSF suggests that neuroinflammation is a significant feature of dengue-associated neurological complications, potentially contributing to the development of encephalitis, encephalopathy, and other CNS disorders. This immune response may exacerbate neuronal damage, highlighting the importance of managing inflammation in severe dengue cases [21]. In this context, Al-Shujairi et al. demonstrated that DENV induces the activation of TCD8 lymphocytes in the CNS of mice. The study also found that genes stimulated by interferon were upregulated, suggesting a virus-driven immune response. This immune activation, including the recruitment of TCD8 lymphocytes and the subsequent inflammatory response, highlights the role of the host’s immune system in contributing to the pathogenesis of neurological complications in dengue infection. The findings further support the notion that immune-mediated mechanisms, including the activation of cytotoxic T cells, play a significant role in dengue-related CNS inflammation [22].

Neurovirulence may be due to some molecular specificities of some subtypes of the DENV virus. The evidence demonstrated in the DENV strain 1 shows a correlation between the domain of helicase E and non-structural-3 (NS3), increasing the capacity for infection and neuronal replication [23]. There are also samples of replication of the DENV2 in neurons [24]. Another study in mice showed behavior similar to anxiety associated with increased inflammatory cytokines such as IL-6 and tumor necrosis factor-alpha (TNF) and neuronal loss in the hippocampus [25]. These findings are corroborated by another study, which found that DENV 3 induces meningoencephalitis and behavioral changes in mice [26].

3.1. Guillain-Barre Syndrome

Guillain-Barré syndrome (GBS), also known as acute idiopathic polyradiculoneuropathy, is an acute, inflammatory, demyelinating, and immune-mediated neurological disorder. The hallmark features of GBS include areflexia (loss of reflexes), ascending motor paralysis, and an elevated protein concentration in the CSF without an increase in white blood cells (pleocytosis), a phenomenon known as albuminocytological dissociation. This pattern is characteristic of GBS and reflects the disruption of the blood-nerve barrier and inflammatory changes in the peripheral nervous system. GBS is often triggered by infections, including viral infections like dengue, and the immune system’s response can damage peripheral nerves, leading to muscle weakness and, in severe cases, respiratory failure. Early diagnosis and prompt treatment, such as intravenous immunoglobulins or plasmapheresis, are crucial for improving outcomes [8]. In GBS, approximately 70% of cases are preceded by a respiratory or gastrointestinal infection, typically viral, occurring 1 to 3 weeks before the onset of neurological symptoms. The most common microbiological agents associated with GBS include Cytomegalovirus, Epstein-Barr virus, Campylobacter jejuni, Mycoplasma pneumoniae, and HIV. These infections are believed to trigger an immune response that mistakenly targets peripheral nerves, leading to the inflammatory and demyelinating effects characteristic of GBS. The immune response may involve molecular mimicry, where the immune system attacks nerves that share similar structures to those of the pathogen, contributing to the development of GBS [27]. A study from Mexico found 14.5 cases of GBS for every 10000 individuals diagnosed with dengue [28]. In Brazil, Matos et al. found a prevalence of 10% of dengue in individuals with GBS in an endemic area of dengue [29]. For a list of cases of GBS associated with DENV infection, read Table 4.

GBS and its variants account for 5% of neurological complications in pediatric patients with dengue fever (DF). The typical time between the onset of dengue symptoms and the development of GBS is approximately eleven days [32]. Acute motor and sensory axonal neuropathy (AMSAN) was the most common subtype of Guillain-Barré syndrome (GBS) in these patients with dengue fever. AMSAN is characterized by the damage to both motor and sensory axons, often leading to severe, rapidly progressing weakness, sensory loss, and respiratory complications. It typically involves the peripheral nervous system’s axonal structures, with an autoimmune response that damages the axonal membrane and disrupts nerve conduction. Following AMSAN, the next most common subtype was acute motor axonal neuropathy (AMAN), which primarily affects motor axons, leading to paralysis without significant sensory involvement. AMAN is often less severe than AMSAN but still results in considerable motor weakness and can involve respiratory muscles, requiring close monitoring. Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) is the classic form of GBS and was also observed, though less frequently. AIDP involves the inflammatory destruction of the myelin sheath surrounding peripheral nerves, leading to muscle weakness and sensory disturbances, often in a symmetric and ascending pattern. It is more commonly associated with viral infections. Lastly, Miller Fisher syndrome (MFS), a rare variant of GBS, was also reported. MFS typically presents with ataxia, ophthalmoplegia, and areflexia. It is often considered a variant of GBS, though its pathophysiology may differ slightly, and it is more often associated with infections such as Campylobacter jejuni but can also occur with dengue [12]. Both GBS and MFS are associated with immune-mediated complications of DF [35]. Another variant of GBS reported in association with dengue fever is the pharyngeal-cervical-brachial variant. This variant primarily affects the muscles of the throat, neck, and upper limbs, leading to symptoms such as dysphagia (difficulty swallowing), respiratory distress, and weakness in the arms and shoulders. It is considered a rare but significant manifestation of GBS in dengue-infected patients, reflecting the diverse range of neurological complications that can arise from the infection [34].

An intriguing case report described two brothers who simultaneously developed the axonal variant of GBS following DENV infection [33]. Although neither of the two brothers exhibited typical symptoms of dengue fever, this case report supports the possibility of a genetic predisposition contributing to the development of GBS following DENV infection. The simultaneous onset of the axonal variant of GBS in both siblings suggests that genetic factors may play a role in their heightened susceptibility to immune-mediated complications associated with dengue. This raises the possibility that certain genetic markers or immune system variations could predispose individuals to develop GBS or other neurological manifestations when infected with the DENV.

Since most cases of GBS occur after the acute phase of dengue, it is widely believed that these manifestations have an immunological origin. The immune system’s response to the DENV, possibly involving mechanisms like molecular mimicry or the activation of autoreactive immune cells, is thought to contribute to the development of GBS. This delayed onset, typically one to three weeks after the initial infection, suggests that GBS is a post-infectious complication driven by the body’s immune response rather than direct viral invasion of the nervous system [35]. The evidence supporting the immunological origin of GBS following dengue infection is based on the involvement of similar pro-inflammatory substances in both conditions. These substances, including tumor necrosis factor (TNF), interleukins, and complement proteins, play key roles in the immune response against the DENV and in the pathogenesis of GBS. The immune response triggered by dengue may inadvertently cross-react with peripheral nerve tissues due to molecular mimicry, where antibodies or immune cells target components of the nervous system, such as myelin or peripheral nerve axons. This cross-reactivity may contribute to the development of GBS following dengue infection [31].

A common presentation of dengue and lower extremity weakness is related to hypokalemia, which was already reported in adults and pediatric individuals [42]. A basic metabolic panel should be obtained because they are usually misdiagnosed with GBS due to the symptoms of distal weakness and decreased reflexes. Hypokalemia is found in around 1.3 to 13.7% of the cases of dengue and severe dengue respectively [43,44].

3.2. Myopathy

Myalgia is a common symptom of dengue fever, with studies showing that up to 90% of patients report muscle pain as part of their illness. This widespread occurrence of myalgia is often considered one of the hallmark symptoms of dengue, along with fever, headaches, and joint pain. The muscle pain in dengue is typically intense and can be associated with general malaise, further contributing to the overall discomfort experienced by patients [45]. Muscular alterations were detected in biopsies from 12 out of 15 patients who did not report muscle weakness, suggesting that muscular changes can occur even in the absence of overt symptoms. This indicates that muscle involvement may be more widespread in dengue patients than previously recognized, and some individuals may experience subclinical or asymptomatic muscular alterations that do not manifest as weakness but may still contribute to the overall disease process [46]. For a full understanding of the cases of myopathy associated with DENV infection, read Table 5.

Myopathy is a common complication of dengue infection. In a study of 116 patients, 34 exhibited muscle weakness and elevated creatine kinase (CK) serum levels, highlighting the prevalence of muscle involvement in dengue cases. This suggests that muscle dysfunction, including weakness and increased CK levels, is a significant aspect of the disease’s clinical presentation [11]. In another study, 14 out of 30 patients with acute myopathy were diagnosed with dengue fever. Of these 14 patients, 9 had normokalemia, indicating that dengue-associated myopathy can occur regardless of potassium levels. The presence of normokalemia in a majority of the cases suggests that other factors, apart from electrolyte imbalances, may contribute to the development of myopathy in dengue fever [53].

The severity and clinical presentation of acute myopathy associated with dengue fever can vary widely, ranging from subclinical elevations in creatine kinase (CK) levels to severe muscle weakness. This variability underscores the diverse spectrum of muscle involvement in dengue infection, with some patients exhibiting only mild biochemical changes, while others experience significant muscular dysfunction that can severely impact mobility and overall health [50,52]. Rhabdomyolysis and myocarditis can occur simultaneously with dengue acute myopathy, further complicating the clinical picture. These serious complications can lead to severe muscle damage, electrolyte imbalances, and cardiac dysfunction, increasing the risk of organ failure. Prompt diagnosis and intervention are critical to managing these co-occurring conditions and preventing long-term damage [48]. Electromyography (EMG) studies, when performed in patients with dengue-related myopathy, typically do not reveal characteristics of inflammatory myositis. This suggests that, despite the presence of muscle weakness and elevated creatine kinase (CK) levels, the muscle dysfunction in dengue may not be primarily due to an inflammatory process. Instead, it may result from other mechanisms, such as viral-induced muscle injury or metabolic disturbances [51].

Myopathy associated with dengue is typically self-limited and does not result in long-term sequelae. Most patients experience a full recovery, with muscle weakness and elevated creatine kinase (CK) levels resolving within a few weeks. However, early recognition and appropriate management are essential to ensure a smooth recovery and prevent complications in severe cases [52]. In 2006, Finsterer and colleagues reported a case of a 38-year-old male who contracted dengue fever during a holiday in Thailand. He presented with fever, headache, and sore eyes, accompanied by intense myalgia rated 10/10 on a visual scale, which persisted for over 60 days. Electromyography revealed spontaneous activity in the subscapularis muscle. After three weeks of corticosteroid treatment, the myositis resolved, highlighting the potential for prolonged muscle pain and the need for corticosteroid therapy in severe cases of dengue myopathy [47].

It is worth mentioning that dengue can lead to GBS and also myositis, and sometimes the pattern of involvement is difficult to be isolated. Gulia et al. reported a case of a patient developing both GBS and myositis [59].

3.3. Encephalitis

Encephalopathy, as a manifestation of dengue fever, is more commonly secondary to multisystem complications caused by infectious factors such as shock, hepatitis, coagulation disturbances, and even concomitant bacterial infections. These systemic issues can exacerbate the effects of the virus on the central nervous system, leading to encephalopathy in some patients. This highlights the complex interplay between dengue and other complications that may contribute to neurological manifestations [60]. However, this mechanism is different when it comes to encephalitis (Table 6).

In the study by Bhushan et al., of the 79 patients with immune-mediated neurological complications, 9 developed acute disseminated encephalomyelitis (ADEM), 3 experienced isolated cerebellar demyelination, and 1 was diagnosed with limbic encephalitis [12]. Considering these three manifestations, it was found that 0.8% of patients with dengue fever developed encephalitis associated with DENV infection. This suggests that encephalitis, while rare, can occur as a complication of dengue infection. In a separate pediatric study, which had a smaller sample size of 71 patients, a higher incidence of 8% of children was reported to have encephalitis related to dengue fever. Tragically, 3 out of 4 children with dengue-related encephalitis in this study died, highlighting the severe and potentially fatal nature of encephalitis in the context of dengue infection, especially in younger patients. This increased mortality rate underscores the importance of early diagnosis and intervention in managing severe complications like encephalitis in dengue cases [13]. Fong et al. reported 10% of prevalence of DENV infections in patients with acute necrotising encephalopathy in the pediatric population from Malaysia [82].

Although rarer, dengue encephalitis is caused by direct neuronal infiltration of the DENV. The virus can induce neurological damage both through direct infection of the neurons and by triggering immunological mechanisms. The immune response to the virus can lead to inflammation and tissue damage in the brain, which may contribute to neurological symptoms such as altered mental status, seizures, and focal neurological deficits. The exact mechanisms of how the immune system contributes to this damage are not fully understood but likely involve an exaggerated inflammatory response or immune-mediated injury. This dual mechanism—direct viral invasion and immune-mediated damage—can lead to severe neurological complications in some patients [60]. While dengue is not traditionally classified as a neurotropic virus, meaning it does not typically target the nervous system, there is increasing evidence linking it to encephalitis. This neurological complication is distinct from encephalopathy (a general term for brain dysfunction), and it is not associated with the other common features of dengue, such as fever or rash. Dengue-related encephalitis is considered when CSF analysis reveals the presence of the DENV or dengue IgM antibodies, indicating direct involvement of the virus in the central nervous system. The detection of these markers helps differentiate dengue encephalitis from other neurological conditions and supports the diagnosis of viral encephalitis caused by dengue [61]. Encephalitis in dengue occurs during the viremic stage of the disease, when the virus is present in the bloodstream, whereas encephalopathy typically develops later, after the acute phase of the infection has subsided. Encephalitis is a direct consequence of the virus’s ability to invade the central nervous system, while encephalopathy is a more generalized brain dysfunction that may result from immune or metabolic factors related to the infection. Evidence suggests that DENV-2 and DENV-3, two of the four DENV serotypes, are the most commonly associated with neurotropism—the ability of the virus to infect and damage nervous tissue. These serotypes have been more frequently identified in cases of dengue-related encephalitis, indicating a stronger propensity to affect the brain compared to other serotypes [71]. There are anecdotal reports of DENV-4 found in the CSF in patients with encephalitis [83]. Also, some authors recommend performing nonstructural protein 1 (NS1) antigen in the CSF to differentiate dengue encephalitis from encephalopathy [84].

In cases where encephalitis is present, the manifestation typically includes headache, confusion, dizziness, disorientation, behavioral symptoms, and drowsiness. These symptoms reflect the neurological impact of the infection, which can range from mild cognitive disturbances to more severe alterations in consciousness and behavior [8]. Occasionally, patients with dengue-related encephalitis may also experience cranial nerve palsy, diminished deep tendon reflexes, hypotonia, and hemiparesis. Seizures are not commonly observed, but there have been reports of patients progressing to coma in severe cases. These additional neurological manifestations highlight the potential for varied and serious outcomes in individuals with dengue encephalitis [71]. Dengue-related encephalitis may be accompanied by typical dengue symptoms such as fever, arthralgia, myalgia, and vomiting. In addition to these, leukopenia, thrombocytopenia, and anemia are common findings, which are characteristic of the viral infection itself. These hematological abnormalities occur as a result of the virus’s impact on bone marrow function and immune system response, contributing to the overall clinical picture of severe dengue [71].

Diagnostic criteria for dengue-related encephalitis dictate the management approach. As established by Carod-Artal et al., the diagnosis requires the presence of clinical signs and symptoms of central nervous system (CNS) injury, along with confirmation of DENV involvement. This includes positive testing for DENV RNA, IgM, or NS1 antigen in cerebrospinal fluid (CSF), along with the presence of CSF lymphocytic pleocytosis (an elevated white blood cell count in the CSF, indicating inflammation). It is also essential that other neuroinvasive pathogens are ruled out, which is done by testing negative for other potential infectious diseases. These criteria help ensure an accurate diagnosis and appropriate treatment for patients with dengue-related encephalitis [8]. Following this assay, Cristiane and colleagues, in a supplementary study, defined dengue encephalitis as the presence of fever along with acute signs of cerebral involvement, such as confusion or altered consciousness. The diagnosis was further supported by the detection of reactive IgM antibodies, NS1 antigen, or positive dengue PCR in both serum and CSF. Additionally, the definition required the exclusion of other viral causes of encephalitis and encephalopathy to ensure that the symptoms were directly attributable to dengue. This approach helped refine the criteria for diagnosing dengue encephalitis, distinguishing it from other potential neurological complications [62].

Neuroimaging in DENV encephalitis usually shows no major abnormalities [64]. Vyas et al. reported normal brain MRI (magnetic resonance imaging) in only 30% of the individuals with dengue encephalitis, the other individuals had encephalitic and encephalopathic changes, and interestingly, around 15% had micro/macro-hemorrhages [85]. Once the affection is verifiable through MRI, dengue-related encephalitis is commonly demonstrated as abnormal multifocal hyperintensity on T2-weighted (T2W) and Fluid-Attenuated Inversion Recovery (FLAIR) sequences. These abnormalities are typically seen in both hemispheres, the periventricular zones, and the basal ganglia, areas of the brain involved in movement and coordination. These imaging findings reflect the inflammation and damage caused by the virus in the central nervous system [66]. Some distinctive patterns have been associated with dengue encephalitis on MRI, including the “double doughnut sign” and the “Jack-o’-lantern sign.” These patterns are related to the bilateral nature of the lesions seen in dengue-related encephalitis. The “double doughnut sign” refers to ring-like hyperintensities on T2W or FLAIR sequences, which are seen in the basal ganglia or periventricular areas. Similarly, the “Jack-o’-lantern sign” describes lesions that appear with a central area of hypointensity surrounded by a hyperintense rim, resembling a jack-o’-lantern shape. These patterns are not only characteristic of dengue encephalitis but also help in differentiating it from other causes of encephalitis [69]. In cases of dengue encephalitis, the thalamic double doughnut sign should be used to further specify the diagnosis, but there are no studies regarding the prevalence of this finding in cases of dengue encephalitis. Other areas reported to be affected in dengue-related encephalitis include the brainstem, cerebellum, corpus callosum, and bilateral thalami. In some patients, the lesions may involve both white and gray matter of the brain. These regions are critical for functions such as motor control, coordination, communication between brain hemispheres, and sensory processing. The involvement of both types of brain tissue suggests a widespread inflammatory response in the central nervous system, which can contribute to the diverse neurological symptoms observed in dengue encephalitis [64]. Noteworthy, tumefactive lesions were already observed with DENV encephalitis [86].

Regarding laboratory analysis, the dengue NS1 antigen test must be positive in serum to confirm the infection. CSF is typically described as colorless and transparent, with the presence of lymphocytic pleocytosis, indicating inflammation. Additionally, CSF testing should be negative for other infectious serologies, helping to rule out other potential causes of encephalitis. This combination of findings aids in diagnosing dengue-related encephalitis and differentiating it from other neurological infections [61]. IgM testing in the CSF using enzyme-linked immunosorbent assay (ELISA) for dengue antibodies is widely applied and reliable in diagnosing dengue-related encephalitis. This test has both high sensitivity (92%) and specificity (99%), making it a valuable tool in clinical practice. The presence of IgM antibodies in the CSF indicates recent DENV infection and supports the diagnosis of dengue encephalitis, particularly when other potential causes of encephalitis have been ruled out [71]. The gold standard for diagnosing dengue-related encephalitis would be isolating the virus in cell culture, followed by antibody identification through fluorescence. This method, while highly accurate, is rarely used in clinical practice due to its technical complexity and limited availability in many settings. As a result, other diagnostic tests, such as NS1 antigen detection and IgM antibody testing, are more commonly employed for practical and timely diagnosis [66].

It is equally important to test both the serum and CSF for other potential causes of encephalitis, including herpes simplex virus, Mycobacterium tuberculosis, cytomegalovirus, human T cell lymphotropic virus type-1, Epstein-Barr virus, and varicella-zoster virus. These tests help rule out other infectious agents that could be responsible for the neurological symptoms. Once the results for these viruses and pathogens are negative, it strengthens the diagnosis of dengue-related encephalitis, allowing for more targeted management [12].

Moreover, encephalitis must be distinguished from encephalopathy of other etiology. In such cases, detecting the DENV, NS1 antigen, or IgM dengue virus-specific antibodies in the CSF will support the diagnosis of dengue-related encephalitis. These diagnostic markers help differentiate between encephalitis caused by dengue and encephalopathy resulting from other underlying conditions, ensuring that appropriate treatment is administered [8]. The presence or absence of the Japanese encephalitis virus IgM is helpful to detect its presence which is one of the main differentials [70]. It is necessary for physicians to be aware of cross-reactivity and to consider the epidemiology context. The PCR exam can determine the concomitant infection of both viruses [67].

Although there is no specific antiviral agent for the DENV, treatments such as acyclovir, corticosteroids, and sodium valproate are occasionally used in the management of dengue encephalitis. Acyclovir may be used as an empirical treatment in cases where herpes simplex virus or other viral infections are suspected. Corticosteroids are sometimes employed to reduce inflammation in the central nervous system, while sodium valproate may be used to manage seizures, which can occur in severe cases of dengue encephalitis. However, the mainstay of management remains supportive care, as there is no proven antiviral therapy specifically for dengue-related encephalitis [71]. Supportive care is always necessary in the management of dengue encephalitis. This includes the use of antipyretic drugs to manage fever, analgesics for pain relief, and oral rehydration to prevent dehydration. These measures help alleviate symptoms and maintain hydration, which is crucial for patient recovery. On the other hand, the use of most non-steroidal anti-inflammatory drugs (NSAIDs), particularly acetylsalicylic acid (aspirin), is contraindicated in dengue cases. NSAIDs can increase the risk of bleeding, a common complication of dengue, and should be avoided to prevent worsening of this risk [8]. Mun et al. reported a case of encephalitis that was responsive to steroids [79], but there are reports of steroid-resistant dengue encephalitis [87].

Post-mortem analysis in patients with dengue-related encephalitis typically reveals non-specific edema lesions in the brain. These lesions are characterized by swelling of brain tissue, which is a common response to inflammation or injury. The edema observed is often diffuse and non-specific, meaning it does not point to a particular underlying cause or pattern of damage. This type of lesion reflects the generalized brain inflammation seen in severe cases of dengue encephalitis. However, further histological examination may reveal other subtle signs of viral infection or immune-mediated damage [8]. In cases where an autopsy was performed, the histopathological patterns observed in the brains of patients with dengue-related encephalitis included cerebral edema, vascular congestion, hemorrhage, perivascular lymphocyte infiltration, inflammation, and brain matter necrosis. These findings indicate significant damage to the brain tissue, with swelling, blood vessel changes, immune cell infiltration, and areas of tissue death, all of which are consistent with severe inflammation caused by the viral infection. These pathological features help confirm the diagnosis of dengue encephalitis and provide insight into the extent of the neurological damage [68]. Through immunoperoxidase staining, the presence of DENV antigens can be detected in brain tissue. This technique uses antibodies that specifically bind to DENV proteins, allowing for visualization of the virus within the brain tissue. Immunoperoxidase staining can help confirm the diagnosis of dengue encephalitis by identifying viral particles or antigens in the affected areas, such as neurons or inflammatory cells, and it plays a crucial role in understanding the pathogenesis of the disease [71].

There are some anecdotal reports in the literature of dengue fever presenting with psychosis and maniac episodes [88]. Several aspects including high fevers and even encephalitis by DENV can explain these findings that were already observed in the pediatric and adult population [89]. Clues for the diagnosis of this zoonose include the fact that the patient developed fever and coagulation abnormalities, but some patients may be challenging to diagnose especially in cases of mild fever and nonspecific pain [90].

Seizures

There are divergent reports in the literature regarding the prevalence of seizures associated with DENV infection [91]. Some authors describe that as a common finding and that the most frequent semiology is generalized tonic-clonic and epilepsia partialis continua [8]. Others describe that it is an uncommon finding affecting around three percent of the patients affected by DENV [92]. Though not specific, electroencephalogram (EEG) often demonstrates generalized slow waves in cases of encephalitis. These slow waves can be indicative of brain dysfunction, though they are not exclusive to encephalitis. Such changes are frequently attributed to factors like seizures, intracranial hemorrhage, or viral infection, all of which can contribute to altered brain activity. While EEG findings provide valuable insight into the neurological state of the patient, they must be interpreted in conjunction with other clinical and diagnostic information to confirm the underlying cause [71].

3.4. Myelitis

Spinal cord involvement, particularly transverse myelitis (TM), is not a common manifestation of DENV infection, but it should not be ignored. In a study by Sahu et al., out of 484 patients who developed neurological complications, 45 cases were identified, and 7 of those patients had myelitis, resulting in an incidence of 1.4%. While relatively rare, the occurrence of myelitis in dengue infection highlights the potential for serious neurological involvement beyond the more typical manifestations like encephalitis [9]. Additionally, in a study involving 1,627 patients, 79 presented with neurological immune-mediated syndromes. Among these, nine patients had acute disseminated encephalomyelitis, while five had myelitis alone. This further emphasizes that while neurological complications in dengue are relatively rare, they can present in a variety of forms, including both encephalitis and myelitis, highlighting the diverse impact the virus can have on the nervous system [12]. In a study by Sil et al., 5% of the pediatric patients with dengue infection were found to have myelitis as a neurological complication. This highlights that, although rare, myelitis can occur in children with dengue, further illustrating the diverse neurological manifestations of the infection in different age groups [13].

Table 7. Myelitis associated with dengue virus infection.

Reference	Country	N	Commentary
Soares et al. (2006) [93]	Brazil	13	Thirteen patients, including ten females and three men aged 11 to 79 years, developed dengue fever during the 2002 epidemic in Rio de Janeiro and experienced neurological complications. Two of these patients developed myelitis with paraparesis and sphincter retention, although MRI results were abnormal in only one case. CSF analysis revealed that both patients had an elevated Albumin Quotient, suggesting blood-CSF barrier dysfunction, and one also had intrathecal synthesis of antibodies. Additionally, both patients showed high cell and protein levels in the CSF, which indicated direct viral invasion and acute inflammation.
Puccioni-Sohler et al. (2009) [94]	Brazil	10	This retrospective study examined ten patients, aged 22 to 74, who were seropositive for dengue IgM/IgG and presented with neurological symptoms. Among them, three were diagnosed with transverse myelitis, based on MRI findings of the spine and inflammatory changes in the cerebrospinal fluid (CSF). Additionally, one patient showed intrathecal synthesis of dengue antibodies in the CSF, suggesting a possible direct viral involvement in the spinal cord. The findings highlight the potential for DENV to cause neurological complications, including spinal cord involvement, even in patients without typical encephalitis symptoms.
Chanthamat et al. (2010) [95]	Thailand	1	A 61-year-old female developed acute paraplegia, sensory loss, and urinary retention six days after the onset of dengue fever. She was diagnosed with transverse myelitis (TM) and was promptly treated with immunomodulatory therapy. After one month of treatment, she made a full recovery. This case underscores the potential for dengue to cause neurological complications, even in the absence of typical encephalitis symptoms, and highlights the effectiveness of early intervention in managing such complications.
Larik et al. (2012) [96]	India	1	An adolescent male patient presented with high-intensity low back pain and was diagnosed with longitudinally extensive transverse myelitis (LETM) four weeks after the onset of dengue infection. This case illustrates the potential for severe neurological complications, such as LETM, to develop weeks after the initial viral infection, emphasizing the importance of early detection and management.
Tomar et al. (2015) [97]	India	1	A middle-aged male developed longitudinally extensive transverse myelitis (LETM) during the acute parainfectious phase of dengue fever. On the third day of fever, he began experiencing neurological symptoms, including lower limb weakness, urinary retention, and sensory impairment. Despite the typically poor prognosis associated with LETM, the patient responded well to intravenous corticosteroid treatment and made a full recovery, with no residual neurological deficits. This case highlights the potential for recovery even in severe cases of dengue-related myelitis when treated promptly.
Fong et al. (2016) [98]	Malaysia	1	A 12-year-old girl became the first reported pediatric case of longitudinally extensive transverse myelitis (LETM) associated with dengue fever. On the 8th day of infection, she developed flaccid quadriplegia. She was treated with pulse methylprednisolone, intravenous immunoglobulin, and plasmapheresis, eventually achieving near-complete recovery after six months, with only mild residual limb weakness. This case highlights both the severity of neurological complications in pediatric dengue patients and the potential for recovery when treated aggressively.
Patras et al. (2016) [99]	India	1	Transverse myelitis in an 8-month-old child.
Mota et al. (2017) [100]	Brazil	1	A 21-year-old male patient with dengue fever developed transverse myelitis (TM). This case indicates that the actual prevalence of dengue-associated TM may be significantly underestimated, suggesting the need for greater clinical vigilance and further research to better understand the neurological complications of dengue.
Badat et al. (2018) [101]	United Kingdom	Not applicable	Until 2017, there were 61 cases of dengue and myelitis in the literature. They represented 2.3% of the presentation of dengue.
Chaudhry et al. (2018) [102]	India	1	A 55-year-old female who tested positive for the dengue IgM antibody developed spontaneous subarachnoid hemorrhage and longitudinally extensive transverse myelitis (LETM). She was treated with pulse methylprednisolone therapy and physical rehabilitation. However, after a one-month follow-up, she showed minimal improvement, underscoring the severity and difficult prognosis of neurological complications related to dengue infection, despite appropriate treatment.
Lana-Peixoto et al. (2018) [103]	Brazil	2	Two patients diagnosed with neuromyelitis optica spectrum disorder (NMOSD) developed symptoms following dengue fever (DF) infection. Both patients tested positive for aquaporin-4 (AQP4) antibodies, a hallmark of NMOSD, indicating an autoimmune response triggered by the viral infection. In both cases, the patients experienced neurological complications typical of NMOSD, such as transverse myelitis and optic neuritis, after recovering from the acute phase of dengue. This suggests that dengue infection may potentially act as a trigger for NMOSD in predisposed individuals, highlighting the complex interplay between viral infections and autoimmune disorders.
Malik et al. (2018) [104]	India	1	An adolescent patient presented with symptoms of transverse myelitis (TM) four weeks after contracting dengue fever (DF). The authors discuss the distinction between the acute (parainfectious) and late (post-infectious) stages of dengue with neurological manifestations. They suggest that in the parainfectious phase, the DENV directly infects the spinal cord, leading to neurological symptoms. In contrast, the post-infectious phase is primarily characterized by immune-mediated reactions that contribute to the development of neurological complications such as TM. This distinction emphasizes the different mechanisms involved in dengue-related neurological damage at various stages of infection.
Landais et al. (2019) [105]	France	1	A 24-year-old female developed myelitis on the 7th day of dengue fever. Spinal MRI revealed diffuse hyperintense lesions in the spinal cord, suggesting acute inflammation. She was treated with intravenous pulse methylprednisolone, immunoglobulin plasmapheresis, and physiotherapy. After five months of treatment, she achieved almost complete recovery, with only mild residual symptoms. This case highlights the potential for significant neurological recovery with appropriate and timely treatment in dengue-related myelitis.
Singh et al. (2019) [106]	India	1	Patient improved with steroid course.
Tan et al. (2019) [107]	Malaysia	1	Longitudinal extensive myelitis. High-index of suspicion in endemic regions is needed.
Comtois et al. (2021) [108]	Canada	1	Positive aquaporin-4 IgG titer in individual with longitudinal extensive myelitis.
Karishma et al. (2024) [109]	Pakistan	1	Acute transverse myelitis with serology positive for immunoglobulin M to DENV and non-structural protein
Kumar et al. (2024) [109]	India	1	Dengue serology positive in the CSF
Mangudkar et al. (2024) [110]	India	1	IVIG and steroids IV and taper.
Shrestha et al. (2024) [111]	Nepal	1	Drastic improvement with steroid course.

Table 7. Myelitis associated with dengue virus infection.

Reference	Country	N	Commentary
Soares et al. (2006) [93]	Brazil	13	Thirteen patients, including ten females and three men aged 11 to 79 years, developed dengue fever during the 2002 epidemic in Rio de Janeiro and experienced neurological complications. Two of these patients developed myelitis with paraparesis and sphincter retention, although MRI results were abnormal in only one case. CSF analysis revealed that both patients had an elevated Albumin Quotient, suggesting blood-CSF barrier dysfunction, and one also had intrathecal synthesis of antibodies. Additionally, both patients showed high cell and protein levels in the CSF, which indicated direct viral invasion and acute inflammation.
Puccioni-Sohler et al. (2009) [94]	Brazil	10	This retrospective study examined ten patients, aged 22 to 74, who were seropositive for dengue IgM/IgG and presented with neurological symptoms. Among them, three were diagnosed with transverse myelitis, based on MRI findings of the spine and inflammatory changes in the cerebrospinal fluid (CSF). Additionally, one patient showed intrathecal synthesis of dengue antibodies in the CSF, suggesting a possible direct viral involvement in the spinal cord. The findings highlight the potential for DENV to cause neurological complications, including spinal cord involvement, even in patients without typical encephalitis symptoms.
Chanthamat et al. (2010) [95]	Thailand	1	A 61-year-old female developed acute paraplegia, sensory loss, and urinary retention six days after the onset of dengue fever. She was diagnosed with transverse myelitis (TM) and was promptly treated with immunomodulatory therapy. After one month of treatment, she made a full recovery. This case underscores the potential for dengue to cause neurological complications, even in the absence of typical encephalitis symptoms, and highlights the effectiveness of early intervention in managing such complications.
Larik et al. (2012) [96]	India	1	An adolescent male patient presented with high-intensity low back pain and was diagnosed with longitudinally extensive transverse myelitis (LETM) four weeks after the onset of dengue infection. This case illustrates the potential for severe neurological complications, such as LETM, to develop weeks after the initial viral infection, emphasizing the importance of early detection and management.
Tomar et al. (2015) [97]	India	1	A middle-aged male developed longitudinally extensive transverse myelitis (LETM) during the acute parainfectious phase of dengue fever. On the third day of fever, he began experiencing neurological symptoms, including lower limb weakness, urinary retention, and sensory impairment. Despite the typically poor prognosis associated with LETM, the patient responded well to intravenous corticosteroid treatment and made a full recovery, with no residual neurological deficits. This case highlights the potential for recovery even in severe cases of dengue-related myelitis when treated promptly.
Fong et al. (2016) [98]	Malaysia	1	A 12-year-old girl became the first reported pediatric case of longitudinally extensive transverse myelitis (LETM) associated with dengue fever. On the 8th day of infection, she developed flaccid quadriplegia. She was treated with pulse methylprednisolone, intravenous immunoglobulin, and plasmapheresis, eventually achieving near-complete recovery after six months, with only mild residual limb weakness. This case highlights both the severity of neurological complications in pediatric dengue patients and the potential for recovery when treated aggressively.
Patras et al. (2016) [99]	India	1	Transverse myelitis in an 8-month-old child.
Mota et al. (2017) [100]	Brazil	1	A 21-year-old male patient with dengue fever developed transverse myelitis (TM). This case indicates that the actual prevalence of dengue-associated TM may be significantly underestimated, suggesting the need for greater clinical vigilance and further research to better understand the neurological complications of dengue.
Badat et al. (2018) [101]	United Kingdom	Not applicable	Until 2017, there were 61 cases of dengue and myelitis in the literature. They represented 2.3% of the presentation of dengue.
Chaudhry et al. (2018) [102]	India	1	A 55-year-old female who tested positive for the dengue IgM antibody developed spontaneous subarachnoid hemorrhage and longitudinally extensive transverse myelitis (LETM). She was treated with pulse methylprednisolone therapy and physical rehabilitation. However, after a one-month follow-up, she showed minimal improvement, underscoring the severity and difficult prognosis of neurological complications related to dengue infection, despite appropriate treatment.
Lana-Peixoto et al. (2018) [103]	Brazil	2	Two patients diagnosed with neuromyelitis optica spectrum disorder (NMOSD) developed symptoms following dengue fever (DF) infection. Both patients tested positive for aquaporin-4 (AQP4) antibodies, a hallmark of NMOSD, indicating an autoimmune response triggered by the viral infection. In both cases, the patients experienced neurological complications typical of NMOSD, such as transverse myelitis and optic neuritis, after recovering from the acute phase of dengue. This suggests that dengue infection may potentially act as a trigger for NMOSD in predisposed individuals, highlighting the complex interplay between viral infections and autoimmune disorders.
Malik et al. (2018) [104]	India	1	An adolescent patient presented with symptoms of transverse myelitis (TM) four weeks after contracting dengue fever (DF). The authors discuss the distinction between the acute (parainfectious) and late (post-infectious) stages of dengue with neurological manifestations. They suggest that in the parainfectious phase, the DENV directly infects the spinal cord, leading to neurological symptoms. In contrast, the post-infectious phase is primarily characterized by immune-mediated reactions that contribute to the development of neurological complications such as TM. This distinction emphasizes the different mechanisms involved in dengue-related neurological damage at various stages of infection.
Landais et al. (2019) [105]	France	1	A 24-year-old female developed myelitis on the 7th day of dengue fever. Spinal MRI revealed diffuse hyperintense lesions in the spinal cord, suggesting acute inflammation. She was treated with intravenous pulse methylprednisolone, immunoglobulin plasmapheresis, and physiotherapy. After five months of treatment, she achieved almost complete recovery, with only mild residual symptoms. This case highlights the potential for significant neurological recovery with appropriate and timely treatment in dengue-related myelitis.
Singh et al. (2019) [106]	India	1	Patient improved with steroid course.
Tan et al. (2019) [107]	Malaysia	1	Longitudinal extensive myelitis. High-index of suspicion in endemic regions is needed.
Comtois et al. (2021) [108]	Canada	1	Positive aquaporin-4 IgG titer in individual with longitudinal extensive myelitis.
Karishma et al. (2024) [109]	Pakistan	1	Acute transverse myelitis with serology positive for immunoglobulin M to DENV and non-structural protein
Kumar et al. (2024) [109]	India	1	Dengue serology positive in the CSF
Mangudkar et al. (2024) [110]	India	1	IVIG and steroids IV and taper.
Shrestha et al. (2024) [111]	Nepal	1	Drastic improvement with steroid course.

When transverse myelitis (TM) occurs, it can be associated with challenging clinical recovery, often leading to long-term disability. The severity of neurological damage and the extent of recovery can vary, but in many cases, the condition results in lasting impairments, such as weakness, sensory loss, or bladder dysfunction, which may require prolonged rehabilitation and management. Early diagnosis and treatment are crucial to improving outcomes, although complete recovery is not always achievable [96]. When a spinal injury involves more than three vertebral segments, it is classified as longitudinally extensive transverse myelitis (LETM), a rare and more severe form of myelitis. LETM can result in significant morbidity, including severe neurological impairments such as paralysis, sensory deficits, and bladder dysfunction. Due to the extensive involvement of the spinal cord, the condition often requires intensive treatment and rehabilitation, and recovery may be incomplete, leading to long-term disability in many cases [98].

Symptoms commonly associated with transverse myelitis (TM) include weakness or paralysis of the upper and lower limbs, urinary retention, and sensory alterations such as numbness or tingling. These symptoms result from inflammation of the spinal cord, which disrupts normal nerve function. Depending on the severity and extent of the inflammation, individuals may experience varying degrees of motor and sensory deficits, which can significantly impact daily functioning and quality of life [102]. It is suggested that temporal factors significantly influence the presentation of pathology in transverse myelitis (TM). During the acute phase, patients typically exhibit flaccid paralysis, which is associated with direct viral or inflammatory damage to the spinal cord. In contrast, during the post-infectious stage, which often begins 1-2 weeks after the initial symptoms, patients are more likely to present with spastic weakness, a condition that results from the spinal cord’s response to immune-mediated damage. This distinction highlights the evolving nature of TM and its varied clinical manifestations over time [97,104].

According to Mota et al., the initial signs of transverse myelitis (TM) associated with DF may arise in two phases. Initially, the symptoms can be attributed to the direct viral impact on the spinal cord. Subsequently, the progression of the disease is often influenced by an immune response, where the body’s immune system targets the spinal cord as a result of the dengue infection. This twofold mechanism emphasizes the complex interplay between viral infection and immune-mediated damage in the development of TM in dengue patients [100]. The diagnosis of direct viral invasion in cases of TM associated with dengue fever is supported by IgG and IgM tests, which detect antibodies specific to the DENV. Additionally, isolating the virus in CSF during the very early stages of infection can provide further evidence of direct viral invasion. These diagnostic methods help confirm the presence of the DENV in the central nervous system and distinguish it from other potential causes of neurological symptoms [95]. A retrospective study involving ten patients with neurological complications associated with DF revealed that seven of the patients tested positive for IgM antibodies, while nine tested positive for IgG antibodies specific to the DENV in CSF. This finding supports the presence of DENV in the central nervous system and highlights the importance of serological testing in diagnosing dengue-related neurological complications [94]. The detection of elevated protein and leukocyte levels in the CSF could also suggest an acute inflammatory process, likely resulting from the local effects of the viral infection. These abnormalities in the CSF are indicative of inflammation and may help differentiate dengue-related neurological complications from other conditions, providing valuable diagnostic insight into the nature and severity of the infection [93]. Diagnostic imaging methods, such as MRI, can also be utilized to detect signs of inflammation in the central nervous system and assist in the differential diagnosis of dengue-related neurological complications. MRI can reveal characteristic abnormalities, such as lesions or hyperintensities in areas like the spinal cord or brain, which are indicative of inflammation caused by the viral infection. These imaging findings are crucial for confirming the diagnosis and ruling out other potential causes of neurological symptoms [104].

A 2018 report described two patients with neuromyelitis optica spectrum disorder (NMOSD) who tested positive for aquaporin-4 antibodies and developed the condition concurrently with an acute dengue fever infection. This finding highlights the potential for dengue to trigger or exacerbate autoimmune disorders such as NMOSD, suggesting that dengue fever may be a possible precipitating factor in the onset of neurological diseases characterized by autoimmune-mediated damage to the central nervous system [103].

There are ongoing controversies regarding treatment decisions for TM. Even with appropriate therapy, many patients require months to regain neurological function, and some continue to experience residual symptoms. Currently, there is a lack of high-level evidence to definitively support the use of intravenous corticosteroids. Nevertheless, pulse therapy with methylprednisolone remains the primary treatment option for TM. In cases where the response is inadequate, therapeutic plasma exchange may be considered as a secondary treatment approach to help reduce inflammation and improve outcomes [104]. A case report of a 24-year-old female who tested positive for dengue IgM/IgG antibodies and developed acute myelitis showed that despite receiving treatment with intravenous pulse methylprednisolone, immunoglobulin plasmapheresis, and physiotherapy, she was unable to achieve complete recovery of her motor and sensory deficits after five months. This case highlights the challenging nature of dengue-related myelitis, where even with aggressive treatment, full recovery may not always be attainable, and patients may experience long-term neurological impairments [105]. Although myelitis is a rare complication of dengue fever (DF), clinicians must remain vigilant and consider it as a potential cause of neurological symptoms in patients with typical dengue symptoms. Early recognition and investigation of myelitis in such cases are crucial, as prompt diagnosis and appropriate treatment can help manage the condition and potentially improve outcomes, reducing the risk of long-term neurological impairments [97].

3.5. Acute Disseminated Encephalomyelitis

As previously discussed, myelitis and encephalitis can occur as separate entities within the spectrum of neurological complications associated with dengue fever. Another neurological complication linked to dengue fever is acute disseminated encephalomyelitis (ADEM), which presents with a combination of both encephalitis and myelitis symptoms. ADEM is an autoimmune-mediated disorder that can develop after a viral infection like dengue, leading to widespread inflammation in the brain and spinal cord, and may present with a range of neurological deficits depending on the extent and location of the damage (Table 8).

In their study, Bhushan et al. discovered that among patients suffering from dengue fever, 11% experienced immune-mediated neurological complications specifically identified as Acute Disseminated Encephalomyelitis (ADEM). This finding highlights a significant association between DENV infection and the onset of neurological disorders, emphasizing the need for heightened awareness and monitoring of such complications in patients with dengue fever [12]. In a different study, Sil et al. assessed a group of children and discovered that 5% of pediatric patients diagnosed with dengue fever had experienced ADEM [13]. A meta-analysis conducted in 2017 found that the prevalence of Acute Disseminated Encephalomyelitis (ADEM) among patients with dengue fever is approximately 0.4%. This finding suggests that a small yet significant percentage of individuals infected with dengue may experience this severe neurological condition. It emphasizes the importance of awareness regarding potential neurological complications in dengue patients, highlighting the necessity for careful monitoring and prompt intervention when neurological symptoms arise [113].

Neurological symptoms typically arise between 3 to 19 days after the initial signs of illness. Altered mental status is the most common, affecting 58% of patients and often presenting as confusion, disorientation, or changes in consciousness. Seizures and urinary issues were noted in 35% of cases, while visual disturbances, including blurred vision and difficulty focusing, affected 31%. Slurred speech was reported by 23%, indicating motor function disruptions. Additionally, walking difficulties impaired mobility and balance in 15% of individuals, and ataxia, characterized by uncoordinated muscle movements, was present in 12%. These findings underscore the wide-ranging neurological effects that can follow the onset of illness [113]. Also, the authors found that there is little information on the spinal MRI of the patients [113]. Still, nine patients with ADEM associated with DENV infection were reported. Of these, 7 had an LETM, as featured in the image study [12]. A different study that examined 22 cases indicates a similar conclusion, noting that the majority of patients experienced significant myelitis with a tendency towards the cervical and thoracic regions [114].

Recently, three unusual instances of ADEM linked to dengue fever have been reported. In the first case, an individual with a 5-day fever history was discovered in a state of diminished vitality by their sister and arrived at the emergency department with a Glasgow Coma Scale score of 5, requiring mechanical ventilation; they subsequently received treatment in the intensive care unit with steroids and made a recovery [115]. In the remaining two cases, there were two patients diagnosed with ADEM (Acute Disseminated Encephalomyelitis) associated with dengue fever. Their MRI scans exhibited patterns and lesions that closely resembled those typically seen in multiple sclerosis, highlighting the complexities of accurately diagnosing these conditions [112].

The therapies administered included intravenous immunoglobulin, steroids, plasma exchange, and various other forms of immunotherapy. Regarding prognosis, in the meta-analysis conducted by Kamel et al., out of 29 cases studied, three individuals passed away, seven experienced partial recovery, and sixteen achieved complete recovery. Those who fully recovered exhibited lower body temperatures compared to the groups with partial recovery and poor outcomes [113].

3.6. New Daily Persistent Headache

New daily persistent headache (NDPH) is a primary headache characterized by abrupt onset and daily occurrence without remission [119]. Some inciting events for NDPH have been described, such as viral infections, surgeries, and stress. However, the pathogenesis remains unclear (Table 9). Numerous studies have established a correlation between Epstein-Barr Virus (EBV) infection and the development of New Daily Persistent Headache (NDPH). Research indicates that individuals who contract EBV may experience a variety of neurological symptoms, among which NDPH is notably prevalent. This connection suggests that EBV infection could be a potential trigger for the onset of chronic headache disorders, highlighting the importance of investigating the underlying mechanisms linking viral infections to neurological conditions [112]. Notably, the connection between dengue and NDPH has been recently documented. Abreu et al. found that among 450 patients with dengue, 3 had NDPH, resulting in a prevalence rate of 0.67%, which surpasses the estimated prevalence of 0.03-0.1% found in the general population [120].

Bordini et al. reported two cases of new daily persistent headache (NDPH) following dengue fever infections. In the first case, a 23-year-old Caucasian male experienced daily bilateral headaches for two years, characterized by a severe pressure-like pain. His headaches were resistant to treatments like amitriptyline and valproic acid but showed temporary relief from nerve blockade. The second case involved a 42-year-old Caucasian female who developed a bilateral pressure-type headache shortly after her dengue fever diagnosis, confirmed by serological tests. Her headaches ranged from moderate to severe and were accompanied by nausea and sensitivity to light and sound, persisting for seven months. She finally found relief after a 10-day course of dexamethasone. These cases illustrate NDPH as a possible post-viral complication of dengue fever and the challenges in managing persistent headache disorders [121].

3.7. Acute Meningitis

Headaches are the most common symptom related to dengue fever. Some patients can develop acute meningitis signs with fever, headache, and nuchal rigidity. In an endemic area of dengue, around ten percent of the patients with acute viral meningitis had seropositivity in their CSF for dengue [122]. It is worth mentioning that meningeal contrast enhancement was already reported in individuals with acute viral meningitis due to dengue [123].

3.8. Movement Disorders

A review found that the movement disorders associated with dengue are ataxia, dystonia, parkinsonism, myoclonus, and stereotypy [124]. One of the most frequently observed associations are dystonia and parkinsonism, and less frequent is isolated parkinsonism. Batra et al. and Panda et al. reported cases of dengue-associated parkinsonism [125,126]. Interestingly, there are dengue-induced movement disorders in pediatric and adult individuals [127].

3.9. Others

The “other” neurological symptoms linked to dengue fever warrant a review because of the variety of disorders related to the virus found in the literature (Table 10). These atypical connections span from rapidly progressing dementia in an older patient to psychiatric conditions associated with dengue [128], as an Indian patient with maniac symptoms [129]. In a similar situation in Saudi Arabia, two additional patients experienced recurring migraine-like episodes accompanied by an intense fear of a near-death experience, along with symptoms of dysautonomia following viral meningitis caused by dengue [130].

In their research, Misra et al. discovered that 11% of individuals with dengue encephalitis experienced movement disorders [148]. There have been reports indicating that both adults and children with dengue may experience parkinsonism [132,133]. One of the neurological manifestations linked to DENV infection is the occurrence of opsoclonus-myoclonus. This condition is characterized by irregular, rapid eye movements known as opsoclonus, alongside sudden, involuntary muscle jerks or twitches referred to as myoclonus [135,139], cerebellar syndrome [136], and ocular flutter with truncal ataxia [137]. These symptoms can significantly affect a patient’s coordination and overall neurological function.

These diverse manifestations of the disease still encompass multiple motor neuropathy that responds to intravenous immunoglobulin [140], isolated cranial nerve paralysis [134,142], and neuralgic amyotrophy, which took 3 months for recovery in 2 out of 3 patients in a case series [131]. Additionally, there is an instance of immune-mediated cauda equina syndrome in a European patient following a trip to Brazil, with positive CSF for IgM antibodies to dengue, along with the presence of oligoclonal bands [141]. Moreover, there is a documented case of hemiconvulsion hemiplegia triggered by dengue infection [138], and two patients who were reported in the study by Bhushan and colleagues experienced painful retrobulbar optic neuritis [12]. Chang et al. reported increased risk of developing dementia after dengue fever [149].

4. Challenge

4.1. Challenges in Diagnosis

There is a significant increase of cases in developed countries due to traveling availability. It is always worth to ask regarding travelling history, and let the alerts for reminder to ask about travel history on. Kim et al. reply to the comment by readers as since dengue infection is not endemic and extremely rare in South Korea, the authors tested a wide range of possible infections [150].

4.2. Challenges for Prevention

Some of the main challenges in the development of vaccines for dengue is the fact they should cover the four serotypes of DENV. Also, they need to prevent cross-immunity. Currently, there are about seven vaccines and many ongoing clinical trials. The CYD-TDV (Dengvaxia^®) was the first vaccine to be developed, and unfortunately the patient needs to have at least one episode of dengue before receiving vaccination. In the case of TAK-003 (Qdenga^®) administration, it is independent of dengue serological status of the patient. And, interestingly the TV003 (TV005) is based on attenuated viruses [151]. It is worth mentioning that the current vaccines showed decreased cases of severe dengue in general, but there is no specific analysis of cases related to neurological manifestations. Furthermore, the CYD-TDV vaccine given to individuals with serological status negative for dengue more commonly developed severe dengue with neurological manifestations [152].

5. Limitations

This manuscript did not employ a systematic search methodology. Instead, all articles included in the study were sourced exclusively from the PubMed database. While this approach allowed for a broad exploration of available literature, the inclusion of diverse types of manuscripts introduces potential variability in the interpretation of the clinical neurological manifestations associated with DENV infection. The selected articles reflect a range of perspectives and methodologies, which may contribute to a more nuanced but less uniform understanding of the topic. This variability underscores the challenge of drawing definitive conclusions from heterogenous data.

Despite these limitations, the primary objective of this manuscript is to offer a comprehensive overview of the neuroinvasion characteristics of DENV, synthesizing current knowledge to better understand its neurological impacts. The manuscript also seeks to highlight critical gaps in the existing literature, providing a foundation for future research in this area. By summarizing diverse findings, it aims to inform clinicians and researchers about the spectrum of neurological complications linked to dengue. Additionally, this work underscores the importance of interdisciplinary approaches in studying viral neuroinvasion, as the mechanisms remain complex and multifactorial. Ultimately, this review hopes to contribute to a deeper understanding of how the DENV affects the central nervous system and to support the development of more targeted diagnostic and therapeutic strategies.

6. Conclusion

This scoping review highlights the diverse and significant neurological manifestations of DENV infection beyond cerebrovascular disorders. Dengue, a globally prevalent arboviral infection, has traditionally been associated with systemic and febrile illness. However, increasing evidence reveals its capacity to affect the central and peripheral nervous systems through direct viral invasion, immune-mediated mechanisms, and metabolic derangements. These manifestations encompass a wide spectrum, including encephalitis, myelitis, Guillain-Barré syndrome, transverse myelitis, and acute disseminated encephalomyelitis, among others. The variability in clinical presentations underscores the need for heightened clinical suspicion, particularly in endemic regions. Neurological complications can occur across all age groups and are often associated with more severe forms of the disease, such as dengue hemorrhagic fever and dengue shock syndrome. Timely recognition and intervention are crucial to mitigate long-term morbidity, which includes persistent cognitive, motor, and sensory deficits. However, diagnosis is often challenging due to overlapping symptoms with other tropical infections and the lack of specific neurological biomarkers. Our review identifies critical gaps in the understanding of the pathophysiological mechanisms underlying these complications. Additionally, there is a paucity of large-scale epidemiological studies that delineate the incidence, risk factors, and outcomes of neurological involvement in dengue. Addressing these gaps is essential for developing targeted diagnostic and therapeutic strategies. In conclusion, the neurological spectrum of dengue is broader than traditionally appreciated, warranting further research and a multidisciplinary approach to diagnosis and management. Clinicians, particularly in endemic areas, should maintain vigilance for neurological symptoms in dengue patients, ensuring prompt referral and comprehensive care. Enhanced awareness, along with public health measures to control the spread of dengue, will be pivotal in reducing the burden of these disabling complications.