https://orcid.org/0000-0002-3336-6135
Figures
Abstract
Dengue virus (DENV) is a flavivirus that is a significant cause of human disease costing billions of dollars per year in medical and mosquito control costs. It is estimated that up to 20% of DENV infections affect the brain. Incidence of DENV infections is increasing, which suggests more people are at risk of developing neurological complications. The most common neurological manifestations of DENV are encephalitis and encephalopathy, and movement disorders such as parkinsonism have been observed. Parkinsonism describes syndromes similar to Parkinson’s Disease where tremors, stiffness, and slow movements are observed. Parkinsonism caused by viral infection is characterized by patients exhibiting at least two of the following symptoms: tremor, bradykinesia, rigidity, and postural instability. To investigate DENV-associated parkinsonism, case studies and reports of DENV-associated parkinsonism were obtained from peer-reviewed manuscripts and gray literature. Seven reports of clinically diagnosed DENV-associated parkinsonism and 15 cases of DENV encephalitis, where the patient met the case criteria for a diagnosis of viral parkinsonism were found. Clinically diagnosed DENV-associated parkinsonism patients were more likely to be male and exhibit expressionless face, speech problems, and lymphocytosis. Suspected patients were more likely to exhibit tremor, have thrombocytopenia and low hemoglobin. Viral parkinsonism can cause a permanent reduction in neurons with consequential cognitive and behavior changes, or it can leave a latent imprint in the brain that can cause neurological dysfunction decades after recovery. DENV-associated parkinsonism is underdiagnosed and better adherence to the case definition of viral parkinsonism is needed for proper management of potential sequalae especially if the patient has an ongoing or potential to develop a neurodegenerative disease.
Author summary
Dengue Virus (DENV) causes generalized fever in most patients and is transmitted via Aedes aegypti mosquitos. A small proportion of DENV infected patients have neurological complications associated with the critical phase of the illness. The usual neurological manifestations are encephalitis and encephalopathy, but there can also be movement disorders such as parkinsonism. DENV patients with parkinsonism present with tremor, bradykinesia, instability, and rigidity on top of the typical febrile manifestations of the disease. We searched the literature and uncovered 7 cases of clinically diagnosed DENV parkinsonism patients and 15 cases of suspected DENV parkinsonism. We found that the clinically diagnosed patients were more likely to be male, have expressionless face, speech issues and lymphocytosis. The suspected cases often had a diagnosis of encephalitis and were more likely to have tremors, thrombocytopenia, and low hemoglobin.
Citation: Hopkins HK, Traverse EM, Barr KL (2022) Viral Parkinsonism: An underdiagnosed neurological complication of Dengue virus infection. PLoS Negl Trop Dis 16(2): e0010118. https://doi.org/10.1371/journal.pntd.0010118
Editor: Johan Van Weyenbergh, KU Leuven, BELGIUM
Received: August 12, 2021; Accepted: December 21, 2021; Published: February 9, 2022
Copyright: © 2022 Hopkins et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript.
Funding: The authors received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Dengue virus (DENV) is a flavivirus that is a significant cause of human disease [1–3]. It is spread by the mosquitos Aedes aegypti and Aedes albopictus and humans are a crucial part of the viral life cycle [1,2,4,5]. The virus is endemic in over 100 nations and is a persistent cause of human infection with about 100 million people developing a clinically apparent DENV infection and about 22,000 people dying every year [5–7]. Additionally, the financial burden of the disease is significant, costing billions of dollars per year in medical and mosquito control costs [2,3,5,6].
Disease caused by a DENV infection is of concern because of the lasting effects it can have on those infected. DENV infection can be broken into two categories: dengue and severe dengue [5–7]. Dengue typically presents as a self-limited febrile illness, while severe dengue can result in plasma leakage, organ impairment and hemorrhagic fever [7]. Severe dengue also includes any DENV infection resulting in neurological manifestations [7]. Once thought to be non-neurotropic, it is now estimated that anywhere from 0.5% to 20% of DENV infections affect the brain [8–13]. Neurologic complications of DENV were first described in 1945 by a doctor in the Central Pacific who described 13 of his patients as having “unilateral attacks of neuritis” including the “facial, palatine, long thoracic, ulnar, peroneal and sciatic nerves” [14]. These observations were not reported again until much later in 1976 [8–15]. The most common neurological manifestations of severe dengue are encephalitis and encephalopathy, while movement disorders such as parkinsonism have been observed [8,16–32].
Parkinsonism is a term used to describe syndromes similar to Parkinson’s Disease where tremors, stiffness, and slow movements are observed [33]. Parkinsonism caused by viral infection is characterized by patients exhibiting at least two of the following symptoms: tremor, bradykinesia, rigidity, and postural instability [34]. Several viruses cause parkinsonism and regardless of the virus, there are some common symptoms that may appear including bradykinesia, tremor, hypokinesia, mask-like facies, tremor, postural instability, rigidity, and abnormal gait [35]. A study of two flaviviruses, Japanese Encephalitis Virus (JEV) and West Nile Virus (WNV), found that parkinsonism improved over time, though patients with reoccurring JEV infection had a higher rate of developing parkinsonism [35]. Many viruses including: influenza A, coxsackie virus, HIV, and many flaviviruses including JEV, St. Louis Encephalitis Virus, and WNV can cause primary or secondary parkinsonism, including encephalitis lethargica[33,36,37]
A growing body of evidence is indicating that viruses that cause parkinsonism are also associated with idiopathic Parkinson’s Disease (PD) [35,38]. PD is lifelong, characterized by neuronal death, and has about a 15-year life expectancy after the onset of symptoms [33]. Around 10% of PD cases can be attributed to a genetic etiology, while the other 90% are categorized as sporadic or idiopathic PD [33,39]. Like PD, parkinsonism is associated with reduced dopamine production resultant from neuron damage [40,41]. In addition, patients with viral parkinsonism often have cell damage that inhibits the production and uptake of dopamine[42]. Thus, treatment with levodopa may not be helpful in ameliorating symptoms [33]. Viral parkinsonism is theorized to be a result of immune mediated complications resulting in neuroinflammation even though in many cases, CT and MRI are normal [24,43]. Recent work has shown that blockage of the IFN1 pathway causes mitochondrial dysfunction in the brain which causes neuronal death [38]. Many viruses, including DENV, block IFN1 in order to evade the immune system and establish infection [44,45]. It is theorized that viral activation of microglia causes hypercytokinemia and aggregation of microglia around dopa neurons which then leads to a state of chronic inflammation and neuronal damage [46]. Viruses can also induce more neuronal damage via replication and cell lysis [47,48].
While viruses can cause acute neuroinflammation and parkinsonism, little attention has been given to long-term sequalae following recovery from the acute phase of infection. Upon immune clearance of virus from the brain, there can be a permanent reduction in neurons with consequential cognitive and behavior changes in the patient [49,50]. Many viruses can be found residing in the brain for months following recovery from the acute phase of disease in the absence of neurological symptoms [51–53]. And some viruses, like polio and WNV, have been shown to leave a “latent imprint” in the brain that causes neurological dysfunction decades after recovery [49,54,55].
Incidence of DENV infections is increasing, which suggests more people are at risk of developing neurological complications [5,56]. Viral parkinsonism caused by DENV infection may be more common than previously thought. The mechanism of DENV infection in the brain is still largely unknown, but it is theorized that damage can occur either by direct viral invasion, through an autoimmune response, or through metabolic disturbances [8,57].The likeliest route of entry is the blood brain barrier (BBB), which is a series of brain capillaries essential for the transport of oxygen and nutrients to neurons [58]. These capillaries are lined by endothelial cells that control permeability between the vascular space and parenchyma [58]. It is proposed the DENV most likely invades the brain though inter-endothelial tight junction disruption, endothelial cell infection and passage through infected monocytes [58].
In order to investigate DENV-associated parkinsonism, case studies and reports of DENV-associated parkinsonism were obtained from peer-reviewed manuscripts and gray literature. Clinical features and demographics were analyzed to determine if any hallmark features were associated with the diagnosis of parkinsonism.
Methods
Case definition
Inclusion criteria for DENV-associated parkinsonism were as follows: a clinical diagnosis of a DENV infection with laboratory confirmation and a diagnosis of parkinsonism either during or immediately following the acute phase of infection. Patients with a clinical diagnosis of a DENV infection and at least two of the diagnostic symptoms of parkinsonism (bradykinesia, tremor, hypokinesia, mask-like facies, tremor, postural instability, rigidity, and abnormal gait) either during or immediately following the acute phase of infection but no officially diagnosed parkinsonism, were included in a separate group since they met criteria for a clinical diagnosis [33,34].
Search Strategy.
Manuscripts and case reports were obtained from Pubmed, Scopus, CINAHL, Embase, LILACs, Google Scholar, and gray literature from medical and government agencies. The search terms used to find cases were “dengue + Parkinson” and “dengue + parkinsonism.” In order to find suspected case reports of dengue parkinsonism, infections with overlapping symptoms, the search terms used were: “dengue + tremor,” “dengue + bradykinesia,” “dengue + rigidity,” “dengue + instability,” and “dengue + encephalitis + case.”
Statistical analysis
Patients were divided into two groups which included: patients with viral parkinsonism as a primary diagnosis (Clinical Cases) and patients with symptoms of viral parkinsonism but lacking a clinical diagnosis of parkinsonism (Suspect Cases). Clinical laboratory values were compared against the normal reference range for the appropriate sex as needed (i.e. hematocrit). Statistical analyses were performed using MedCalc version 17.9.7–64-bit. Logistic regression for dichotomous independent variables was performed. Odds ratios were calculated with 95% confidence intervals. Ratios with a p<0.05 were considered significant. When the odds ratios were less than 1, the binary values in the analysis were reversed to obtain the inverse odds ratio. When the 95% CI was not calculated by the software due to small sample size, p-values were reported. When appropriate, ANOVA with Tukey-Kramer post-hoc test was performed.
Results
Dengue parkinsonism
The literature search produced 1,990 sources though when examined, most reports did not include sufficient data to determine if the patient had parkinsonism. Thus, only seven case reports of clinically diagnosed DENV-associated parkinsonism were found and included for analysis (Table 1). The first reported case occurred in 2013 in Kuala Lumpur, Malaysia and after reports originated from Kuala Lumpur, Malaysia; Kandy, Sri Lanka; Calicut, India; Northern India; New Delhi India; and the Karnataka State in India (Fig 1), [24]. Many reports did not provide a serotype as patients were diagnosed via ELISA for either NS1, IgG or IgM. Thus, serotype was inferred through sequence submissions to NCBI and peer-reviewed outbreak reports from locations where and when these cases occurred. In 2013, Kuala Lumpur, Malaysia had an outbreak of DENV-1 and DENV-2 [59], while only having DENV-1 in 2014 [60]. DENV-2 was present in Kandy, Sri Lanka in 2017 [61]. Calicut, India had DENV-3 in circulation in 2019 [62]. The serotype of DENV in Northern India and New Delhi in 2020 was not able to be determined. The serotype in India in 2021 was DENV-1 based on reference sequences in the NCBI virus database [63].
Only cases with location available were included. Dot location is approximate and there is location overlap for some cases. Serotype was inferred through sequence submissions to NCBI and peer-reviewed outbreak reports from locations where and when these cases occurred. The base layer of this map is from (https://commons.wikimedia.org/wiki/File:A_large_blank_world_map_with_oceans_marked_in_blue.svg) by Petr Dlouhý, July 25, 2006. Wikimedia Commons.
Searches for DENV with suspected parkinsonism produced 544 papers. Here too, most authors failed to include sufficient information to determine if the patient had parkinsonism. Thus, only 15 cases met the inclusion criteria for DENV with viral parkinsonism (Table 2). Cases were identified from India, Brazil, Mexico, Sri Lanka, Vietnam, and Tahiti (Fig 1). Most cases did not report serotype, however the serotypes of many of the other case studies were inferred as described above. Five reports were associated with outbreaks of DENV-2 [64–73]. Three of the case studies were associated with outbreaks of DENV-1 [74–77]. Two were associated with DENV-3 and none with DENV-4 [78–81]. One case was in a region with all four serotypes present, and two in a region where DENV-1 and DENV-2 were co-circulating [82–87].
Patient demographics
The average age of patients with a clinical diagnosis of parkinsonism was 28.14 years (SD +/- 22.36) with a range of 63 years (Table 3, Fig 2). Five of the 7 cases were aged 25 or younger while one was aged 48 and the oldest was 69 (Fig 2). 85.71% were male and 14.29% female (Table 3). Two of the six cases had a significant medical history: one had chicken pox two months prior to DENV infection [24] and another had a history of non-Hodgkin’s lymphoma [88]. For suspect cases, 46% were male and 54% female (Table 3). The average patient age was 31.58 (SD +/- 19.30) with a range of 66.25 years (Table 3, Fig 2). Here, 7 of the patients were aged 25 or younger while 6 were between the ages of 39 to 45 and the 2 remaining patients were aged 55 and 67 (Fig 2). Of note, there were no patients between 26 and 42 years of age. Patients with a clinical diagnosis of parkinsonism were 6.85 times more likely to be male than patients without a clinical diagnosis of parkinsonism (Table 3).
The center line indicates the median value (50th percentile), while the box contains the 25th to the 75th percentiles. Error bars represent 95% confidence interval.
OR = odds ratio, CI = confidence interval, NS = not significant.
Vital statistics
Heart rate and blood pressure were within normal range for both groups (Table 4). Both groups had an average temperature over 38°C (Table 4). For both groups of patients, vital statistics were not a significantly different from each other (p >0.1) (Table 4).
Bpm = beats per minute, mmHg = millimeters of mercury.
Clinical manifestations
For patients with a clinical diagnosis of parkinsonism, symptom onset occurred immediately after or concurrently with the critical phase of a severe dengue fever [88–91]. Additionally, three of the seven clinically diagnosed patients in the studies tested positive for IgG which indicates a likely secondary infection [24,89,92]. No patient deaths were reported [24,88–91,93], but one outcome was not described [92]. All patients with a diagnosis of parkinsonism also had severe DENV as defined by the World Health Organization [7]. Symptoms for the clinical case group were expressionless face in 5 of 7 cases (Table 5), [88,89,91–93]. Two of seven experienced imbalance [24,93] and four of seven had confusion (Table 5), [89–92]. Of the seven case studies, six had slurring of speech (Table 5), [24,88–91,93]. Six had slow movements [24,88–91,93], four had tremors/dystonia [24,90–92] and five had gait issues (Table 5), [24,88,89,91,93]. Four case studies reported stiffness/rigidity (Table 5), [88,90,91,93]. The clinical case group was 16.25 times more likely to exhibit expressionless faces than the suspect group (Table 5). In the clinical case group, speech problems were 6.86 times more likely to be reported, slow movements were 4 times likely to be reported, and encephalitis was equally likely to be diagnosed than the suspect group (Table 5). Levodopa was prescribed in 6 of the 7 clinical cases and 2 out of 4 suspect cases where prescribing information was included. While levodopa was 6 times more likely to be used following clinical diagnosis of parkinsonism, it was only 60% vs 50% effective in the symptomatic group (Table 5).
Patients in the suspect case group, were 2.19 times more likely to experience imbalance and 3.0 times more likely to have tremor than the clinical group (Table 5). Additionally, they were 2.33 times more likely to report abnormal CSF and 3.36 times more likely to have an abnormal MRI (Table 5). Infecting serotype was not a significant factor for either group (Table 5). However, death was significantly more likely to occur in the suspect group (p = 0.0016) (Table 5).
The major neurological symptoms were varied for suspect cases. Slow movements were reported in 9 out of the 15 cases (Table 5), [67,68,74–76,78,82,86,94]. These patients exhibited slow movements and bradykinesia, an “akinetic state” and reduced spontaneity of movement, and dysdiadochokinesia (Table 5), [67,68,74–76,78,82,86,94]. Slurring or disruption of speech was also common (Table 5), [67,68,74,76,80,82,84]. Seven of the case reports describe gait instability, ataxia, motor incoordination or postural instability (Table 5), [64,67,68,74,76,80,82].
Tremors, myoclonic movements, tonic-clonic movements, generalized convulsion, clonic flexion jerks, involuntary movements, involuntary twitching, or spasticity were reported in 12 of the cases (Table 5), [64,65,67,69,75,78,80,82,84,86,94,95]. Additionally, patients exhibited cogwheel rigidity, mask-like facies, increased muscle tone, rigidity, quadriplegia, and involuntary muscle tightening (Table 5), [67–69,82,84,86,95]. Of these cases, 33.33% perished (Table 5), [65,75,78,86,95].
MRI manifestations
MRI findings were normal for all but three patients with a clinical diagnosis of parkinsonism. One of which had microinfarcts of the basal ganglia [90] and the other had a double-doughnut sign that is typical of dengue encephalitis [92]. Another patient had brain atrophy [91]. CSF was also normal for all but three patients in this group, with one having reported lymphocytopenia, protein (58 mg/dL) [88] and another with lymphocytic pleocytosis with elevated protein (296 mg/dL) [92]. The third had abnormally high CSF total protein levels (557 mg/L) [24].
For the suspect cases, nine reported abnormal MRI’s. One reported bilaterally symmetrical T2/FLAIR hyperintensities in the caudate and lentiform nuclei [82]. Another described the young girl having “inflammatory changes” in her right maxillary, ethmoid, and sphenoid sinuses [64]. Another described their patient as having bilateral intensities in the lentiform nuclei, external capsule, and pons [67]. An additional case had hyperintense areas in the cerebellar hemisphere [74] and another reported high intensity in the subcortical white matter and cortical gray matter with some meningeal enhancement in the front temporal area [94]. A different patient had a bilateral symmetrical high signal with periventricular and deep cerebral white matter [84]. Another patient had white matter paucity in the left high parietal area [78]. Another case study reported their patient as having diffuse hyperintensities in the brainstem and cerebellum [68]. While another case report depicted the patient as having hypersignal in the T2/FLAIR sequence of the basal nuclei, cerebral penduncle and internal capsule [80].
Hematology
Aspartate aminotransferase was not a significant feature between the 2 groups, but the clinical cases were 2.5 times more likely to have lower alanine aminotransferase (Table 6). Clinical cases were also 8.0 times more likely to have lower lymphocyte count (Table 6). Conversely, suspect cases were 1.33 times more likely to exhibit thrombocytopenia and 2.5 times more likely to have decreased hemoglobin (Table 6).
Discussion
DENV was not recognized to cause neurotropic disease until recently [8]. Thus, there is an acknowledged gap of DENV associated neuropathologies [96]. The current theorized mechanism for DENV-associated parkinsonism is infiltration of the BBB via damage from cytokines [96]. This leads to vascularization of the barrier and permeability is increased as has been shown in mice studies with cytotoxic factor (CF) and macrophage cytotoxic factor (CF2) [97]. These two T-lymphocyte factors are involved in macrophage and helper T cell destruction and facilitate the release of histamine which increases vascular permeability [97]. In one review, it was reported DENV can cause damage to endothelial cells, which comprise the BBB, and other neuronal cells [58]. DENV can also induce responses of microglial cells that are susceptible to DENV regardless of serotype [4,58].
In this study, the most common neurological symptoms of the clinically diagnosed DENV parkinsonism cases were mask-like facies, imbalance, confusion, slurring of speech, slow movements, tremors/dystonia, gait issues, and stiffness/rigidity. For the suspected cases, the most common neurological symptoms were slow movements, slurring/disruption of speech, instability of gait and movement, tremors/clonic movements/involuntary movements and rigidity. The officially diagnosed cases had no fatalities, while the suspected cases had a death rate of 33.33%. Additionally, the clinical cases were mostly male, while the suspect cases were only 46% male. Parkinsonism is traditionally more prevalent in men, but this also could highlight a disparity in diagnosis in women of this condition [98]. A recent review only includes parkinsonism from DENV as a childhood complication of infection, but the data gathered here shows that it can be present in all ages (Table 3), [8].
For the clinical cases, many had odds ratios greater than one and included expressionless face, confusion, speech problems, slow movements, problems with gait, rigidity, and encephalitis. These symptoms adhere to the literature regarding other flaviviruses [35,43,99]. In other studies, both WNV and JEV patients present with rigidity, hypokinesia, facial masking, bradykinesia, and postural instability, which are consistent with the criteria for a parkinsonism diagnosis [37,44].
The suspect cases had higher odds ratios for imbalance, weakness, tremor, and abnormal CSF and MRI. The most interesting of these is that suspect patients were 3 times more likely to have a tremor reported by their doctor. This raises 2 questions, the first being, could this tremor have been the typical 4–6 Hz resting tremor seen in Parkinson’s patients? Secondly, is there a reason the doctors ruled out parkinsonism as a diagnostic possibility [98]. Another factor could be the lack of information on DENV neurotropism, viral parkinsonism, or DENV parkinsonism in adults.
Two patients had hyponatremia and their doctors attributed their parkinsonism to it rather than DENV [67,82]. Hyponatremia is common in patients with both severe dengue fever and dengue shock syndrome. This is thought to be a result of either sodium depletion or excess water production due to metabolic increase as a result of disease, renal dysfunction or inhibition of the sodium potassium pump [100,101]. Parkinsonism is sometimes reported after hyponatremia of origins other than DENV [102,103]. The role hyponatremia plays in dengue-associated parkinsonism is unknown [67]. The broad range of clinical manifestations could be leading to misdiagnosis or incorrect interpretations of symptoms. Of note, roughly half of the cases in this review had normal CSF and normal MRI’s which agrees with CSF and MRI findings for other viruses that cause parkinsonism [24,88–91,93]. The absence of DENV viral particles in the CSF of the majority of patients is not surprising given that at the time of collection, viremia would have passed.
Viral parkinsonism is difficult to diagnose. In addition to physical signs and symptoms, imaging via MRI and tests of dopamine levels can help paint a picture but still may not provide evidence for a diagnosis unless significant damage to dopaminergic neurons and reduced dopaminergic levels are found. Unfortunately, vague descriptions of neurological syndromes with the generic diagnosis of encephalitis hinders the ability to collect more data on DENV-associated viral parkinsonism. The broad range of neurological symptoms exhibited by patients may be a reason (Table 5). DENV can cause Guillan-Barré syndrome, myositis, cerebellar syndrome, neuritis, hypokalemic paralysis, and many other syndromes [8,11,20,97,104–106].
Encephalitis can often show signs of “cerebral involvement,” which includes cognitive impairment and convulsions [8,107]. Myositis is characterized by “asymmetrical limb weakness” and cerebellar syndrome by nystagmus, dysarthria, and ataxia [8,20,97,104]. These overlapping symptoms to those of parkinsonism can make diagnosis difficult.
DENV-associated viral parkinsonism is likely being underdiagnosed and thus, not being described fully in the literature. The 15 suspect cases had vague diagnoses but met the case criteria for parkinsonism outlined in this paper. Some of the cases have a questionable origin for the cause of their neurological symptoms [82], others were diagnosed into the broad category of an “encephalitis” diagnosis [64], or “cerebellitis” [74], some were grouped in with seizure disorders [95]. With this variety of symptoms reported in the case studies, a more uniform reporting of symptoms could provide a clearer picture and help with differential diagnoses. Clinicians should also consider using imaging and dopamine levels of neurological cases where at least 2 characteristics of parkinsonism are present. Though this may not be possible in resource limited areas where DENV is most prevalent.
A major limitation for this study was the incomplete reporting and description of DENV encephalitis. Many reports did not include basic clinical parameters like blood counts or metabolic tests. Further, symptom descriptions were vague such as stating “patient had a fever” without providing the temperature. Hundreds of sources were excluded as they discussed patients with encephalitis but provided no clinical information or symptom description beyond headache and fever. Further, most reports did not list any information on patient outcome and patient survival could not be quantified. The widespread lack of clinical data in clinical reports hinder population-based investigations or meta-analyses that could identify patterns for risk or potential treatments. Thus, we suggest that authors making clinical reports include, at the bare minimum: age, sex, temperature, complete blood count, complete metabolic panel, complete list of symptoms, any treatments given, imaging reports (if performed), and patient outcome.
The long-term sequelae and impacts of viral encephalopathies are understudied with most reports following patients for a year or less. In pediatric reports, children with encephalitis have higher prevalence for learning disabilities and lower IQ scores [107–109]. While sequelae have been reported in over 60% of pediatric arboviral encephalitis cases, no studies performed neurocognitive testing or evaluated the efficacy of rehabilitation therapies [110,111]. Long-term cohort studies of WNV encephalitis report unresolving cognitive and mood disorders [99,112,113]. Emerging data from COVID-19 studies show that neurological infections can induce parkinsonism and worsen Parkinson’s disease [114–118]. It is clear neurological infections can have severe and permanent impacts even if patients “recover” from the acute infection.
Conclusions
This study showed that viral parkinsonism from DENV infection may not be an isolated occurrence. Neurological manifestations of DENV are increasing in incidence and better adherence to the case definition of parkinsonism is needed for proper management of potential sequalae especially if the patient has an ongoing or potential to develop a neurodegenerative disease [8]. The inclusion of the suspected cases in this review highlights that underdiagnosis is occurring via non-adherence to the case definition for parkinsonism. This is likely due to the lack of education on DENV parkinsonism, and the symptom overlap with other neurological complications of DENV.
References
- 1. Estofolete CF, Milhim BHGA, Zini N, Scamardi SN, Selvante JDA, Vasilakis N, et al. Flavivirus infection associated with cerebrovascular events. Viruses. 2020;12. pmid:32580374
- 2. Guzman MG, Gubler DJ, Izquierdo A, Martinez E, Halstead SB. Dengue infection. Nat Rev Dis Prim. 2016;2. pmid:27534439
- 3. Shepard DS, Undurraga EA, Halasa YA, Stanaway JD. The global economic burden of dengue: a systematic analysis. Lancet Infect Dis. 2016;16: 935–941. pmid:27091092
- 4. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, et al. The global distribution and burden of dengue. Nature. 2013;496: 504–507. pmid:23563266
- 5.
World Health Organization. Global strategy for dengue prevention and control, 2012–2020. World Health Organization; 2012.
- 6. Harapan H, Michie A, Sasmono RT, Imrie A. Dengue: A minireview. Viruses. 2020;12: 1–35. pmid:32751561
- 7.
World Health Organization. Dengue guidelines for diagnosis, treatment, prevention and control: new edition. 2009.
- 8. Li G-HH, Ning Z-JJ, Liu Y-MM, Li X-HH. Neurological manifestations of dengue infection. Front Cell Infect Microbiol. 2017;7. pmid:28164039
- 9. Murthy JMK. Neurological complications of dengue infection. Neurol India. 2010;58: 581–584. Available: https://www.neurologyindia.com/printarticle.asp?issn=0028-3886;year=2010;volume=58;issue=4;spage=581;epage=584;aulast=Murthy pmid:20739796
- 10. Mamdouh KH, Mroog KM, Hani NH, Nabil EM. Atypical dengue meningitis in Makkah, Saudi Arabia with slow resolving, prominent migraine like headache, phobia, and arrhythmia. J Glob Infect Dis. 2013;5: 183–186. pmid:24672183
- 11. Carod-Artal FJ, Wichmann O, Farrar J, Gascón J. Neurological complications of dengue virus infection. Lancet Neurol. 2013;12: 906–919. Available: www.thelancet.com/neurology pmid:23948177
- 12. Sahu R, Verma R, Jain A, Garg RK, Singh MK, Malhotra HS, et al. Neurologic complications in dengue virus infection: A prospective cohort study. Neurology. 2014;83: 1601–1609. pmid:25253749
- 13. Saini L, Chakrabarty B, Pastel H, Israni A, Kumar A, Gulati S. Dengue fever triggering hemiconvulsion hemiplegia epilepsy in a child. Neurol India. 2017;65: 636. pmid:28488637
- 14. Kaplan A, Lindgren A. Neurologic Complications following Dengue. Nav Med Bull. 1945;45: 506–510.
- 15.
Sanguansermsri T, Poneprasert B, Phornphutkul B. Acute Encephalopathy Associated with Dengue Infection. Bangkok: SEAMEO TROPMED. 1976; 10–11.
- 16. Pancharoen C, Thisyakorn U. Neurological Manifestations in Dengue Patients. 2001;32: 341.
- 17. Nimmannitya S, Thisyakorn U, Hemsrichart V. Dengue haemorrhagic fever with unusual manifestations. Southeast Asian J Trop Med Public Heal. 1987;18: 398–406. pmid:3433170
- 18. Srivastava VK, Suri S, Bhasin A, Srivastava L, Bharadwaj M. An epidemic of dengue haemorrhagic fever and dengue shock syndrome in Delhi: A clinical study. Ann Trop Paediatr. 1990;10: 329–334. pmid:1708958
- 19. Angibaud G, Luaute J, Laille M, Gaultier C. Brain involvement in Dengue fever*. J Clin Neurosci. 1992;183: 63–65.
- 20. Misra UK, Kalita J, Syam UK, Dhole TN. Neurological manifestations of dengue virus infection. J Neurol Sci. 2006;244: 117–122. pmid:16524594
- 21. Liou LM, Lan SH, Lai CL. Electroencephalography burst suppression in a patient with dengue encephalopathy: A case report. Clin Neurophysiol. 2008;119: 2205–2208. pmid:18448389
- 22. Rittmannsberger H, Foff C, Doppler S, Pichler R. Psychiatric manifestation of a dengue-encephalopathy. Wien Klin Wochenschr. 2010;122: 87–90. pmid:20924690
- 23. Oehler E, Le Hénaff O, Ghawche F. Manifestations neurologiques de la dengue. Press Medicale. 2012;41. pmid:22534135
- 24. Azmin S, Sahathevan R, Suehazlyn Z, Kang Law Z, Rabani R, Nafisah WY, et al. Post-Dengue Parkinsonism. BMC Infect Dis. 2013;13. Available: http://www.biomedcentral.com/1471-2334/13/179 pmid:23594500
- 25. Gupta M, Nayak R, Khwaja GA, Chowdhury D. Acute disseminated encephalomyelitis associated with dengue infection: A case report with literature review. J Neurol Sci. 2013;335: 216–218. pmid:24035291
- 26. Solomon T, Mallewa M. Dengue and other emerging flaviviruses. J Infect. 2001;42: 104–115. pmid:11531316
- 27. Soares CN, Cabral-Castro MJ, Peralta JM, De Freitas MRG, Zalis M, Puccioni-Sohler M. Review of the etiologies of viral meningitis and encephalitis in a dengue endemic region. J Neurol Sci. 2011;303: 75–79. pmid:21292281
- 28. Baldaçara L, Ferreira JR, Prestes Seixas Filho LC, Venturini RR, Veloso Costa Coutinho OM, Camarço W, et al. Behavior Disorder After Encephalitis Caused by Dengue. J Neuropsychiatry Clin Neurosci. 2013;25. pmid:23487229
- 29. Madi D, Achappa B, Ramapuram JT, Chowta N, Laxman M, Mahalingam S. Dengue encephalitis-A rare manifestation of dengue fever. Asian Pac J Trop Biomed. 2014;4: S70–S72. pmid:25183150
- 30. Mathew T, Badachi S, Sarma G, Nadig R. “Dot Sign” in Dengue Encephalitis. Ann Indian Acad Neurol. 2015;18: 77–79. pmid:25745317
- 31. Garg RK, Rizvi I, Kumar N, Uniyal R, Malhotra HS. Case Report: Right Hemispheric Neuroimaging Abnormalities in a Patient with Dengue Encephalopathy. Am J Trop Med Hyg. 2018;99: 1291–1293. pmid:30334519
- 32. Wulur H, Jahja E, Gubler DJ, Suharyono W, Sorensen K. Clinical observations on virologically confirmed fatal dengue infections in Jakarta, Indonesia. Bull ofthe World Heal Organ. 1983;61: 693–701. pmid:6605216
- 33. Jang H, Boltz DA, Webster RG, Smeyne RJ. Viral Parkinsonism. Biochim Biophys Acta—Mol Basis Dis. 2009;1792: 714–721. pmid:18760350
- 34.
Common Symptoms of Parkinson’s Disease. In: American Parkinson Disease Association [Internet]. [cited 2 Aug 2021]. Available: https://www.apdaparkinson.org/what-is-parkinsons/symptoms/
- 35. Limphaibool N, Iwanowski P, Holstad MJV, Kobylarek D, Kozubski W. Infectious etiologies of Parkinsonism: Pathomechanisms and clinical implications. Front Neurol. 2019;10. pmid:31275235
- 36. Dale RC, Church AJ, Surtees RAH, Lees AJ, Adcock JE, Harding B, et al. Encephalitis lethargica syndrome: 20 New cases and evidence of basal ganglia autoimmunity. Brain. 2004;127: 21–33. pmid:14570817
- 37. Casals J, Elizan TS, Yahr MD. Postencephalitic Parkinsonism- A Review. J Neural Transm. 1998;105: 645–676. pmid:9826109
- 38. Magalhaes J, Tresse E, Ejlerskov P, Hu E, Liu Y, Marin A, et al. PIAS2-mediated blockade of IFN-β signaling: a basis for sporadic Parkinson disease dementia. Mol Psychiatry. 2021. pmid:34234281
- 39. Deng H, Wang P, Jankovic J. The genetics of Parkinson disease. Ageing Res Rev. 2017;42: 72–85. pmid:29288112
- 40. Yanbing D, Lixia H, Jun C, Song H, Fahu Y, Jinwen T. Corilagin attenuates the Parkinsonismin Japanese encephalitis virus induced Parkinsonism. Transl Neurosci. 2018;9: 13–16. pmid:30042861
- 41. Wichmann T. Changing views of the pathophysiology of Parkinsonism. Mov Disord. 2019;34: 1130–1143. pmid:31216379
- 42. Koutsilieri E, Sopper S, Scheller C, Ter Meulen V, Riederer P. Parkinsonism in HIV dementia. J Neural Transm. 2002;109: 767–775. pmid:12111466
- 43. Sejvar JJ, Haddad MB, Tierney BC, Campbell GL, Marfin AA, Van Gerpen JA, et al. Neurologic Manifestations and Outcome of West Nile Virus Infection. JAMA. 2003;290: 511. Available: www.jama.com pmid:12876094
- 44. Morrison J, Laurent-Rolle M, Maestre AM, Rajsbaum R, Pisanelli G, Simon V, et al. Dengue Virus Co-opts UBR4 to Degrade STAT2 and Antagonize Type I Interferon Signaling. PLoS Pathog. 2013;9. pmid:23555265
- 45. Rai KR, Shrestha P, Yang B, Chen Y, Liu S, Maarouf M, et al. Acute Infection of Viral Pathogens and Their Innate Immune Escape. Front Microbiol. 2021;12. pmid:34239508
- 46. Rohn TT, Catlin LW. Immunolocalization of influenza a virus and markers of inflammation in the human Parkinson’s disease brain. PLoS One. 2011;6. pmid:21655265
- 47. Amor S, Puentes F, Baker D, Van Der Valk P. Inflammation in neurodegenerative diseases. Immunology. 2010;129: 154–169. pmid:20561356
- 48. Sadasivan S, Sharp B, Schultz-Cherry S, Smeyne RJ. Synergistic effects of influenza and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can be eliminated by the use of influenza therapeutics: experimental evidence for the multi-hit hypothesis. npj Park Dis. 2017;3. pmid:28649618
- 49. van den Pol AN, Mao G, Chattopadhyay A, Rose JK, Davis JN. Chikungunya, Influenza, Nipah, and Semliki Forest Chimeric Viruses with Vesicular Stomatitis Virus: Actions in the Brain. J Virol. 2017;91. pmid:28077641
- 50. van den Pol AN. Viral Infection Leading to Brain Dysfunction: More Prevalent Than Appreciated? Neuron. 2009;64: 17–20. pmid:19840542
- 51. Pogodina V V., Frolova G V., Malenko G V., Fokina GI, Koreshkova G V., Kiseleva LL, et al. Study on West Nile Virus Persistence in Monkeys. Arch Virol. 1983;75: 71–86. pmid:6299247
- 52. Diniz JAP, Travassos APA, Rosa DA, Guzman H, Xu F, Xiao S-Y, et al. West Nile Virus Infection of Primary Mouse Neuronal and Neurological Cells: The Role of Astrocytes in Chronic Infection. Am J Trop Med Hyg. 2006;75: 691–696. pmid:17038696
- 53. Appler KK, Brown AN, Stewart BS, Behr MJ, Demarest VL, Wong SJ, et al. Persistence of west Nile virus in the central nervous system and periphery of mice. PLoS One. 2010;5. pmid:20498839
- 54. Weatherhead JE, Miller VE, Garcia MN, Hasbun R, Salazar L, Dimachkie MM, et al. Long-term neurological outcomes in West Nile virus-infected patients: An observational study. Am J Trop Med Hyg. 2015;92: 1006–1012. pmid:25802426
- 55. Murray KO, Nolan MS, Ronca SE, Datta S, Govindarajan K, Narayana PA, et al. The neurocognitive and MRI outcomes of West Nile virus infection: Preliminary analysis using an external control group. Front Neurol. 2018;9. pmid:29636722
- 56. Verma R, Sahu R, Holla V. Neurological manifestations of dengue infection: A review. J Neurol Sci. 2014;346: 26–34. pmid:25220113
- 57. Prabhat N, Ray S, Chakravarty K, Kathuria H, Saravana S, Singh D, et al. Atypical neurological manifestations of dengue fever: A case series and mini review. Postgrad Med J. 2020;96: 759–765. pmid:32900825
- 58. Calderón-Peláez MA, Velandia-Romero ML, Bastidas-Legarda LY, Beltrán EO, Camacho-Ortega SJ, Castellanos JE. Dengue virus infection of blood-brain barrier cells: Consequences of severe disease. Frontiers in Microbiology. Frontiers Media S.A.; 2019. pmid:31293558
- 59. Ng LC, Chem YK, Koo C, Mudin RNB, Amin FM, Lee KS, et al. 2013 dengue outbreaks in Singapore and Malaysia caused by different viral strains. Am J Trop Med Hyg. 2015;92: 1150–1155. pmid:25846296
- 60. Suppiah J, Ching SM, Amin-Nordin S, Mat-Nor LA, Ahmad-Najimudin NA, Low GKK, et al. Clinical manifestations of dengue in relation to dengue serotype and genotype in Malaysia: A retrospective observational study. PLoS Negl Trop Dis. 2018;12. pmid:30226880
- 61. Tissera HA, Jayamanne BDW, Raut R, Janaki S, Tozan Y, Samaraweera PC, et al. Severe Dengue Epidemic, Sri Lanka, 2017. Emerg Infect Dis. 2020;26: 682–691. pmid:32186490
- 62. Das PV, Anukumar B, Balakrishnan S. Identification of Dengue Serotypes using a Single Serum Specimen Algorithm in a Tertiary Care Hospital, Alappuzha, Kerala, India. J Clin Diagnostic Res. 2020;14.
- 63.
Nucleotide [Internet]. Bethesda (MD): National Library of Medicine (US) NC for BI. [2021] -. Accession No. MZ313995, Dengue virus 1 isolate kp780 polyprotein, envelope protein E region, (POLY) gene, partial cds. 20201.
- 64. Shah I. An unusual case of brainstem encephalitis. Dengue Bull. 2007.
- 65. Vasconcelos PFC, Travassos Da Rosa APA, Coehlo ICB, Menezes DB, Travassos Da Rosa ES, Rodrigues SG, et al. Involvement of the Central Nervous System in Dengue Fever: Three Serologically Confirmed Cases from Fortaleza, Ceará, Brazil. Rev Inst MEd Trop S Paulo. 1998;40: 35–39. pmid:9713136
- 66. Vasconcelos PFC, Lima JWO, Travassos Da Rosa APA, Timbó MJ, Travassos Da Rosa ES, Lima HR, et al. Dengue epidemic in a Northeastern Brazil: Random epidemiological serum survey. Rev Saude Publica. 1998;32: 447–454. pmid:10030061
- 67. Khanna L, Batra A, Anand I, Sethi PK, Khanna L. An unusual case of stiffness following dengue fever. Ganga Ram J. 2011;1: 145–146.
- 68. Verma R, Bharti K, Mehta M, Bansod A. Rhombencephalitis associated with Dengue fever. J Clin Virol. 2016;78: 99–101. pmid:27015434
- 69. Doi MLM, Tatsuno SY, Singh G, Tatsuno EM, Mau MM. Neurological Complications in a Polynesian Traveler with Dengue. Hawai’i J Med Public Heal. 2017;76: 275–278.
- 70. Sankari T, Hoti SL, Singh B, Shanmugavel J. Outbreak of dengue virus serotype-2 (DENV-2) of Cambodian origin in Manipur, India-Association with meteorological factors. Indian J Med Res. 2012;136: 649–655. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516033/?report=printable pmid:23168706
- 71. Islam A, Abdullah M, Tazeen A, Naqvi IH, Kazim SN, Ahmed A, et al. Circulation of dengue virus serotypes in hyperendemic region of New Delhi, India during 2011–2017. J Infect Public Health. 2020;13: 1912–1919. pmid:33148496
- 72. Deval H, Behera SP, Agrawal A, Singh R, Misra B, Janardhan V, et al. Genetic characterization of dengue virus serotype 2 isolated from dengue fever outbreaks in eastern Uttar Pradesh and western Bihar, India. J Med Virol. 2020. pmid:32633814
- 73. Aubry M, Teissier Y, Mapotoeke M, Teissier A, Giard M, Musso D, et al. High risk of dengue type 2 outbreak in French Polynesia, 2017. Eurosurveillance. 2017;22. pmid:28422007
- 74. Karunarathne S, Udayakumara Y, Fernando H. Epstein-Barr virus co-infection in a patient with dengue fever presenting with post-infectious cerebellitis: a case report. 2012. Available: http://www.jmedicalcasereports.com/content/6/1/43
- 75. Johnson TP, Larman HB, Lee MH, Whitehead SS, Kowalak J, Toro C, et al. Chronic Dengue Virus Panencephalitis in a Patient with Progressive Dementia with Extrapyramidal Features. Ann Neurol. 2019;86: 695–703. pmid:31461177
- 76. Withana M, Rodrigo C, Chang T, Karunanayake P, Rajapakse S. Dengue fever presenting with acute cerebellitis: A case report. BMC Res Notes. 2014;7. pmid:24598036
- 77. Tissera H, Amarasinghe A, Gunasena S, DeSilva AD, Yee LW, Sessions O, et al. Laboratory-Enhanced Dengue Sentinel Surveillance in Colombo District, Sri Lanka: 2012–2014. PLoS Negl Trop Dis. 2016;10. pmid:26927901
- 78. Samanta M, Kundu CK, Guha G, Chatterjee S. Unique neurological manifestations of dengue virus in pediatric population: A case series. J Trop Pediatr. 2012;58: 398–401. pmid:22241072
- 79. Saha K, Ghosh M, Firdaus R, Biswas A, Seth B, Bhattacharya D, et al. Changing pattern of dengue virus serotypes circulating during 2008–2012 and reappearance of dengue serotype 3 may cause outbreak in Kolkata, India. J Med Virol. 2016;88: 1697–1702. pmid:26991505
- 80. Palma-Da Cunha-Matta A, Soares-Moreno SA, Cardoso-De Almeida A, Aquilera-De Freitas V, Carod-Artal FJ. Neurological complications arising from dengue virus infection. Rev Neurol. 2004;39: 233–237. pmid:15284963
- 81. Aquino VH, Anatriello E, Gonçalves PF, Da Silva E V, Vasconcelos PFC, Vieira DS, et al. Molecular Epidemiology of Dengue Type 3 Virus in Brazil and Paraguay, 2002–2004. Am J Trop Med Hyg. 2006;75: 710–715. pmid:17038699
- 82. Pal R, Das L, Dutta P, Bhansali A. Secondary parkinsonism in a patient of psychogenic polydipsia. BMJ Case Rep. 2017;2017. pmid:28446482
- 83. Kshatri JS, Turuk J, Sabat J, Subhadra S, Ho LM, Rath S, et al. Epidemiology of viral disease outbreaks in Odisha, India (2010 to 2019). Epidemiol Infect. 2020. pmid:32669137
- 84. Nguyen THM, Nguyen HP, Ho DTN, Tran MP, Du TD, Nguyen VVC, et al. Dengue-Associated Posterior Reversible Encephalopathy Syndrome, Vietnam. Emerg Infect Dis. 2018;24: 165–167. pmid:29260666
- 85. Quyen D Le, Le NT, Van Anh CT, Nguyen NB, Van Hoang D, Montgomery JL, et al. Epidemiological, serological, and virological features of dengue in Nha Trang City, Vietnam. Am J Trop Med Hyg. 2018;98: 402–409. pmid:29313471
- 86. Verma R, Varatharaj A. Epilepsia partialis continua as a manifestation of dengue encephalitis. Epilepsy Behav. 2011;20: 395–397. pmid:21216205
- 87. Pandey N, Nagar R, Gupta S, Khan D, Singh D, Mishra G, et al. Trend of dengue virus infection at Lucknow, north India (2008–2010): A hospital based study. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3573610/?report=printable
- 88. Bopeththa BVKM, Ralapanawa U. Post encephalitic parkinsonism following dengue viral infection. BMC Res Notes. 2017;10. pmid:29187231
- 89. Fong CY, Hlaing CS, Tay CG, Ong LC. Post-dengue encephalopathy and Parkinsonism. Pediatr Infect Dis J. 2014;33: 1092–1094. pmid:24776518
- 90. Manappallil RG, Kumar V.G. P, Rao K.S. A. Parkinsonism following basal ganglia infarction in Dengue fever. Asian J Med Sci. 2019;10: 62–64.
- 91. Ganaraja VH, Kamble N, Netravathi M, Holla V V., Koti N, Pal PK. Stereotypy with Parkinsonism as a Rare Sequelae of Dengue Encephalitis: A Case Report and Literature Review. Tremor and Other Hyperkinetic Movements. 2021;11. pmid:34221697
- 92. Mishra A, Pandey S. Generalized Dystonia/Parkinsonism and Double-Doughnut Sign in Dengue Encephalitis. Mov Disord Clin Pract. 2020;7: 585–586. pmid:32626815
- 93. Panda PK, Sharawat IK, Bolia R, Shrivastava Y. Case report: Dengue virus-triggered parkinsonism in an adolescent. Am J Trop Med Hyg. 2020;103: 851–854. pmid:32372748
- 94. Weerasinghe WS, Medagama A. Dengue hemorrhagic fever presenting as encephalitis: A case report. J Med Case Rep. 2019;13. pmid:31488206
- 95. Osnaya-Romero N, Perez-Guille MG, Andrade-García S, Gonzalez-Vargas E, Borgaro-Payro R, Villagomez-Martinez S, et al. Neurological complications and death in children with dengue virus infection: Report of two cases. J Venom Anim Toxins Incl Trop Dis. 2017;23. pmid:28465676
- 96. Sips GJ, Wilschut J, Smit JM. Neuroinvasive flavivirus infections. Rev Med Virol. 2012;22: 69–87. pmid:22086854
- 97. Chaturvedi UC, Dhawan R, Khanna M, Mathur A. Breakdown of the blood-brain barrier during dengue virus infection of mice. J Gen Virol. 1991;72: 859–866. pmid:1707947
- 98. DeMaagd G, Philip A. Parkinson’s Disease and Its Management. Pharm Ther. 2015;40: 504–510.
- 99. Vittor AY, Long M, Chakrabarty P, Aycock L, Kollu V, DeKosky ST. West Nile Virus-Induced Neurologic Sequelae—Relationship to Neurodegenerative Cascades and Dementias. Curr Trop Med Reports. 2020;7: 25–36. pmid:32775145
- 100. Mekmullica J, Suwanphatra A, Thienpaitoon H, Chansongsakul T, Cherdkiatkul T, Pancharoen C, et al. Serum and urine sodium levels in dengue patients. Southeast Asian J Top Med Public Heal. 2005;36: 197–199. pmid:15906667
- 101. Reddy AA, Reddy TP, G. M. P, Pranam U, Manjunath GA. Serum sodium as a prognostic marker in dengue fever cases admitted to PICU in Navodaya hospital, Raichur, India. Int J Contemp Pediatr. 2016;4: 222.
- 102. Sullivan AA. Parkinsonism aftercorrection of hyponatremiawith radiological centralpontine myelinolysis andchanges in the basalganglia. 2000.
- 103. Perikal PJ, Jagannatha AT, Khanapure KS, Furtado SV, Joshi KC, Hegde AS. Extrapontine Myelinolysis and Reversible Parkinsonism After Hyponatremia Correction in a Case of Pituitary Adenoma: Hypopituitarism as a Predisposition for Osmotic Demyelination. World Neurosurg. 2018;118: 304–310. pmid:30055367
- 104. Paliwal VK, Garg RK, Juyal R, Husain N, Verma RR, Sharma PK, et al. Acute dengue virus myositis: A report of seven patients of varying clinical severity including two cases with severe fulminant myositis. J Neurol Sci. 2011;300: 14–18. pmid:21081241
- 105. Weeratunga PN, Caldera HPMC, Gooneratne IK, Gamage R, Perera WSP, Ranasinghe G V., et al. Spontaneously resolving cerebellar syndrome as a sequelae of dengue viral infection: A case series from Sri Lanka. Pract Neurol. 2014;14: 176–178. pmid:23840070
- 106. Patey O, Ollivaud L, Breuil J, Lafaix C. Unusual Neurologic Manifestations Occurring during Dengue Fever Infection. Am J Trop Med Hyg. 1993;48: 783–802. pmid:8333572
- 107. Maurya PK, Kulshreshtha D, Singh AK, Thacker AK. Rapidly Resolving Weakness Related to Hypokalemia in Patients Infected With Dengue Virus. 2016;18. Available: http://journals.lww.com/jcnmd
- 108. Quist-Paulsen E, Ormaasen V, Kran AMB, Dunlop O, Ueland PM, Ueland T, et al. Encephalitis and aseptic meningitis: short-term and long-term outcome, quality of life and neuropsychological functioning. Sci Rep. 2019;9. pmid:31695095
- 109. Michaeli O, Kassis I, Shachor-Meyouhas Y, Shahar E, Ravid S. Long-term motor and cognitive outcome of acute encephalitis. Pediatrics. 2014;133. pmid:24534397
- 110. Pöyhönen H, Setänen S, Isaksson N, Nyman M, Nyman A, Peltola V, et al. Neurological and Cognitive Performance After Childhood Encephalitis. Front Pediatr. 2021;9. pmid:33889554
- 111. Chow C, Dehority W. Long-Term Outcomes in Children Surviving Tropical Arboviral Encephalitis: A Systematic Review. J Trop Pediatr. 2021;67. pmid:34109400
- 112. Liu B, Liu J, Sun H, Xie M, Yang C, Pan Y, et al. Autoimmune encephalitis after Japanese encephalitis in children: A prospective study. J Neurol Sci. 2021;424. pmid:33773410
- 113. Sheppard DP, Woods SP, Hasbun R, Salazar L, Nolan MS, Murray KO. Does intra-individual neurocognitive variability relate to neuroinvasive disease and quality of life in West Nile Virus? J Neurovirol. 2018;24: 506–513. pmid:29696579
- 114. Ou A, Ratard R. One-year sequelae in patients with West Nile Virus encephalitis and meningitis in Louisiana. Louisiana Morb Rep. 2005; 1–4. Available: www.oph.dhh.state.la.us/infectiousdisease/index.html pmid:15887668
- 115. Méndez-Guerrero A, Laespada-García MI, Gómez-Grande A, Ruiz-Ortiz M, Blanco-Palmero VA, Azcarate-Diaz FJ, et al. Acute hypokinetic-rigid syndrome following SARS-CoV-2 infection. Neurology. 2020;95: e2109–e2118. pmid:32641525
- 116. Boika A V., Sialitski MM, Chyzhyk VA, Ponomarev V V., Fomina EG. Post-COVID worsening of a Parkinson’s disease patient. Clin Case Reports. 2021;9. pmid:34257979
- 117. Kamel WA, Ismail II, Ibrahim M, Al-Hashel JY. Unexplained worsening of parkinsonian symptoms in a patient with advanced Parkinson’s disease as the sole initial presentation of COVID-19 infection: a case report. Egypt J Neurol Psychiatry Neurosurg. 2021;57. pmid:34025113
- 118. Ghosh R, Biswas U, Roy D, Pandit A, Lahiri D, Ray BK, et al. De Novo Movement Disorders and COVID -19: Exploring the Interface. Mov Disord Clin Pract. 2021. pmid:34230886