Clinical spectrum and management of dystonia in patients with Japanese encephalitis: A systematic review

Abstract Background Japanese encephalitis (JE) is a potentially fatal viral infection with a wide range of manifestations and can also present with a variety of movement disorders (MD) including dystonia. Dystonic features in JE are uncommon. Here, we have tried to summarize the clinical features and management of dystonia among JE patients with a comprehensive literature search. Methods Various databases, including PubMed, Embase, and Google Scholar, were searched against the predefined criteria using suitable keywords combination and boolean operations. Relevant information from observational and case studies was extracted according to the author, dystonic features, radiological changes in the brain scans, treatment options, and outcome wherever provided. Result We identified 19 studies with a total of 1547 JE patients, the diagnosis of which was confirmed by IgM detection in serum and/or cerebrospinal fluid in the majority of the patients (88.62%). 234 (15.13%) of JE patients had dystonia with several types of focal dystonia being present in 131 (55.98%) either alone or in combination. Neuroimaging showed predominant involvement of thalami, basal ganglia, and brainstem. Oral medications including anticholinergics, GABA agonists, and benzodiazepines followed by botulinum toxin were the most common treatment modalities. Conclusion Dystonia can be a disabling consequence of JE, and various available medical therapies can significantly improve the quality of life. Owing to insufficient studies on the assessment of dystonia associated with JE, longitudinal studies with a larger number of patients are warranted to further clarify the clinical course, treatment, and outcome of dystonia.


INTRODUCTION
Movement disorders (MD) can be primary, which is a presentation of an underlying neurodegenerative disorder, or secondary that arises from other disease states or brain injury (Jhunjhunwala et al., 2014). Infections, cerebrovascular disease, space-occupying lesions, and trauma have been described as various etiological factors causing secondary MDs (SMDs) (Mehanna & Jankovic, 2013). Dystonia, a type of MD, is characterized by sustained muscle contractions producing twisting, repetitive, and patterned movements or abnormal postures (Albanese, 2003;Steeves et al., 2012). A broad variety of dystonia, such as orofacial, limb, and axial, are reported . Dystonia has a wide clinical spectrum ranging from minimal or benign selflimiting features to severe cases (Albanese, 2003;Fernández-Alvarez, 2010).
Japanese encephalitis (JE), caused by the Japanese encephalitis virus (JEV) and transmitted by Culex mosquitoes, is the most common human endemic encephalitis (Solomon et al., 1998). It is found throughout South and Southeast Asia, encompassing an area delimited by Pakistan to the west, the Philippines and Japan to the east, and the Australian Torres Strait Islands to the south (Turtle & Solomon, 2018).
The most inclusive approximation of incidence within the past decade suggests that 69,000 cases of JE occur every year (Campbell et al., 2011). Once replication completes, the virus amplifies to produce viremia and crosses the blood-brain barrier to enter the central nervous system, causing a diffuse brain infection or encephalitis in some cases (Hoke et al., 1992). The onset of the illness ranges from abrupt to gradual, and the disease progresses through prodromal (2 to 5 days), encephalitis (1 to 3 weeks), and late (weeks to several months) stages, with a variety of MD associated, including dystonia (Richter & Shimojyo, 1961;Tiroumourougane, 2002).

Netravathi et al. in their study had reported infectious causes
representing up to 20.4% of all secondary MD (Netravathi et al., 2012).
Viral organisms such as JEV, human immunodeficiency virus (HIV), dengue, mumps, polio, coxsackie, varicella-zoster, and measles have been reported causing a whole range of MDs (Duvoisin & Yahr, 1965;Howard & Lees, 1987). MDs are common in JE and have been reported in up to 60% of patients . Kalita and Misra in their study on JE had reported predominant post-encephalitic dystonia Tse et al., 2004). Further, only a small proportion of studies on dystonia in JE have been conducted. In this review, we compile and describe the clinical features, diagnostic findings, treatments, and outcomes of dystonic patients with JE.

Data collection
Databases such as PubMed, Embase, and Google Scholar were searched to identify all relevant published articles from 2000 until September 1, 2021, using the terms dystonia, movement disorder, muscle dystonia, dyskinesia, dystonic disorders, Japanese encephalitis, Encephalitis, Japanese B Viral Encephalitis, Viral Encephalitis, JE with suitable boolean operators "AND" and "OR" wherever deemed necessary. Further, references of included articles were screened for additional studies. The search strategy used is provided in Appendix

Inclusion and exclusion criteria
All articles were considered eligible for inclusion if: For two or more studies, including the same set of patients, we included the study with more sample size. The PRISMA diagram detailing the selection process is shown in Figure 1.

Literature search results
The search returned 1983 articles and one was added after going through the references of selected papers (PubMed: 580, Embase: 1403, and Google Scholar: 1). After removing the duplicates, 1542 articles were evaluated based on their titles and abstracts, and 35 full-text articles were reviewed using the eligibility criteria. Finally, 19 articles met our inclusion criteria and were included in the study.

Study characteristics
Of the 19 studies included, nine were prospective studies, five case reports, two observational studies, two retrospective analyses, and one cohort study. The total number of JE patients included was 1547, ranging from 1 to 649 per included study. Most studies were from India (12), followed by Nepal (2), and each from China, Japan, Malaysia, Vietnam, and Italy. Details about selected studies can be found in Table 1.  five studies with 52 dystonic patients mentioned the onset of dystonia. Kalita et al. mentioned the onset of dystonia as 1 to 3 weeks after the fever in a study comprising nine dystonic patients from 50 JE cases . Another study by Kalita et al. consisted of 14 patients with dystonia, which occurred 2 to 4 weeks after encephalitis (Kalita et al., 2011). Dystonia was present 12 to 32 days after recovery from the first phase of illness in one patient, as mentioned by Pradhan et al., and Maurya et al. revealed that oromandibular dystonia in an 11-year-old boy was present during the second phase of the JE illness (Maurya et al., 2020;Pradhan et al., 2001).

Demographic and clinical characteristics
Only four studies with 62 dystonic patients had information about the severity of dystonia. Two studies also stated the severity index as 0: normal, 1: slight, 2: moderate, 3: severe, and 4: marked. Five patients had markedly severe dystonia (MSD) in the study by Kalita et al., with grade 4 dystonia appearing over 1 to 3 weeks . Dystonic spasms occurred in these five patients with 20 to 30 attacks per day, and the duration of each attack was 2 to 3 min. During the attacks of MSD, all the patients had grade 4 retrocollis, opisthotonos, and limb dystonia. Along with this, fever, severe pain, exhaustion, tachycardia, sweating, tachypnea, hypertension, and pupillary dilatation were also associated. Although fixed dystonia persisted, attacks of MSD were decreased during the night but were aggravated with full bladder and fever. Misra et al. also described the presence of MSD in 14 patients in whom dystonic spasms occurred every 10 to 30 min, each episode lasting 2 to 10 min, accompanying exhaustion, autonomic dysfunction, breathing, and feeding difficulty . The median severity score of dystonia was 4 in 14 dystonic patients, as mentioned by Kalita et al. in another study (Kalita et al., 2011). Grade 4 oromandibular dystonia, with the range of severity of dystonia ranging from 0 to 4, as described by Maurya et al. in one patient, led to persistent mouth opening and tongue protrusion causing impairment in swallowing, drooling of saliva, and difficulty in speaking (Maurya et al., 2020).

Diagnostic findings
JE was confirmed by JEV-specific IgM antibody detection in serum and/or cerebrospinal fluid (CSF) in 13 studies comprising 1371 patients with JE. Along with the viral-specific IgM detection, hemagglutination inhibition titer and 2-mercaptoethanol test were also used for the confirmation of JE in 117 patients in two studies Kalita et al., 2003). Titers of hemagglutinin inhibition antibodies were solely used for six patients, whereas no confirmatory test was mentioned in one study (Hamano et al., 2004;Pradhan et al., 2001).
Polymerase chain reaction and viral isolation methods were also used along with the above-mentioned investigation for 67 patients in one study and 649 patients from two studies, respectively (Kalita et al., 2003;Sarkari et al., 2012

Treatment for dystonia
Only seven studies mentioned the treatment of dystonia associated with JE, as shown in Table 3  . These five patients also had dystonic spasms, and during severe spasms, injection of haloperidol and diazepam were used. Trihexyphenidyl with clonazepam was used for upper limb dystonia in one patient (Ghosh et al., 2020). Maurya et al. mentioned the use of oral sodium valproate, TBZ, trihexyphenidyl, and clonazepam for oromandibular dystonia in one patient for 2 weeks, and when there was no improvement, 40 units of botulinum toxin injection was used in bilateral genioglossus and lateral pterygoid (10 units each) (Maurya et al., 2020). The duration of the treatment was not mentioned in the rest of the studies. Anticholinergic along with botulinum toxin was used in one patient for generalized dystonia and cervical dystonic tremor (Spagnolo et al., 2014). Tracheostomy was done for one patient with laryngeal dystonia (Hamano et al., 2004). Twelve studies did not report on any treatment the patients received.

Outcome
On the basis of dependency for the activities of daily living, the outcome was defined in only four of the studies into poor (bedridden),  partial (dependent), and complete (independent) recovery, and the assessment was done at the end of 6 months in three studies, and the end of 3 months in one study (Kalita et al., 2003;Kalita et al., 2011;Maurya et al., 2020;. With this definition, complete recovery was seen in six patients and was poor in four patients from two studies with 22 patients (Kalita et al., 2011;Misra & Kalita, 2002). Dystonia disappeared in 71% of the patients in 6 months among 38 patients in the study by . A significant reduction in dystonia in 3 months' follow-up from grade 4 to 2 was seen in an 11-year-old boy with oromandibular dystonia from Nepal (Maurya et al., 2020). Stridor, as a result of laryngeal dystonia, was improved after tracheostomy in 1 patient (Hamano et al., 2004). Basumatary et al. mentioned that the dystonia improved in all 38 dystonic children (Basumatary et al., 2013). Dystonia in 13 patients had improvement in 6 to 9 months (Dutta et al., 2021). Five patients with dystonic spasms had MSD for a variable period of time ranging from 1 to 6 months and on 6 months' follow-up of four of these patients, one was ambulatory with support and the rest were bedridden because of fixed axial dystonia, and at the end of 1 year, one patient had a complete recovery, one had a partial recovery, and two were still bedridden . Eight studies with patients neither defined the outcome nor mentioned the outcome of dystonia, as shown in Table 3.

DISCUSSION
JE is commonly a disease of children in endemic areas, but in newly affected areas, it infects both adults and children . Annually about 50,000 cases of JE occur worldwide, and 15,000 of them die. The age-specific attack rates are highest between 3 and 6 years of age which have been attributed to high outside exposure, especially playing in the evening and subsequent high risk of mosquito bites to poorly clothed children in villages, and the attack rates decline after the age of 14 years owing to high levels of neutralizing antibodies due to natural exposure and subclinical infection . Children less than 14 years of age comprised 31% of the total JE case as per our review. A study from Cuddalore district, Tamil Nadu, reported 27.3% of the patients were children affected by JE among AES cases that were hospitalized (Kabilan et al., 2004). Our study showed males were more affected by JE as compared to females, with the male to female ratio being 1.78. A study from India showed similar data, with males comprising 58% of all JE cases (Jacobson & Sivalenka, 2004).
Almost 89% of the JE cases included in our study were confirmed by JEV-specific IgM antibody detection in serum and/or CSF, as IgM antibody detection is known to reliably differentiate the JE virus from related flavivirus (Gadkari & Shaikh, 1984).
JE is the most common cause of dystonia among flavivirus . Our review showed that dystonia was present in 15.13% of the JE patients, with males being more affected corresponding to the male to female ratio in JEV infection. Furthermore, almost 46% of the dystonic patients were children. This could be due to the fact that the age of insult plays an important role in the presence of the type of MD, with dystonia being a much more common finding in patients with younger age of insult (Jhunjhunwala et al., 2014).
Our review showed the development of dystonia was usually reported after 1 to 4 weeks of encephalitis. The period of latency from the insult to the SMD might be due to the time required for inflammation, oxidative reactions, remyelination, ephaptic transmission, transsynaptic neuronal degeneration, central synaptic reorganization, and diaschisis mediated by collateral sprouting and denervation supersensitivity (Burke et al., 1980;Hilaire et al., 1991;Jankovic, 1994;Jhunjhunwala et al., 2014). After insult to the brain, dendritic plasticity and changes in the synaptic activity could result in pathological neuronal circuitry that could facilitate the development of MD, including dystonia (Jankovic, 1994;. Various types of focal dystonia, either alone or in combination, were the most frequent type of dystonia occurring in almost 56% of post-JE patients, while the remainder had generalized dystonia. Dystonia in JE usually involves both the axial and limb muscle and is commonly of fixed type resulting in opisthotonos, retrocollis, and oromandibular and limb dystonia (Misra, 2017). Dystonia in JE can be very severe from the beginning in some cases, and there can also be worsening of previous mild-to-moderate dystonia or precipitation of severe one due to infection or initiation or withdrawal of certain drugs . There have been reports of chest or urinary infection leading to worsening of dystonia (Manji, 1998;Vaamonde et al., 1994). Attacks of MSD in five patients from one study included in our review were exacerbated with fever and full bladder while reduced at night. Dystonic spasms can also occur in dystonic patients with fever, tachycardia, exhaustion, perspiration, and breathing and feeding difficulty being the usual results requiring intensive care and sometimes mechanical ventilation .
Our review highlighted the presence of dystonic spasms in 19 patients with a clinical presentation similar to as mentioned above without the need for any mechanical ventilation. Securing the airway by tracheostomy was done for one patient with laryngeal dystonia having severe respiratory difficulty.
MRI done in JE patients with dystonia revealed abnormal signals in the thalamus, which was the most common site to be involved along with basal ganglia, brainstem, cortex, and substantia nigra. Dystonic patients in whom CT was done showed abnormality in bilateral thalami in all patients, and SPECT revealed perfusion defect and uptake abnormalities. Bilateral T2 hyperintense and T1 isointense to hypointense thalamic lesions, especially hemorrhagic lesions, have been reported as typical findings of JE in a suitable clinical setting (Basumatary et al., 2013).
Damage to numerous regions of the brain can bring out dystonia, most commonly the basal ganglia, but also the thalamus, cerebellum, parietal lobe, and brainstem (Geyer & Bressman, 2006). Dystonia might also develop from partial restraint of competing motor patterns because of insufficient surrounding inhibition of competing motor pattern generators (Mink, 2003). Overflow contraction of the adjacent muscles are led by the declaration of the facilitatory center as a result of defective surrounding inhibition. Improper disinhibition of undesired muscle activity thus occurs due to diminished efficacy of the surrounding area with or without extension of the center (Mink, 2003). Thalamic involvement and perfusion flaw suggest malfunction in thalamocortical and basal ganglia circuits (Kalita et al., 2011;Mink, 2003). Similarly, dysfunction in the cerebello-thalamocortical pathway and cortico-striato-pallido-thalamo-cortical pathway along with relative dopamine deficiency or its receptor malfunction can manifest as both generalized and focal dystonia (Perlmutter et al., 1997;Simonyan, 2018). Dystonia in JE patients included in our review can be explained by the involvement of the thalamus, basal ganglia, brainstem, cortex, and substantia nigra. Further, involvement of these areas by JEV leading to MD including dystonia has been supported by the fact that JEV antigen was found distributed in the thalamus, substantia nigra, and medulla oblongata in human autopsies (Desai et al., 1995).
Several classes of medication, including high doses of anticholinergics, gamma-aminobutyric acid (GABA) agonists, and dopaminergic agents are used in the management of dystonia (Jankovic, 2006). Anticholinergic agents are generally the most successful oral medications, with trihexyphenidyl being the most commonly used agent (Burke et al., 1986;Jankovic, 2006 (Burke et al., 1986).
With the oral medications most frequently used for dystonic patients in the studies included in our review, trihexyphenidyl was used in all oral medication combinations. Despite the lack of evidence for efficacy in absence of large controlled studies, benzodiazepines are often used in dystonia, clonazepam being the most commonly used (Fahn, 1983). In an open study, clonazepam and other benzodiazepines were found to be beneficial in 16% of patients with various types of dystonia (Fahn, 1983). TBZ depletes vesicular stores of dopamine by inhibiting the vesicular monoamine transporter 2 (VMAT-2) and is another effective drug for the treatment of dystonia as well as other hyperkinetic MD, such as chorea, tics, tardive dyskinesia, and myoclonus (Kenney et al., 2007). Clonazepam and TBZ were also used for the treatment of dystonia in the patients included in our study along with other oral medications.
Intramuscular injections of botulinum toxin can reduce symptoms of focal as well as generalized dystonia in some cases by acting at the neuromuscular junction (Dressler & Adib Saberi, 2005). Botulinum toxin, a toxic protein produced by the bacterium Clostridium botulinum, exerts its therapeutic benefit by blocking the release of acetylcholine into the neuromuscular junction and thus, reduces the excessive activity of affected muscles in dystonia (Breakefield et al., 2008;Dressler & Adib Saberi, 2005). A patient with oromandibular dystonia was given oral medication for 2 weeks, and when no improvement was seen, botulinum toxin was then used, which caused a significant reduction in dystonia from grade 4 to grade 2. Botulinum toxin has become the treatment of choice for most patients with focal or segmental dystonia, including those with blepharospasm, spasmodic dysphonia, and cervical, oromandibular, and lingual dystonia (Cloud & Jinnah, 2010).
Apart from the oral drugs mentioned above, numerous other oral pharmaceutical agents either alone or in combinations have been mentioned in anecdotal reports in the improvement of dystonia, which include pregabalin, midazolam, pimozide, eperisone, verapamil, gabapentin, levetiracetam, and vitamin E (van den Heuvel et al., 2016).
Without the availability of strong evidence in support of the use of any oral drugs for acquired dystonia, the location of dystonia has no bearing on the choice of medication, and among the various drugs available, usually anticholinergic is started as a first-line and baclofen or clonazepam as a second-line agent (Termsarasab et al., 2016;van den Heuvel et al., 2016).
Although no patient in our study underwent surgical procedures for acquired dystonia secondary to JE, these can be done if the above- Drug treatment for MSD is often empirical due to inadequate knowledge about the pharmacological basis of MSD (Marsden et al., 1984). Once levodopa responsive dystonia is excluded, anticholinergics, haloperidol, and TBZ and its analogs are used (Marsden et al., 1984). Markedly severe dystonic patients included in our review were first given oral medications in combinations, and they eventually improved over 6 months; only one patient was prescribed botulinum toxin injection on top of oral drugs for grade 4 dystonia leading to a downgrading of grade to 2 in 3 months' follow-up. Some anecdotal reports also recommend using anticonvulsants and baclofen (Vaamonde et al., 1994). Muscle relaxants, along with sedatives, might prove useful in controlling painful spasms of dystonia Vaamonde et al., 1994). Haloperidol and diazepam were used in patients with severe dystonic spasms as mentioned in our review.
Dystonia in the patients post-JE included in our review has regressed over a variable amount of time during follow-up. This improvement in dystonia secondary to JE is consistent with the natural history of encephalitis in which there is a regressive course for most MD, and even complete recovery is seen in milder ones (Kalita et al., 2003;Misra & Kalita, 2002). When compared with other MD following JE, like parkinsonism, dystonia regressed at a slower rate during the follow-up period, and the presence of dystonia might suggest more severe illness and a poorer prognosis (Misra & Kalita, 2002).

Limitations
The major strength of our study is that this is the first systematic review conducted exploring dystonia post-JE which is a major cause of encephalitis. However, our review has several limitations. This study has covered data from only seven countries, which is the main shortcoming. The exclusion of non-English articles was another limitation.
Unpublished literature was not included, and we did not contact authors for unpublished supplementary data as well. Due to the lack of enough studies, detailed information in botulinum toxin and surgical management of dystonia could not be explored in depth.

FUNDING INFORMATION
No funding was received.

CONFLICT OF INTEREST
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

AUTHOR CONTRIBUTIONS
RA, SS, and SH conceptualized and designed the study. RA, SS, and SH were involved in collecting and analyzing data, and writing the manuscript. SK, SC, KS, RK, RR, BPG, and RO were involved in revising the manuscript critically for important intellectual content. RO supervised the research and manuscript writing process. All authors were involved in the review of the manuscript. Furthermore, all the authors read and approved the final version of the manuscript.

TRANSPARENT PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1002/brb3.2496

DATA AVAILABILITY STATEMENT
The datasets of the current study are available from the corresponding author on reasonable request.