Case Report: Dystonic Storm Following Japanese Encephalitis Virus Infection

ABSTRACT.

Dystonic storm (also called status dystonicus) is a neurological emergency characterized by sustained/intermittent involuntary generalized muscle contractions resulting in repetitive painful twisting movements and abnormal postures. It is commonly documented in patients with diagnosed primary dystonic syndromes or secondary dystonic states (i.e., patients with inborn errors of metabolism, dystonic cerebral palsy, Wilson’s disease, pantothenate kinase-associated neurodegeneration, and exposure to drugs, among others). However, viral-induced dystonic storm cases have rarely been reported. We describe the case of an 11-year-old girl from rural West Bengal (India) with a dystonic storm after Japanese encephalitis. Generalized dystonic spasms lasted for about 10–20 minutes and occurred 20–30 times/day. They were associated with extreme pain, fever, exhaustion, sweating, tachycardia, tachypnea, pupillary dilatation, arterial hypertension, and mutism and were precipitated by a full bladder and relieved somewhat during sleep. When dystonic spasms abated, she had high-grade generalized rigidity of all four limbs and fixed cervical and truncal dystonia. She was put on invasive ventilation and deep intravenous sedation with continuous midazolam infusion and other supportive measures and had a good clinical recovery. During the 12 months of follow-up, she did not have any other episode of a dystonic storm. However, axial rigidity and intermittent appendicular (upper limb) dystonic posturing were observed. The authors also have briefly discussed the differential diagnoses and treatment plans for such a neurological emergency.

INTRODUCTION

Dystonic storm (also called status dystonicus) is a neurological emergency characterized by sustained/intermittent involuntary generalized muscle contractions resulting in repetitive painful twisting movements and abnormal postures.^1–6 Although it typically occurs in patients with diagnosed primary dystonic syndromes (i.e., DYT-1 mutation-associated dystonia), it can be seen in secondary dystonic states (i.e., patients with inborn errors of metabolism, dystonic cerebral palsy, Wilson’s disease, pantothenate kinase-associated neurodegeneration, and exposure to drugs, among others).^1–6 Treatment of this neurological emergency is demanding and requires admission to the intensive care unit.^1–6 Stoppage of inciting agents/drugs and prescription of anticholinergics, benzodiazepines, baclofen, and dopamine depletors remain the mainstay of medical management.^1–6 Mechanical ventilation for several days to weeks with intravenous sedation, airway protection, and paralysis have often been the ultimate need to resolve the crisis.^1–6 Even with the best possible management, the mortality rate is nearly 10%.⁵ And even in cases of survival, recovery is seldom complete, and residual deficits and relapses are frequent.⁵

Movement disorders, especially parkinsonism and dystonia after Japanese encephalitis virus (JEV) infection, have been known for a long.⁷ However, dystonic storm after JEV infection is exceedingly rare.⁸ It is highly likely that this disorder is underdiagnosed or misdiagnosed in JEV infection endemic zones.

We describe the clinical findings of a patient with a dystonic storm after JEV infection who required prolonged invasive ventilation, intravenous sedation and other supportive measures to control the crisis. The authors also have briefly discussed the differential diagnoses and treatment plans for such a neurological emergency.

CASE REPORT

A previously healthy 11-year-old girl from rural West Bengal (India) noticed high-grade fever and chills, severe headache, neck stiffness, and vomiting, for which her parents consulted a local “quack” (uncertified and untrained indigenous medical practitioner in India) for a remedy, which failed to resolve the symptoms. On day 3 of this febrile illness, she developed a few episodes of unclassified seizures, followed by unconsciousness, which prompted her parents to admit her to the hospital, where she was diagnosed with JEV infection. Cerebrospinal fluid (CSF) analysis showed raised opening pressure (30 cm H₂O), lymphocytic pleocytosis (180 cells/µL, all lymphocytes) with increased protein (90 mg/dL; normal reference range 15–45 mg/dL), and normal glucose and chloride levels; IgM antibody capture ELISA demonstrated JEV-specific antibody in serum and CSF. A real-time polymerase chain reaction was performed further on CSF to confirm the presence of JEV, for which she was treated accordingly. Magnetic resonance imaging (MRI) of the brain revealed bithalamic and midbrain involvements due to encephalitis (Figure 1). Although her consciousness improved and seizures abated, she was still mute when discharged from the hospital 14 days later.

Figure 1.

Magnetic resonance imaging of the brain reveals nonenhancing asymmetrical bilateral (right more than left) signal changes, hyperintense on T2-weighted imaging (A), and fluid-attenuated inversion recovery (B) sequences, with diffusion restriction in diffusion-weighted imaging (C), and apparent diffusion coefficient (D) sequences at bilateral basal ganglia and thalamus.

Three weeks after the diagnosis of JEV infection, she was brought to the emergency department with generalized dystonic posturing that gradually increased over the last 7 days. She had generalized dystonic spasms (status dystonicus), which lasted for about 10–20 minutes and occurred 20–30 times/day. They were associated with extreme pain, fever, exhaustion, sweating, tachycardia, tachypnea, pupillary dilatation, arterial hypertension, and mutism and were precipitated by a full bladder and relieved somewhat during sleep. When dystonic spasms abated, she had high-grade generalized rigidity of all four limbs and fixed cervical and truncal dystonia. She was put on assisted mechanical ventilation and deep sedation with continuous midazolam infusion (at 5 mcg/kg/minutes and titrated to 12 mcg/kg/minute). A neurological assessment performed in the interposing therapeutic windows (5–10 minutes every 8 hours) revealed that dystonic spasms relapsed soon after the withdrawal of continuous midazolam infusion. Sedation and mechanical ventilation were maintained for the next 7 days; afterward, a midazolam drip of 3 mcg/kg/minute was maintained and gradually tapered under close monitoring of vital signs. Trihexyphenidyl (started as 1 mg two times a day and gradually up titrated to 15 mg/day), diazepam (started as 1 mg three times a day and up titrated to 10 mg three times/day), and baclofen (started as 5 mg three times/day and up titrated to 40 mg/day) in gradually increasing dosages were prescribed. Relevant investigations to exclude other etiologies, especially autoimmune encephalitis (anti-glutamate receptor against NR1 subunit, anti-glutamate-GluR1, anti-glutamate-GluR2, GABA-B receptor antibody, LGI-1 antibody, and CASPR2 antibody) tested by cell-based assay on CSF and neuronal/paraneoplastic encephalitis (amphiphysin, CV2.1, PNMA2 (Ma2/Ta), ANNA-1/Hu, ANNA-2/Ri, PCA-1/Yo, and anti-GAD) tested by immunoblot assay, were negative. Tests were also negative for rhabdomyolysis, myoglobinuria, and acute kidney injury. There was hyperCKemia, hyperkalemia, and mild metabolic acidosis. She showed improvement after 3 weeks of continuous intensive care treatment. The dystonic spasms (dystonic storm) completely resolved when she was discharged; axial and facial dystonia reduced. During the sixth month of follow-up, she could swallow oral feeds, comprehend verbal commands, and talk in a hypophonic voice, but sometimes, she needed partial assistance for activities of daily living because of persistent axial rigidity. During the 12 months of follow-up, she did not have any other episode of a dystonic storm. However, axial rigidity and intermittent appendicular (upper limb) dystonic posturing were observed.

DISCUSSION

Differential diagnoses of a dystonic storm, that is, status dystonicus, include neuroleptic malignant syndrome, malignant hyperthermia, serotoninergic syndrome, autoimmune encephalitis, lethal catatonia, drug intoxication, choreic storm, delirium tremens, tetanus, osmotic demyelination syndrome, mitochondrial disorders with encephalopathy, botulism, and status epilepticus.^1–6 All of them share common features like hyperthermia, hyperCKemia, muscle pain, and rigidity to a similar extent.¹ Presence of triggers, age of presentation, course of illness, associated neuropsychiatric signs/symptoms, and presence of autonomic disturbances provide vital clues for inclusion/exclusion of differential diagnoses.¹

We feel that although the central nervous system infection (JEV) was evident in our patient, it should not be considered a triggering event; rather, it has to be considered the primary insult. Dystonic storms usually occur in patients with known dystonic disorders, poorly treated.^4,9 However, in one-third of cases, dystonic storms may appear unprovoked,^5,10 as in our patient. In known prior dystonic disorders, there is a premonitory clinical phenomenon known as “prodromal of dystonic storm” (that occurs just before the full-blown storm), which, if identified promptly, can prevent the development of a further life-threatening crisis.¹ However, there are no such premonitory clinical warnings in new-onset dystonic storms, making it more difficult for clinicians.

Literature regarding infection-associated new-onset movement disorders is limited.¹¹ Postinfectious secondary de novo dystonic storms are rare,⁸ particularly after JEV infection.⁸ Back at the beginning of this century, Indian researchers reported markedly severe generalized dystonia (axial, appendicular, and bulbar) after JEV infection in five patients.⁸ Similar to cases in their series,⁸ ours developed persistent painful dystonic spasms that started nearly after 3 weeks of JEV infection, and the deficits did not recover completely. The partial recovery, in this case, might be attributed to neuronal plasticity, reorganization of neural networks, and subsidence of inflammation. Our patient had mesencephalon–thalamic encephalitis characteristic of JEV infection. The severe bilateral axial and appendicular dystonia might be ascribed to bithalamic involvement.^12–14 The damage to the thalamus and midbrain receiving pallidal and nigral inputs might result in dystonia.^12–15

In closing, this case primarily emphasizes the importance of recognizing phenomenology/semiology of abnormal involuntary movements for appropriate diagnosis of emergencies like a dystonic storm, which we believe to be grossly misdiagnosed and underreported. Second, we also reinforce the importance of considering mesencephalon–encephalitis (especially JEV infection) as a potential etiology of a new-onset dystonic storm, particularly in endemic zones of the tropics. Finally, vaccination against JEV in the endemic zones can aid in preventing the infection and its deadly sequels.