Age: 59.0
Sex: F
Vaccine: COVID19, FLUX
Symptoms: Facial paralysis, Flow cytometry, Interleukin level, Interleukin-2 receptor assay, Laboratory test
Clinical narrative: Neuronal intranuclear inclusion disease; Right facial droop involving the forehead; Meningitis; Febrile; This spontaneous literature case was received on 16-Oct-2023 and concerned 59-year-old female patient.   Neuronal intranuclear inclusion disease (NIID), a neurodegenerative disease previously thought to be rare, is increasingly recognized despite heterogeneous clinical presentations. NIID is pathologically characterized by ubiquitin and p-62 positive intranuclear eosinophilic inclusions that affect multiple organ systems, including the brain, skin, and other tissues. Although the diagnosis of NIID is challenging due to phenotypic heterogeneity, a greater understanding of the clinical and imaging presentations can improve accurate and early diagnosis. In this literature article, three cases of pathologically proven adult-onset NIID were presented, all presenting with episodes of acute encephalopathy with protracted workups and lengthy time between symptom onset and diagnosis.  The patient's historical conditions included right middle cerebral artery (MCA) stroke which was complicated with localization-related epilepsy. The patient's concurrent conditions included location-related epilepsy and systemic sclerosis. The patient's concomitant medications were not reported.  On an unspecified date, the patients were vaccinated with influenza vaccine (brand not specified; dose, route of administration, anatomical location and indication: not reported). The batch number was not reported.  On the same date, the patient was vaccinated with non-company, co-suspect Moderna COVID-19 vaccine (elasomeran; dose, route of administration, anatomical location and indication: not reported). The batch number was not reported.  On an unspecified date, 15 days after receiving influenza vaccine and non-company, co-suspect Moderna COVID-19 vaccine, the patient was admitted to the hospital for acute-onset encephalopathy and global aphasia. At the hospital presentation, the patient was febrile to 101.2?F. Magnetic resonance imaging (MRI) of the brain was performed and did not show acute changes. Continuous electroencephalogram (EEG) showed diffuse slowing and epileptiform discharges over the right posterior quadrant without seizures. Empiric antibiotics and antiviral medications were started for presumed meningitis or encephalitis, acyclovir at a dose of 450mg every eight hours, ampicillin at a dose of 2 mg twice a day and ceftriaxone at a dose of 2gq a day.  On an unspecified date, after four days as reported, the patient was found to have a right facial droop involving the forehead and right upper extremity hemiparesis. A repeat MRI was performed an was negative again for acute infarct. Lumbar puncture showed mildly increased protein at 55 mg/dL, <5 white blood cells (WBCs) WBCs per mm3, oligoclonal bands between the cerebrospinal fluid (CSF) and serum were matching, performed cytopathology and flow cytometry were normal, but CSF IL-6 was elevated to 67.6 pg/mL and soluble IL-2R cytokines to 29.2 pg/ml. An extensive laboratory workup was performed and was largely unremarkable for toxic, metabolic, and infectious etiologies.   On an unspecified date, on hospital day eight, the patient underwent a repeat MRI brain which demonstrated new left hemispheric gyral swelling and edema involving the occipital, parietal, temporal, and posterior frontal lobes with cortical/pial enhancement and marked hyperperfusion throughout that region. Empiric steroids were not administered given the concern of possibly provoking a scleroderma renal crisis, and she was treated with a course of intravenous immunoglobulin and antiepileptic medications (levetiracetam at a dose of 2 g, twice a day and lacosamide at a dose of 200 mg, twice a day).  On an unspecified date, on hospital day 12, there was no clinical improvement and a repeat MRI on found worsened left hemispheric gyral swelling and enhancement but decreased hyperperfusion. Clinically, there was a concern for possible adult-onset mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS), and patient was treated with intravenous arginine at a dose of 500mg/kg per day, for five days, alpha lipoic acid at a dose of 500mg daily, taurine at a dose of 1g daily, levocarnitine at a dose of 330mg three times a day, vitamin C at a dose of 500mg twice a day, and coenzyme Q10 at a dose of 400mg daily.  On an unspecified date, on hospital day 13, the patient underwent a brain biopsy which showed neuronal eosinophilic intranuclear inclusions, immunoreactive for ubiquitin, consistent with NIID. In addition, it was noted on biopsy that was prominent neuronal central chromatolysis, where neurons appeared enlarged with Nissl substance pushed to the cytoplasmic periphery.   On an unspecified date, on hospital day 14, a repeat MRI showed persistent gyral swelling and edema but the resolution of enhancement and normalized perfusion.  On an unspecified date, on hospital day 22, repeat lumbar puncture was notable for normalized cytokines and protein.   On an unspecified date, on day 25 in the hospital, the patient was speaking in three- to five-word sentences.   On an unspecified date, three months later, upon follow-up, there was a significant improvement in patient's aphasia and encephalopathy with only minor residual deficits.   On an unspecified date, six months later after the acute episode, and follow-up MRI was performed and revealed resolved cortical swelling with residual encephalomalacia and gliosis.  At the time of initial reporting, the patient was recovering from the event of neuronal intranuclear inclusion disease.  The outcome of the events of 'meningitis', 'pyrexia' and facial droop was not reported.  The reporter did not provide a causality assessment. However, as reported, while it was not clear what provokes these attacks, the patient in case one had recently received COVID-19 and influenza vaccinations two weeks prior to presentation and immunological stress may be related to her presentation.  In conclusion, Neuronal intranuclear inclusion disease remains an elusive diagnosis and should be considered in cases with atypical and recurrent episodes of acute encephalopathy, particularly when occurring on a background of progressive dementia. Furthermore, NIID should still be considered even in the absence of the more typical and well-described MRI finding of symmetric corticomedullary DWI hyperintensity, which may be more associated with the chronic phase of the disease. Given that less invasive methods of biopsy are now available, clinicians should have a low threshold to utilize skin biopsy in diagnosing this disease in the proper clinical context. Prognostic markers in this rare disease are generally lacking, as is guidance on the management during acute episodes of encephalopathy. However, increased awareness of this condition and its myriad clinical and imaging findings will promote a better understanding of the prevalence and phenotypic spectrum of this disease, which will aid in developing evidence based guidance for its management.   Company comment: A 59-year-old patient experienced pyrexia 15 days after receiving the suspect product influenza vaccine and non-company, co-suspect Moderna COVID-19 vaccine. The patient was admitted to the hospital for acute-onset encephalopathy and global aphasia. The patient underwent continuous electroencephalogram, which showed diffuse slowing and epileptiform discharges over the right posterior quadrant without seizures. Reportedly, empiric antibiotics and antiviral medications were started for presumed meningitis or encephalitis. After four days the patient was found to have right facial paralysis involving the forehead and right upper extremity hemiparesis. Lumbar puncture showed increased protein, white blood cells, CSF IL-6, and soluble IL-2R cytokines. The patient underwent a repeat MRI brain, on hospital day eight, and it showed new left hemispheric gyral swelling and edema involving the occipital, parietal, temporal, and posterior frontal lobes with cortical/pial enhancement and marked hyperperfusion throughout that region. Afterwards, the patient underwent a brain biopsy which showed neuronal eosinophilic intranuclear inclusions, immunoreactive for ubiquitin, consistent with neuronal intranuclear inclusion disease. The patient's significant medical history included right middle cerebral artery stroke which was complicated with localization-related epilepsy as well as systemic sclerosis. Based on biological and chronological implausibility, causal role of the suspect vaccine is assessed as not related.; Reporter's Comments: While it was not clear what provokes these attacks, the patient in case one had recently received COVID-19 and influenza vaccinations two weeks prior to presentation and immunological stress may be related to her presentation.; Sender's Comments: A 59-year-old patient experienced pyrexia 15 days after receiving the suspect product influenza vaccine and non-company, co-suspect Moderna COVID-19 vaccine. The patient was admitted to the hospital for acute-onset encephalopathy and global aphasia. The patient underwent continuous electroencephalogram, which showed diffuse slowing and epileptiform discharges over the right posterior quadrant without seizures. Reportedly, empiric antibiotics and antiviral medications were started for presumed meningitis or encephalitis. After four days the patient was found to have right facial paralysis involving the forehead and right upper extremity hemiparesis. Lumbar puncture showed increased protein, white blood cells, CSF IL-6, and soluble IL-2R cytokines. The patient underwent a repeat MRI brain, on hospital day eight, and it showed new left hemispheric gyral swelling and edema involving the occipital, parietal, temporal, and posterior frontal lobes with cortical/pial enhancement and marked hyperperfusion throughout that region. Afterwards, the patient underwent a brain biopsy which showed neuronal eosinophilic intranuclear inclusions, immunoreactive for ubiquitin, consistent with neuronal intranuclear inclusion disease. The patient's significant medical history included right middle cerebral artery stroke which was complicated with localization-related epilepsy as well as systemic sclerosis. Based on biological and chronological implausibility, causal role of the suspect vaccine is assessed as not related.