A 75-year-old male patient (Han Chinese ethnicity) had headache and clusters of millet-sized blisters without fusion on the right side of the head and neck on February 24, 2022. The blisters were tight and shiny with surrounding redness, and the blister fluid was clear. The initial diagnosis was herpes zoster, and the patient was treated with 10 mg/kg of acyclovir every 12 h. On March 7, 2022, the patient's headache and herpes blisters were improved, so he stopped taking medicine. On March 12, 2022, the patient started to have left-sided headache, followed by herpes on the left side of the head and neck. He was diagnosed with recurrence of herpes zoster and was re-treated with acyclovir (10 mg/kg every 12 h). On March 16, 2022, the patient had hoarse voice and choking cough while keeping clear consciousness and movable limbs. He went to the Fifth People's Hospital of Jinan where he underwent clinical examinations on March 17, 2022. The CT scan of the lungs revealed pneumonia, and magnetic resonance brain imaging and CT imaging of the abdomen and pelvis did not demonstrate any significant abnormalities. An extensive biochemical assay revealed normal electrolytes, renal, thyroid, and parathyroid function, and negative serology for HIV, hepatitis B, and syphilis. The neurological examination showed the patient had clear consciousness and mental competence despite having decreased memory and impaired calculation, orientation, and judgment abilities. The patient could not speak clearly and fluently and had a choked cough when drinking water. Spasms were present with several minutes of paroxysmal painful muscle stiffness in the right upper limb, and the paroxysmal painful spasms were easily triggered by light touches and startling. The rest of the neurological examination was normal.
On March 19, 2022, the spasms frequently developed as a cluster accompanied by paroxysmal sympathetic hyperactivity (PSH), which was characterized by sinus tachycardia (110-160 beats/min), elevated systolic blood pressure (180-227 mmHg), tachypnea (30-50 breaths/min), and hypoxemia. An emergent electrocardiogram revealed that the patient had paroxysmal supraventricular tachycardia. The symptoms lasted for 3 min and were self-relieved. On March 21, 2022, the patient began with spasms of the right upper limb, followed by spasms involving all four limbs with loss of consciousness. Two minutes later, these symptoms were self-relieved. Due to his critical condition, the patient was transferred to the intensive care unit on the same day. His blood test results were unremarkable except for elevated serum levels of leukocytes (16.99 x 109/L) and neutrophils (14.91 x 109/L). A chest CT scan revealed manifestation of inflammation in both lungs, which was more aggravated than before. A lumbar puncture showed 22*106 leukocytes/L (95% monocytes), and the rest of the biochemistry parameters were normal. At this point, the patient was diagnosed with central nervous system infection with high probabilities of varicella-zoster virus encephalitis, and the antibiotics treatment was switched to ceftriaxone sodium (2 g every 12 h) plus acyclovir (10 mg/kg every 12 h). Sedative and analgesic drugs as well as phenobarbital sodium were also given to control spasms. Recurrent spasms caused prolonged apnea, ultimately leading to a need for mechanical ventilatory support.
The patient's condition did not improve with these treatments, so he was transferred to the intensive care unit of the First Affiliated Hospital of Shandong First Medical University on March 29, 2022. The patient had coronary atherosclerotic heart disease in the past, could tolerate general physical activities, and had been diagnosed with hypertension for 3 months. The admission examination revealed that the patient had low and coarse breath sounds with scattered moist rales in the lower part of both the lungs. The patient was kept under sedation and mechanical ventilatory support. Laboratory examinations (performed on 29 March 2022) showed a leukocyte count of 11.48 x 109/L, a neutrophil count of 9.96 x 109/L, and a myoglobin count of 355.2 ng/mL. The rest of the biochemistry parameters were normal. The cerebrospinal fluid (CSF) opening pressure was 17 cmH2O, with 9 x 106/L leukocytes/L and 43.4 mg IgG protein/L; normal protein and glucose levels; negative oligoclonal bands; and negative microscopy and culture for tuberculosis, fungi, and virology. Cardiac ultrasound and ultrasound of deep and superficial veins of bilateral lower extremities did not show any significant abnormalities.
At that time, the patient was diagnosed with intracranial infection, so acyclovir (10 mg/kg every 8 h) was used. The sputum sucked from the patient was thick and purulent yellow, and the fungal 1-3-beta-D-glucan quantitative test result of the sputum was 683.3 pg/mL. Therefore, the patient was suspected to have fungal infection; thus, voriconazole was given for antifungal treatment. Midazolam, remifentanil, phenobarbital sodium, and sodium valproate were added to further control the spasms. Despite an increased dosage of drugs, the spasms gradually worsened with increased frequency and could be triggered by phlegm suction, turning over, and backslap. Spasms began in the right upper limb, followed by muscle spasms in the left upper limbs, lower limbs, shoulders, neck, and back, which triggered a generalized tonic-clonic seizure (Supplementary Video 1). The electroencephalogram (EEG) showed slow waves (4-7 Hz) interspersed with low amplitude of brain electrical activity. Spike waves occurred in the sphenoid bone (Figure 1). Blood and cerebrospinal fluid tissue-based assay (TBA) screening showed weakly positive antibodies against cell membranes in the brainstem (Figure 2). No significant abnormalities were found in paraneoplastic antibodies (Hu, Yo, Ri, CV2, PNMA2, amphiphysin, recoverin, SOX1, titin, Zic4, GAD65, and Tr), and demyelinating antibodies (AQP4, MOG, MAP, and GFAP). Serum and cerebrospinal fluid cell-based assay (CBA) screening for autoimmune encephalitis antibodies showed that IgG antibodies against glycine receptor (GlyR) was positive at 1:100 in both serum and cerebrospinal fluid (Figure 3), while the remaining proteins or receptor antibodies (NMDAR, LGI1, CASPR2, GABABR, AMPAR1, AMPAR2, IgLON5, DPPX, GAD65, and mGluR5, D2R) were all negative.
Putting the patient's clinical symptoms and auxiliary test results together (Figure 4), a diagnosis of anti-GlyR antibody-positive PERM induced by varicella-zoster virus was made. The patient was then given 0.4 g/kg/d immunoglobulin treatment for 5 days. Considering fungal infection, he was also temporarily treated with methylprednisolone (120 mg/d). After the 5-day treatment, the spasms were significantly less frequent than before. However, the patient's family insisted on automatic discharge despite continuous persuasion from the medical staff and actively helping in raising funds for the hospitalization on April 8, 2022. The patient then passed away on April 13, 2022.