The Japanese patient first experienced myoclonus at 3 months of age generalized onset clonic seizures appeared at 6 months of age. His birth history was unremarkable, and he had no family history of neuromuscular disease, including epilepsy. Fever or hyperthermia triggered recurrent seizures, and at the age of 1 year and 5 months, the patient was diagnosed with DS at another hospital specializing in epilepsy. Valproate, sodium bromide, and zonisamide were administered. The patient’s childhood seizures were limited to generalized onset absence seizures after waking and partial seizures during sleep, and generalized onset clonic seizures were present only once a month when his body temperature was elevated, for example, during bathing. Developmental delay was observed in language, motor skills, and bulbar function. His speech was limited to single words, and the patient crawled on all four extremities and could take oral food with assistance. He had no medical history other than DS. He also had no history of drinking, smoking, or allergies and was living at home under the care of his family.

At the age of 24 years, the patient had aspiration pneumonia and fever accompanied by generalized onset clonic seizures, for which he was treated in our department for the first time. His vital signs were as follows: a heart rate of 143 beats/minute blood pressure of 123/86 mmHg, respiratory rate of 32 breaths/minute, body temperature of 39.9 °C, and SPO₂ of 92% (room air). Jaundice in the ocular conjunctiva, swollen lymph nodes in the neck, and heart murmur were not noted. However, coarse crackles were observed in the left lung upon inspiration. Furthermore, the abdomen was flat and soft with no tenderness. He had no percussion pain in the lumbosacral region or edema in the lower extremities. No other skin rashes were observed, except for numerous acne lesions on the face. Neurological examination revealed motor aphasia, resulting in the absence of speech. His pupils were 3 mm in diameter bilaterally, his eyes were in the midline, and his light reflex was rapid. Soft palate elevation was poor and tongue movement was minimal. Muscle strength could not be measured as indicated, but the extremities could be moved by the patient voluntarily, implying no tetraplegia. Tendon reflexes were normal, and no sensory deficits or cerebellar ataxias were evident. However, he had difficulty maintaining a sitting position. Initial laboratory studies showed the following: a white blood cell count of 5200/mm³, hemoglobin of 15.0 g/dL, platelet count of 126 × 10³/ μL, C-reactive protein of 0.76 mg/dL, aspartate aminotransferase of 15 IU/L, alanine aminotransferase of 9 IU/L, blood urea nitrogen of 12.3 mg/dL, creatinine of 0.54 mg/dL, sodium of 138 mEq/L, potassium of 3.9 mEq/L, and chloride of 190 mEq/L. His blood valproic acid concentration was 80.8 μg/mL. Urinalysis revealed a urine specific gravity of 1.013 and a pH of 7.5, with no glucose, protein, fresh blood, leukocytes, or bacteria detected. Additionally, sputum culture detected Haemophilus influenzae. Chest X-ray showed no clear evidence of pneumonia, but chest computed tomography revealed pneumonia in the lower lobe of the left lung.

After admission, his temperature was often in the range of low-to-high 37 °C. Brain magnetic resonance imaging identified no abnormalities. The clinical course is shown in Fig. 1. His antiseizure medication (ASM) regimen consisted of 1800 mg/day of valproate, 3.8 g/day of sodium bromide, and 200 mg/day of zonisamide and remained unchanged for more than 5 years. All ASMs were orally administered. We treated the patient for aspiration pneumonia with antibiotics, although his generalized onset clonic seizures occurred during fever. Once the fever subsided, the frequency of generalized onset clonic seizures returned to that before admission. Once the fever associated with his infection resolved, the frequency of his seizures returned to his baseline level.

At the age of 25 years, the patient had pneumonia that required admission to a hospital. Pneumonia improved with antibiotics but soon worsened again, leading to respiratory failure. The patient was intubated and placed on a ventilator and underwent tracheostomy and gastrostomy. Nutrition, fluids, and medications were administered through the gastrostomy. The seizures were repeatedly triggered by a variety of factors, including fever due to urinary tract infection or skin and soft tissue infection, and high body temperature due to bathing.

Infection and seizures themselves caused a temperature elevation, sometimes to 39 °C or higher, which persisted for about 3 days. In the past, he used to have a generalized onset clonic seizure once a month, but he began to have a seizure once every 2–3 days, and sometimes every day.

The seizures caused a further prolonged temperature elevation, which led to the appearance of SE. Gradually, the patient’s SE became more prolonged, and the hospitalization period became longer. In SE, diazepam alone was insufficient to control persistent seizures, and a single dose of high-dose phenobarbital or continuous administration of midazolam or thiopental was often required. The cause remains unclear; perhaps, it could be the frequent administration of antimicrobials, the change from oral to tube feeding, or the resulting reduced absorption of valproic acid from the gut. Notably, blood valproic acid levels continued to decrease after antimicrobial therapy was discontinued. Therefore, the dose of valproate had to be gradually increased with the measurement of the blood levels.

An electroencephalogram (interictal phase) is shown in Fig. 2. We considered the possibility that fever due to repeated infections and repeated seizures, as well as the side effects of zonisamide, may have contributed to the high body temperature. We explained to the family that we were discontinuing zonisamide because it might be contributing to the high body temperature. However, the family did not agree to discontinue zonisamide, which had been used for a long time for the patient.

Clobazam and levetiracetam were added but were discontinued without the effect on seizure control. The patient continued to have SE each time he had hyperthermia. The symptoms tended to worsen, and given that symptoms have been reported to worsen with hyperthermia in DS associated with an SCN1A gene mutation, the patient underwent genetic testing (with the family’s consent) to confirm that the symptoms were caused by DS and not other diseases. Genetic testing revealed a frameshift mutation (c.2176 + 1G>A) in the SCN1A gene. Based on the course and findings, the diagnosis was consistent with DS.

During aspiration pneumonia, the patient experienced poor oxygenation with fever, coarse crackles in the lungs on auscultation, and an increased sputum volume. After respirator attachment, the airway pressure sometimes increased because of sputum accumulation. Sputum culture often detected Pseudomonas aeruginosa and Corynebacterium striatum. For antimicrobial therapy, the patient received 4.5 g of intravenous tazobactam/piperacillin four times a day or 500 mg to 1 g of intravenous vancomycin twice a day (changed according to blood concentration) for 14 days. If no increase in sputum production or poor oxygenation occurred, a urinary tract infection was considered. Urinalysis revealed urinary bacteria, and no other infections were considered. In urine cultures, Klebsiella oxytoca, Escherichia coli (sometimes extended-spectrum β-lactamase-producing bacteria), and P. aeruginosa were found. The above-mentioned dosage of intravenous tazobactam/piperacillin also addressed urinary tract infections. When pneumonia and urinary tract infections could be treated in the outpatient setting, 500 mg of oral levofloxacin was administered once a day for 14 days. Urinary tract infections, pneumonia, and skin infections were treated with antibiotics as early as possible to prevent the occurrence of fever. At the age of 27 years, SE due to hyperthermia continued without infection, and administration of thiopental was continued for 2 weeks in the hospital. With the family’s consent, zonisamide was tapered off, and perampanel was titrated up from 1 mg/day. Repeated episodes of impetigo all over his body were treated with topical antimicrobials each time. Oral minocycline was administered for severe acne. After discontinuing zonisamide in the outpatient setting and switching to perampanel, the patient’s hyperthermia and associated seizures resolved in a short period, occurring only once a week, due in part to the effect of less frequent fever caused by infection and perampanel. His temperature was also in the 36 °C range (previously, his body temperature was often in the 37 °C range), possibly due to the discontinuation of zonisamide.

One and a half years after the discontinuation of zonisamide and switching to perampanel, SE no longer occurred; however, mild seizures continued at least once a week. Perampanel was titrated up to 8 mg/day; however, the patient became mentally restless and attempted to remove the ventilator by hand because of spontaneous movements. We reduced the dose of perampanel to 2 mg/day. No worsening of seizure frequency (once a week) was observed after reducing the dose of perampanel. Furthermore, 3200 mg/day of valproate and 3.8 g/day of sodium bromide were continued. The patient was in a state of total bed rest with no speech, and although he could raise his upper extremities, the lower extremities were almost completely motionless because of disuse. He could no longer swallow.