The patient was a 35-year-old male with no history of major illness or family history of immunodeficiency. He had been doing well until he developed general fatigue, low-grade fever, and vomiting 2 weeks before this admission. Four days before admission, he went to a general hospital because of a persistent headache and a high fever of 39C. Nasopharyngeal swab tests for influenza A and B were both negative, and he was given ibuprofen. At midnight on the day of admission, he suddenly groaned, foamed at the mouth, and lost consciousness, and his wife witnessed his eyes turn upward. He was taken to hospital by ambulance and suffered 5 or 6 generalized seizures. Diazepam and phenobarbital were administered, and he finally was transferred to our hospital.
On physical examination, the patient was found to have a body temperature of 38.9C, a pulse rate of 94 beats/min, and a blood pressure of 131/81 mmHg, and marked hyperhidrosis and dark reddish skin eruptions were noted on the right forehead and scalp. No abnormalities of the chest, abdomen, or extremities were observed. A neurological examination revealed consciousness disturbance (Japan Coma Scale score: 100; Glasgow Coma Scale score: 6 [E1V1M4]), neck stiffness, and hyporeflexia of the bilateral lower extremities.
A chest X-ray and electrocardiogram demonstrated normal results. Brain magnetic resonance imaging (MRI) showed high-intensity lesions in the bilateral hippocampi and periventricular white matter on fluid-attenuated inversion recovery images (Fig. 1a-c). Diffusion-weighted imaging and apparent diffusion coefficient mapping showed high-intensity signals emanating from the lesions, which were suggestive of vasogenic edema (Fig. 1d and e). Contrast-enhanced brain MRI did not show any abnormal enhancement (data not shown).
The patient's white blood cell count was 12,420/mm3 (neutrophils: 88.7%, lymphocytes: 4.8%, monocytes: 4.9%, eosinophils: 0.1%, basophils: 0.3%, and atypical lymphocytes: 0.0%), and a test for C-reactive protein was negative (0.14 mg/dL). His creatine kinase was elevated (2,225 IU/L), which was considered to have been caused by the general seizures. Other routine blood and urine biochemical analyses did not detect any significant abnormalities.
A cerebrospinal fluid (CSF) analysis performed on admission revealed a normal pressure (16 cmH2O), a colorless appearance, pleocytosis (35/mm3) with a predominance of lymphocytes (94%), a high protein level (76.5 mg/dL), a normal glucose level (113 mg/dL; plasma glucose: 160 mg/dL), and a normal IgG level (4.6 mg/dL; IgG index: 0.50).
Polymerase chain reaction (PCR)-based tests of the CSF sample produced a positive result for HHV-7 DNA, but negative results for herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus (CMV), and HHV-6. Repeated CSF tests confirmed the positive HHV-7 DNA result and the results of PCR were verified with positive and negative controls. A quantitative analysis of the HHV-7 DNA detected 3,800 copies/mL in the CSF specimen obtained on the 3rd hospital day, and a blood sample was also positive for HHV-7 DNA. The patient's serum HHV-7-IgG and IgM levels (fluorescence antibody technique) were 80x and <10x on admission, and his serum HHV-7-IgG level had increased on the follow-up examination (peak: 640x after 5 months), but his serum HHV-7-IgM level remained at <10x. The patient's CSF HHV-7-IgG and IgM levels were <1x and <1x, respectively. All viral DNA assays were performed by a commercial laboratory (SRL, Tokyo, Japan) (Fig. 2).
A culture of the patient's CSF did not show any growth of bacteria, mycobacteria, or fungi. PCR-based tests of the patient's CSF for mycobacterium tuberculosis and avium/intracellulare were negative, and a cytological examination did not show any malignant cells. A serological test for human immunodeficiency virus was negative. The rapid plasma reagin test for syphilis and the Treponema pallidum hemagglutinin test were also negative. Similarly, serological tests for autoantibodies including rheumatoid factor, antinuclear antibodies, and paraneoplastic antibodies (anti-Hu, Yo, and Ri) were all negative.
Tumor marker tests (carcinoembryonic antigen, alpha-fetoprotein, squamous cell carcinoma antigen, cytokeratin 19 fragment, and the soluble interleukin-2 receptor) all produced negative results. Contrast-enhanced chest and abdominal computed tomography (CT) exhibited normal findings. Brain single-photon emission CT (SPECT) and 67Ga-scintigraphy did not show any abnormalities. Electroencephalography (EEG) performed on admission showed slow waves in the frontal area, and the follow-up EEG demonstrated spikes in the left hemisphere.
Methylprednisolone (1 g/day, 3 days), intravenous immunoglobulins (IVIG) (5 g/day, 3 days), ceftriaxone (4 g/day, 7 days), acyclovir (1,500 mg/day, l4 days), glycerol (400 mL/day, 14 days), midazolam (20 mg/day, 14 days), and fosfluconazole (100 mg/day, 6 days) were administered. The patient's seizures and fever improved on the 2nd hospital day, and his consciousness gradually became clear. However, he demonstrated a severe memory disturbance. His revised Hasegawa Dementia Scale (HDS-R) score [a modified simple dementia scale in Japan, which is closely compatible with the Mini-Mental State Examination (MMSE)] was 12 points (full score: 30 points) on the 3rd hospital day and he could not recall any of 3 objects even after hints were given. We started to administer valproate (400 mg/day) on the 6th day. On the 9th day, myoclonus appeared; therefore, we added clonazepam (0.5 mg/day) and obtained a good response. His memory disturbance had disappeared by the 31st day [HDS-R score 29/30; MMSE 29/30; Wechsler adult intelligence scale-revised (WAIS-R) intelligent quotient (IQ) 86 verbal IQ (VIQ) 81, performance IQ (PIQ) 96)], and he left our hospital on the 37th hospital day. The patient's CSF cell counts normalized, and the HHV-7 DNA disappeared three months later (Fig. 2).
Since he suffered several seizures after being discharged, phenytoin and clobazam were added serially (Fig. 2). Carbamazepine was also used, but it was terminated because of a drug-induced lip eruption. At present, he is independent in terms of his daily life and ability to work. He has not shown any emotional or behavioral disturbances. He has been followed for 7 years at our clinic without any recurrence of his encephalitis. He is in good health and does not exhibit any signs of an immunocompromised state or autoimmune disorders.
Brain MRI showed a gradual improvement of the high-intensity areas in the hippocampus (data not shown). Blood tests for HHV-7 DNA continued to produce positive results throughout the follow-up period.