Abstract
Article abstract A 19-month-old girl presented with severe neurologic symptoms associated with exanthem subitum. Human herpesvirus type 7 (HHV-7) DNA was detected in the CSF and serum, and supported by serologic studies. The patient was diagnosed with encephalopathy due to an acute HHV-7 infection. Neuron-specific enolase in the CSF was strongly elevated during the acute stage of infection, suggesting that the encephalopathy was due to viral invasion of the brain.
Human herpesvirus type 7 (HHV-7) is a newly described herpesvirus closely related to human herpesvirus type 6 (HHV-6).1 The clinical manifestations of HHV-7 infection are similar to those caused by HHV-6. Primary infection occurs in infants and symptoms vary from a nonspecific high fever to exanthem subitum and febrile seizures.1
Neuroinvasion has been reported with HHV-6, causing focal encephalitis or febrile seizures,2 but neuroinvasion has not yet been proven for HHV-7. However, HHV-7 may cause severe CNS manifestations, accompanied by synthesis of intrathecal antibody against the virus, which suggested that the virus had invaded the brain.3
We report a 19-month-old girl with an infectious encephalopathy. HHV-7 was detected in the CSF by PCR, supporting neuroinvasion by the virus.
Case report.
Prodromal stage.
Symptoms of subacute encephalopathy developed in a 19-month-old girl. Her behavior changed 3 weeks before she was admitted to hospital. She did not react to her name, would lick imaginary water drops in the bath, and developed a peculiar preference for a particular position of both hands and feet.
Acute stage.
Fever with seizures developed, and she was admitted to a local hospital (day 1). Temperature was 39.0 °C on admission. The head preferentially turned to the right side, and it was not possible to communicate with her. Hematologic and blood chemical analyses were negative. For CSF values, see the table. A CT scan of the brain was negative. Antiepileptic and antibiotic treatment was started. On day 4, exanthem subitum developed. The clinical condition deteriorated, and the patient was transferred to our hospital on suspicion of encephalitis. On admission (day 5), her temperature was normal (37.2 °C), and a maculopapular rash was present predominantly on the face and trunk. There was no lymphadenopathy, respiratory tract abnormalities, or visceromegaly. There was spontaneous opening of the eyes, but no response to external stimuli. Optic fundi were normal, pupils alternately reactive. Other brain reflexes were intact. There was no neck rigidity; the limbs moved symmetrically without evidence of paresis. Tendon reflexes were symmetrically normal with flexor plantar responses. Treatment with IV phenytoin, amoxicillin, ceftazidime, and acyclovir was started. Serology was consistent with an active HHV-7 infection (IgM positive with a significant rise in titer for IgG). No evidence was found for other infections. No virus could be isolated from the CSF taken on day 2. The results of serology tests and PCR for HHV-6 and HHV-7 in blood and CSF are shown in the table. The first EEG (on day 2) showed generalized continued polymorphic delta activity with sporadic epileptiform activity. During clinical improvement, normalization of the EEG occurred, and the epileptiform activity disappeared. MRI of the brain at day 23 showed slight atrophy of both hemispheres.
Serologic studies and PCR of human herpesvirus (HHV)6 and HHV7, and CSF brain-specific proteins
Recovery stage.
On day 7, a gradual improvement started during which slight paresis of the left arm and leg became apparent. The patient showed the clinical picture of Klüver-Bucy syndrome. Ten days after admission, the patient reacted to sounds, and gradually improved in the ensuing weeks. The CSF level of neuron-specific enolase, which was initially strongly elevated, returned to normal values on day 40 (table). Two months after discharge, after a period of rehabilitation, she was again able to speak, and to stand and walk alone.
Methods.
Serology.
Routine serology (IgG, IgA, IgM antibodies) for herpes simplex virus, varicella zoster virus, cytomegalovirus, and Mycoplasma pneumoniae was performed by ELISA, as described previously.4 Antibodies against adenovirus and enterovirus were determined by complement fixation assay. Antibodies against Epstein-Barr virus were detected by a commercial ELISA (Biotest AG, Dreieich, Germany).
IgG and IgM antibodies against HHV-6 and HHV-7 were determined by indirect immunofluorescence, essentially as described before.5 Cord blood lymphocytes infected with either the Z29 strain (HHV-6B) or the SB strain (HHV-7) were used as antigens.
PCR.
Primers and probes for HHV-6–specific PCR were selected from Secchiero et al.,6 and for HHV-7–specific PCR from Kidd et al.7 The specificity of the amplicons was assessed by electrophoresis on 1.5% agarose gels stained with ethidium bromide. Southern blot analysis was subsequently performed with HHV-6– and HHV-7–specific oligonucleotide probes6,7 that were 3′-end–labeled with digoxigenin-11-ddUTP (DIG-11-ddUTP; Boehringer Manheim, Mannheim, Germany).
Discussion.
This patient’s disease course can be divided into three stages: first, a prodromal phase of several weeks consisting of behavioral changes; next, a phase with fever, exanthem subitum, convulsions, and pathologic consciousness; and finally, a phase of slow recovery.
The symptoms were attributed to an HHV-7 infection because HHV-7 was found both in the CSF and in serum, with the latter suggesting a viremic phase. Furthermore, HHV-7–specific IgM antibody was present in blood, and a significant rise in antibody titer was observed, from 1:10 on day 7 to 1:160 in a sample obtained 8 days later. IgM antibody for HHV-6 was also found, but IgG antibody remained steady, suggesting primary infection in the past. No other infectious agents were found.
The CNS manifestations caused by HHV-7 might be due to viral invasion of the brain. Alternatively, they might be due to focal impairment of blood flow caused by viral vasculitis. Torigoe et al.3 reported two patients with HHV-7–associated encephalopathy, convulsions, and hemiplegia associated with exanthem subitum. No HHV-7 DNA could be detected in the CSF of these patients. However, in one of these cases, synthesis of intrathecal antibody against HHV-7 was demonstrated. In the current case, both the presence of HHV-7 DNA in CSF and elevated levels of neuron-specific enolase in the CSF supported the hypothesis that HHV-7 invaded the CNS and caused the encephalopathy.8
Human herpesvirus type 7 has a close homology with HHV-6,1 which is sensitive to the antiviral agents foscarnet and ganciclovir, and relatively resistant to acyclovir.9 If HHV-7 encephalopathy is due to a viral invasion of the CNS causing encephalitis, then treatment with foscarnet or ganciclovir should be considered. However, further studies are necessary before such therapies can be recommended routinely.
It remains difficult to accurately diagnose acute HHV-6 or HHV-7 infections of the CNS. Pleiocytosis of the CSF is seldom found.2 HHV-6 can easily be detected in CSF after the acute phase of a primary childhood infection.2 In contrast, CSF samples from adults are rarely positive for HHV-6.10 If the same holds true for HHV-7, then at least in children, a positive PCR on CSF has to be interpreted with caution. Complementary investigations such as serology are then warranted. As a consequence, diagnosis and decisions about treatment still have to be made on clinical grounds. This case illustrates once again that HHV-7 can cause severe encephalopathy, and that further studies on the natural course and on treatment are warranted.
- Received September 1, 1998.
- Accepted November 28, 1998.
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