Infection DOI 10.1007/s15010-015-0822-6
CASE REPORT
Chronic herpes simplex type‑1 encephalitis with intractable epilepsy in an immunosuppressed patient Christopher Laohathai1 · Daniel J. Weber1 · Ghazala Hayat1 · Florian P. Thomas1
Received: 31 March 2015 / Accepted: 6 July 2015 © Springer-Verlag Berlin Heidelberg 2015
Background Chronic herpes simplex virus type-1 encephalitis (HSE-1) is uncommon. Past reports focused on its association with prior documented acute infection. Here, we describe a patient with increasingly intractable epilepsy from chronic HSE-1 reactivation without history of acute central nervous system infection. Case presentation A 49-year-old liver transplant patient with 4-year history of epilepsy after initiation of cyclosporine developed increasingly frequent seizures over 3 months. Serial brain magnetic resonance imaging showed left temporoparietal cortical edema that gradually improved despite clinical decline. Herpes simplex virus type-1 (HSV1) DNA was detected in cerebrospinal fluid by polymerase chain reaction. Cerebrospinal fluid HSV-1&2 IgM was negative. Seizures were controlled after acyclovir treatment, and the patient remained seizure free at 1-year follow-up. Conclusion Chronic HSE is a cause of intractable epilepsy, can occur without a recognized preceding acute phase, and the clinical course of infection may not directly correlate with neuroimaging changes. Keywords Cyclosporine · Encephalitis · Epilepsy · Herpes simplex · Immunosuppression · Seizure
* Christopher Laohathai [email protected] 1
Department of Neurology and Psychiatry, Saint Louis University, 1438 South Grand Blvd., Saint Louis, MO 63104, USA
Background We report a patient with chronic herpes simplex type-1 encephalitis (HSE-1) who developed intractable epilepsy while on cyclosporine therapy. This case demonstrates that chronic HSE can occur without recognizable preceding acute phase. While there is mounting evidence that chronic HSE is a cause of intractable epilepsy (Table 1), we have found no previous reports of seizures resulting from chronic HSE without preceding acute HSE [1–7]. We propose that, in immunosuppressed individuals, chronic central nervous system infection can be a co-existing cause of intractable epilepsy in addition to drugs such as cyclosporine which are independently associated with seizures [8–10].
Case presentation A 49-year-old man was admitted due to increased seizure frequency. Four years prior to admission he had undergone orthotopic liver transplantation due to hepatitis C cirrhosis and received cyclosporine for immunosuppression. Seizures started at 2 months after initiation of cyclosporine, described as right-sided tonic–clonic movements without loss of consciousness. EEG showed epileptiform discharges at the left temporal region. Brain MRI was normal. He was treated with levetiracetam but during the following year continued to have seizures every 8–12 weeks with occasional generalization. Repeat brain MRI remained normal. He refused lumbar puncture. When the levetiracetam dosage was increased and topiramate was added, seizures diminished to once every 6 months and reverted to simple partial right-sided tonic– clonic events lasting few minutes which remained stable for the next 2 years.
13
13
10 years
Hackney et al. [7]
9 years
10 years
Noc
Used HSV-1&2 pol gene-specific primer
Used HSV I/II, Cell Marque, Rocklin, California
d
Diagnosed with herpes meningitis at 4 months of age
c
b
NA
4 years
3 years
12 years
2 years
NA
Yes, 6 months
Intrauterine growth retardation with neonatal seizure
a
NA data not available
14 years
Yes, 4 months
10 years
Adamo et al. [6]
Yes, 18 months
6 years
Love et al. [5]
Yes, 61 years
66 years
Yamada et al. [4]
Yes, 2 years
Yes, 3 years
6 years
14 years
Yes, 6 months
8.5 years
Asenbauer et al. [3]
Jay et al. [2]
Yes, 7 months
3 years
18 months
15 weeks
Noa
15 weeks
Jay et al. [1]
Duration of deterioration preceding diagnosis of chronic HSE
Prior diagnosis of acute HSE-1, age
Age at diagnosis
References
Table 1 Reports of chronic herpes simplex encephalitis with intractable epilepsy
Negative
Negative
Positive
NA
NA
NA
NA
NA
NA
NA
CSF
NA
Positive
NA
Positive
Granulomas; giant cells; necrosis; positive immunostainingd
Granulomas; necrosis; no viral inclusions; negative immunostaining
Inflammatory infiltrates; giant cells; granulomas; no viral inclusions; negative immunostaining
Inflammatory infiltrates; giant cells; granulomas; no viral inclusions; negative immunostaining
Lymphocytic perivascular aggregate; necrosis; viral inclusions present; immunostaining positive for HSV-1
Lymphocytic perivascular aggregate; no viral inclusions; negative immunostaining
Positiveb
Positive
Extensive inflammatory infiltrates, giant cells; necrosis; no viral inclusions
Lymphocytic perivascular aggregate; no viral inclusions; negative immunostaining
Extensive inflammatory infiltrates; giant cells; no viral inclusions; negative immunostaining
Occasional macrophage; necrosis; no viral inclusions; negative immunostaining
Histopathology report
Positive
Positive
Positive
Positive
Tissue
HSV-1 DNA PCR
MRI: right insula and operculum atrophy with T2 hypersignal intensity
MRI: right temporal atrophy with T2 hypersignal intensity with fluctuating edema; leptomeningeal enhancement
MRI: bilateral temporal atrophy
MRI: left temporal atrophy with T2 hypersignal intensity
CT: diffuse cerebral atrophy
MRI: bilateral suprasylvian T2 hypersignal intensity
MRI: right frontal, temporal and parietal T2 hypersignal intensity
MRI: left temporal, parietal and occipital atrophy; left thalamic signal alteration and right cerebellar atrophy
MRI: left temporal atrophy with T2 hypersignal intensity
CT: diffuse cortical and subcortical calcification and atrophy
Brain imaging preceding the diagnosis of chronic HSE
C. Laohathai et al.
Chronic herpes simplex type-1 encephalitis with intractable…
Fig. 1 (a) T2-FLAIR brain MRI at 8 weeks after onset of clinical deterioration showed left temporoparietal cortical edema. Radiographic improvements were noted at (b) 14 weeks and (c) 15 weeks
despite progressive clinical decline. (d) Repeated imaging at 2 weeks after completion of acyclovir treatment showed complete resolution
Three months prior to admission, the patient developed recurrent seizures and speech difficulty, and came for evaluation about 3 weeks after onset. EEG revealed left hemispheric slowing without epileptiform discharges. Brain MRI performed 8 weeks after onset showed new left temporoparietal cortical edema (Fig. 1a) with subtle diffusion restriction, raising the possibility of an evolving ischemic event or reversible leukoencephalopathy. However, in the ensuing months, his speech progressively deteriorated and seizure frequency increased to once or twice a week. Lacosamide was substituted for topiramate without improvement. Repeat brain MRI 14 weeks after onset of
the clinical decline showed minimal reduction of the cortical signal changes (Fig. 1b). Past medical history was also pertinent for hyperlipidemia and asthma. Several complete blood counts and metabolic profiles were unremarkable. Cyclosporine trough levels ranged between 80 and 120 ng/mL (350– 500 ng/mL). ESR and CRP were elevated at 39 mm/h and 5.69 mg/L, respectively. He was HIV seronegative. On examination, the patient was afebrile and normotensive. He was alert and exhibited global aphasia, right-sided neglect, right pronator drift, and normal reflexes. Serial evaluations indicated fluctuating spontaneous speech, comprehension
13
C. Laohathai et al.
and neglect. Routine EEG demonstrated persistent left hemispheric slowing with electrographic seizures originating from the left temporal region associated with worsening aphasia. Another brain MRI revealed decreased left temporoparietal cortical edema (Fig. 1c). However, despite improvement in neuroimaging, the seizure frequency increased to six motor seizures in 1 day. CSF study revealed the following: glucose 74 mg/dL (normal reference: 40–70 mg/dL), protein 34 mg/ dL (normal reference: 15–45 mg/dL), WBC 1/mm3 [(normal reference: 0–5/mm3), (differential: lymphocyte 74 %, monocyte 24 %, neutrophil 2 %)]. CSF bacterial and viral cultures, VDRL, and cytology were normal. HSV-1 DNA was detected in the CSF by PCR, whereas serum HSV PCR was negative. ELISA showed CSF HSV-1 IgG at 3.36 (positive >1.09), CSF HSV-2 IgG at 4.37 (positive >1.09) and CSF HSV-1&2 IgM screening at 0.09 (positive >1.10). CSF PCR for HSV-2, VZV, EBV, CMV, HHV-6, WNV and JCV were negative. Serologies for WNV, SLE, EEE and WEE were negative. CSF protein 14-3-3 was negative. CSF oligoclonal bands were negative, and CSF IgG index was normal at 0.46. Following the diagnosis of chronic HSE-1, the patient was treated with acyclovir 10 mg/kg IV every 8 h for 21 days. Seizures resolved and his aphasia significantly improved. Brain MRI obtained 2 weeks after completion of treatment showed complete resolution of the lesion (Fig. 1d) and repeat CSF HSV-1 PCR was negative. Cyclosporine was continued throughout the course of his illness. He remained seizure free at 1-year follow-up.
Conclusion Chronic HSE-1 is associated with intractable epilepsy [1–7]. This entity is uncommon; however, it is possible that some patients remain undiagnosed because neuroimaging findings are non-specific [1–7] and CSF DNA detection can be false negative [6, 7]. In contrast to our patient, literature review showed that most cases of chronic HSE-1 had a documented acute central nervous system infection [1–7] up to 13.5 years prior [6]. Few reports of chronic HSE without prior acute infection include an infant with undefined perinatal infection [1] and a patient with asymptomatic HSV-2 infection [11]. Other cases suspicious of chronic HSE lacked etiologic confirmation by CSF PCR or histology [12, 13]. This patient had no history of seizures prior to initiation of cyclosporine and initial evaluation for etiology of his epilepsy was negative, but CSF analysis was not performed. Cyclosporine, even in the conventional therapeutic range, has been associated with new onset seizures [8]. Generalized and focal seizures have both been reported, as well as mesial temporal sclerosis and intractable epilepsy [9, 10]. Case reports exist of intractable and progressive epilepsy in the population receiving cyclosporine. Some
13
of these cases may represent underlying indolent HSV and other infectious etiologies. In this case, HSV-1 conceivably contributed to the onset of post-transplant epilepsy, and reactivation was most likely responsible for the recently increased seizure frequency. However, contribution from cyclosporine and autoimmunity [14] cannot be excluded. Spontaneous improvement in neuroimaging during active infection prior to treatment, observed in this patient, has been previously described [6] and may suggest a possible transient relapsing–remitting inflammation attributable to immune mechanisms [14]. Progressive clinical decline despite neuroimaging improvement suggests that status of chronic HSV-1 infection may not correlate with radiographic findings, and imaging alone is not a sufficient marker of treatment response. While cyclosporineinduced reversible leukoencephalopathy was considered, improvement despite continued cyclosporine use, remote initiation of medication with stable trough levels, absent hypertension, and atypical and protracted resolution of neuroimaging abnormalities did not support this diagnosis. Immunosuppressed patients with neurological changes must be investigated for infectious etiologies, even when they are on medications that can be attributable. When initial investigations are unrevealing, patients require interval reassessment. In this case, the consideration of immunosuppression and unexplained clinical deterioration led to the diagnosis of a treatable etiology. This case raises questions regarding the role of indolent viral infections in patients with intractable epilepsy, and investigation of infectious etiologies and associated immunologic responses may be warranted in this population. Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
References 1. Jay V, Becker LE, Blaser S, et al. Pathology of chronic herpes infection associated with seizure disorder: a report of two cases with tissue detection of herpes simplex virus 1 by the polymerase chain reaction. Pediatr Pathol Lab Med. 1995;15:131–46. 2. Jay V, Hwang P, Hoffman HJ, Becker LE, Zielenska M. Intractable seizure disorder associated with chronic herpes infection: HSV1 detection in tissue by the polymerase chain reaction. Childs Nerv Syst. 1998;14:15–20. 3. Asenbauer B, McEntagart M, King MD, Gallagher P, Burke M, Farrell MA. Chronic active destructive herpes simplex encephalitis with recovery of viral DNA 12 years after disease onset. Neuropediatrics. 1998;29:120–3. 4. Yamada S, Kameyama T, Nagaya S, Hashizume Y, Yoshida M. Relapsing herpes simplex encephalitis: pathological confirmation of viral reactivation. J Neurol Neurosurg Psychiatry. 2003;74:262–4. 5. Love S, Koch P, Urbach H, Dawson TP. Chronic granulomatous herpes simplex encephalitis in children. J Neuropathol Exp Neurol. 2004;63:1173–81.
Chronic herpes simplex type-1 encephalitis with intractable… 6. Adamo MA, Abraham L, Pollack IF. Chronic granulomatous herpes encephalitis: a rare entity posing a diagnostic challenge. J Neurosurg Pediatr. 2001;8:402–6. 7. Hackney JR, Harrison DK, Rozzelle C, Kankirawatana S, Kankirawatana P, Palmer CA. Chronic granulomatous herpes encephalitis in a child with clinically intractable epilepsy. Case Rep Pediatr. 2012. doi:10.1155/2012/849812. 8. Gleeson JG, duPlessis AJ, Barnes PD, Riviello JJ Jr. Cyclosporin A acute encephalopathy and seizure syndrome in childhood: clinical features and risk of seizure recurrence. J Child Neurol. 1998;13:336–44. 9. Faraci M, Lanino E, Dallorso S, et al. Mesial temporal sclerosis—a late complication in four allogeneic paediatric recipients with persistent seizures after an acute episode of cyclosporine— a neurotoxicity. Bone Marrow Transplant. 2003;31:919–22. 10. Gaggero R, Haupt R, Paola Fondelli M, et al. Intractable epilepsy secondary to cyclosporine toxicity in children undergoing
allogeneic hematopoietic bone marrow transplantation. J Child Neurol. 2006;21:861–6. 11. Hori T, Suzuki T, Terashima Y, Kawai N, Shiraishi H, Koi zumi J. Chronic herpes simplex encephalitis with somnambulism: CT, MR, and SPECT findings. Jpn J Psychiatry Neurol. 1990;44:735–9. 12. Sasaguri H, Sodeyama N, Maejima Y, Kanda T, Mizusawa H. Slowly progressive Foix–Chavany–Marie syndrome associated with chronic herpes simplex encephalitis. J Neurol Neurosurg Psychiatry. 2002;73:202–9. 13. Brown WD, Bearer EL, Donahue JE. Chronic active herpes simplex type 2 encephalitis in an asymptomatic immunocompetent child. J Child Neurol. 2010;25:901–8. 14. Conrady CD, Drevets DA, Carr DJ. Herpes simplex type I (HSV1) infection of the nervous system: is an immune response a good thing? J Neuroimmunol. 2010;220:1–9.
13
CASE REPORT
Chronic herpes simplex type‑1 encephalitis with intractable epilepsy in an immunosuppressed patient Christopher Laohathai1 · Daniel J. Weber1 · Ghazala Hayat1 · Florian P. Thomas1
Received: 31 March 2015 / Accepted: 6 July 2015 © Springer-Verlag Berlin Heidelberg 2015
Background Chronic herpes simplex virus type-1 encephalitis (HSE-1) is uncommon. Past reports focused on its association with prior documented acute infection. Here, we describe a patient with increasingly intractable epilepsy from chronic HSE-1 reactivation without history of acute central nervous system infection. Case presentation A 49-year-old liver transplant patient with 4-year history of epilepsy after initiation of cyclosporine developed increasingly frequent seizures over 3 months. Serial brain magnetic resonance imaging showed left temporoparietal cortical edema that gradually improved despite clinical decline. Herpes simplex virus type-1 (HSV1) DNA was detected in cerebrospinal fluid by polymerase chain reaction. Cerebrospinal fluid HSV-1&2 IgM was negative. Seizures were controlled after acyclovir treatment, and the patient remained seizure free at 1-year follow-up. Conclusion Chronic HSE is a cause of intractable epilepsy, can occur without a recognized preceding acute phase, and the clinical course of infection may not directly correlate with neuroimaging changes. Keywords Cyclosporine · Encephalitis · Epilepsy · Herpes simplex · Immunosuppression · Seizure
* Christopher Laohathai [email protected] 1
Department of Neurology and Psychiatry, Saint Louis University, 1438 South Grand Blvd., Saint Louis, MO 63104, USA
Background We report a patient with chronic herpes simplex type-1 encephalitis (HSE-1) who developed intractable epilepsy while on cyclosporine therapy. This case demonstrates that chronic HSE can occur without recognizable preceding acute phase. While there is mounting evidence that chronic HSE is a cause of intractable epilepsy (Table 1), we have found no previous reports of seizures resulting from chronic HSE without preceding acute HSE [1–7]. We propose that, in immunosuppressed individuals, chronic central nervous system infection can be a co-existing cause of intractable epilepsy in addition to drugs such as cyclosporine which are independently associated with seizures [8–10].
Case presentation A 49-year-old man was admitted due to increased seizure frequency. Four years prior to admission he had undergone orthotopic liver transplantation due to hepatitis C cirrhosis and received cyclosporine for immunosuppression. Seizures started at 2 months after initiation of cyclosporine, described as right-sided tonic–clonic movements without loss of consciousness. EEG showed epileptiform discharges at the left temporal region. Brain MRI was normal. He was treated with levetiracetam but during the following year continued to have seizures every 8–12 weeks with occasional generalization. Repeat brain MRI remained normal. He refused lumbar puncture. When the levetiracetam dosage was increased and topiramate was added, seizures diminished to once every 6 months and reverted to simple partial right-sided tonic– clonic events lasting few minutes which remained stable for the next 2 years.
13
13
10 years
Hackney et al. [7]
9 years
10 years
Noc
Used HSV-1&2 pol gene-specific primer
Used HSV I/II, Cell Marque, Rocklin, California
d
Diagnosed with herpes meningitis at 4 months of age
c
b
NA
4 years
3 years
12 years
2 years
NA
Yes, 6 months
Intrauterine growth retardation with neonatal seizure
a
NA data not available
14 years
Yes, 4 months
10 years
Adamo et al. [6]
Yes, 18 months
6 years
Love et al. [5]
Yes, 61 years
66 years
Yamada et al. [4]
Yes, 2 years
Yes, 3 years
6 years
14 years
Yes, 6 months
8.5 years
Asenbauer et al. [3]
Jay et al. [2]
Yes, 7 months
3 years
18 months
15 weeks
Noa
15 weeks
Jay et al. [1]
Duration of deterioration preceding diagnosis of chronic HSE
Prior diagnosis of acute HSE-1, age
Age at diagnosis
References
Table 1 Reports of chronic herpes simplex encephalitis with intractable epilepsy
Negative
Negative
Positive
NA
NA
NA
NA
NA
NA
NA
CSF
NA
Positive
NA
Positive
Granulomas; giant cells; necrosis; positive immunostainingd
Granulomas; necrosis; no viral inclusions; negative immunostaining
Inflammatory infiltrates; giant cells; granulomas; no viral inclusions; negative immunostaining
Inflammatory infiltrates; giant cells; granulomas; no viral inclusions; negative immunostaining
Lymphocytic perivascular aggregate; necrosis; viral inclusions present; immunostaining positive for HSV-1
Lymphocytic perivascular aggregate; no viral inclusions; negative immunostaining
Positiveb
Positive
Extensive inflammatory infiltrates, giant cells; necrosis; no viral inclusions
Lymphocytic perivascular aggregate; no viral inclusions; negative immunostaining
Extensive inflammatory infiltrates; giant cells; no viral inclusions; negative immunostaining
Occasional macrophage; necrosis; no viral inclusions; negative immunostaining
Histopathology report
Positive
Positive
Positive
Positive
Tissue
HSV-1 DNA PCR
MRI: right insula and operculum atrophy with T2 hypersignal intensity
MRI: right temporal atrophy with T2 hypersignal intensity with fluctuating edema; leptomeningeal enhancement
MRI: bilateral temporal atrophy
MRI: left temporal atrophy with T2 hypersignal intensity
CT: diffuse cerebral atrophy
MRI: bilateral suprasylvian T2 hypersignal intensity
MRI: right frontal, temporal and parietal T2 hypersignal intensity
MRI: left temporal, parietal and occipital atrophy; left thalamic signal alteration and right cerebellar atrophy
MRI: left temporal atrophy with T2 hypersignal intensity
CT: diffuse cortical and subcortical calcification and atrophy
Brain imaging preceding the diagnosis of chronic HSE
C. Laohathai et al.
Chronic herpes simplex type-1 encephalitis with intractable…
Fig. 1 (a) T2-FLAIR brain MRI at 8 weeks after onset of clinical deterioration showed left temporoparietal cortical edema. Radiographic improvements were noted at (b) 14 weeks and (c) 15 weeks
despite progressive clinical decline. (d) Repeated imaging at 2 weeks after completion of acyclovir treatment showed complete resolution
Three months prior to admission, the patient developed recurrent seizures and speech difficulty, and came for evaluation about 3 weeks after onset. EEG revealed left hemispheric slowing without epileptiform discharges. Brain MRI performed 8 weeks after onset showed new left temporoparietal cortical edema (Fig. 1a) with subtle diffusion restriction, raising the possibility of an evolving ischemic event or reversible leukoencephalopathy. However, in the ensuing months, his speech progressively deteriorated and seizure frequency increased to once or twice a week. Lacosamide was substituted for topiramate without improvement. Repeat brain MRI 14 weeks after onset of
the clinical decline showed minimal reduction of the cortical signal changes (Fig. 1b). Past medical history was also pertinent for hyperlipidemia and asthma. Several complete blood counts and metabolic profiles were unremarkable. Cyclosporine trough levels ranged between 80 and 120 ng/mL (350– 500 ng/mL). ESR and CRP were elevated at 39 mm/h and 5.69 mg/L, respectively. He was HIV seronegative. On examination, the patient was afebrile and normotensive. He was alert and exhibited global aphasia, right-sided neglect, right pronator drift, and normal reflexes. Serial evaluations indicated fluctuating spontaneous speech, comprehension
13
C. Laohathai et al.
and neglect. Routine EEG demonstrated persistent left hemispheric slowing with electrographic seizures originating from the left temporal region associated with worsening aphasia. Another brain MRI revealed decreased left temporoparietal cortical edema (Fig. 1c). However, despite improvement in neuroimaging, the seizure frequency increased to six motor seizures in 1 day. CSF study revealed the following: glucose 74 mg/dL (normal reference: 40–70 mg/dL), protein 34 mg/ dL (normal reference: 15–45 mg/dL), WBC 1/mm3 [(normal reference: 0–5/mm3), (differential: lymphocyte 74 %, monocyte 24 %, neutrophil 2 %)]. CSF bacterial and viral cultures, VDRL, and cytology were normal. HSV-1 DNA was detected in the CSF by PCR, whereas serum HSV PCR was negative. ELISA showed CSF HSV-1 IgG at 3.36 (positive >1.09), CSF HSV-2 IgG at 4.37 (positive >1.09) and CSF HSV-1&2 IgM screening at 0.09 (positive >1.10). CSF PCR for HSV-2, VZV, EBV, CMV, HHV-6, WNV and JCV were negative. Serologies for WNV, SLE, EEE and WEE were negative. CSF protein 14-3-3 was negative. CSF oligoclonal bands were negative, and CSF IgG index was normal at 0.46. Following the diagnosis of chronic HSE-1, the patient was treated with acyclovir 10 mg/kg IV every 8 h for 21 days. Seizures resolved and his aphasia significantly improved. Brain MRI obtained 2 weeks after completion of treatment showed complete resolution of the lesion (Fig. 1d) and repeat CSF HSV-1 PCR was negative. Cyclosporine was continued throughout the course of his illness. He remained seizure free at 1-year follow-up.
Conclusion Chronic HSE-1 is associated with intractable epilepsy [1–7]. This entity is uncommon; however, it is possible that some patients remain undiagnosed because neuroimaging findings are non-specific [1–7] and CSF DNA detection can be false negative [6, 7]. In contrast to our patient, literature review showed that most cases of chronic HSE-1 had a documented acute central nervous system infection [1–7] up to 13.5 years prior [6]. Few reports of chronic HSE without prior acute infection include an infant with undefined perinatal infection [1] and a patient with asymptomatic HSV-2 infection [11]. Other cases suspicious of chronic HSE lacked etiologic confirmation by CSF PCR or histology [12, 13]. This patient had no history of seizures prior to initiation of cyclosporine and initial evaluation for etiology of his epilepsy was negative, but CSF analysis was not performed. Cyclosporine, even in the conventional therapeutic range, has been associated with new onset seizures [8]. Generalized and focal seizures have both been reported, as well as mesial temporal sclerosis and intractable epilepsy [9, 10]. Case reports exist of intractable and progressive epilepsy in the population receiving cyclosporine. Some
13
of these cases may represent underlying indolent HSV and other infectious etiologies. In this case, HSV-1 conceivably contributed to the onset of post-transplant epilepsy, and reactivation was most likely responsible for the recently increased seizure frequency. However, contribution from cyclosporine and autoimmunity [14] cannot be excluded. Spontaneous improvement in neuroimaging during active infection prior to treatment, observed in this patient, has been previously described [6] and may suggest a possible transient relapsing–remitting inflammation attributable to immune mechanisms [14]. Progressive clinical decline despite neuroimaging improvement suggests that status of chronic HSV-1 infection may not correlate with radiographic findings, and imaging alone is not a sufficient marker of treatment response. While cyclosporineinduced reversible leukoencephalopathy was considered, improvement despite continued cyclosporine use, remote initiation of medication with stable trough levels, absent hypertension, and atypical and protracted resolution of neuroimaging abnormalities did not support this diagnosis. Immunosuppressed patients with neurological changes must be investigated for infectious etiologies, even when they are on medications that can be attributable. When initial investigations are unrevealing, patients require interval reassessment. In this case, the consideration of immunosuppression and unexplained clinical deterioration led to the diagnosis of a treatable etiology. This case raises questions regarding the role of indolent viral infections in patients with intractable epilepsy, and investigation of infectious etiologies and associated immunologic responses may be warranted in this population. Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
References 1. Jay V, Becker LE, Blaser S, et al. Pathology of chronic herpes infection associated with seizure disorder: a report of two cases with tissue detection of herpes simplex virus 1 by the polymerase chain reaction. Pediatr Pathol Lab Med. 1995;15:131–46. 2. Jay V, Hwang P, Hoffman HJ, Becker LE, Zielenska M. Intractable seizure disorder associated with chronic herpes infection: HSV1 detection in tissue by the polymerase chain reaction. Childs Nerv Syst. 1998;14:15–20. 3. Asenbauer B, McEntagart M, King MD, Gallagher P, Burke M, Farrell MA. Chronic active destructive herpes simplex encephalitis with recovery of viral DNA 12 years after disease onset. Neuropediatrics. 1998;29:120–3. 4. Yamada S, Kameyama T, Nagaya S, Hashizume Y, Yoshida M. Relapsing herpes simplex encephalitis: pathological confirmation of viral reactivation. J Neurol Neurosurg Psychiatry. 2003;74:262–4. 5. Love S, Koch P, Urbach H, Dawson TP. Chronic granulomatous herpes simplex encephalitis in children. J Neuropathol Exp Neurol. 2004;63:1173–81.
Chronic herpes simplex type-1 encephalitis with intractable… 6. Adamo MA, Abraham L, Pollack IF. Chronic granulomatous herpes encephalitis: a rare entity posing a diagnostic challenge. J Neurosurg Pediatr. 2001;8:402–6. 7. Hackney JR, Harrison DK, Rozzelle C, Kankirawatana S, Kankirawatana P, Palmer CA. Chronic granulomatous herpes encephalitis in a child with clinically intractable epilepsy. Case Rep Pediatr. 2012. doi:10.1155/2012/849812. 8. Gleeson JG, duPlessis AJ, Barnes PD, Riviello JJ Jr. Cyclosporin A acute encephalopathy and seizure syndrome in childhood: clinical features and risk of seizure recurrence. J Child Neurol. 1998;13:336–44. 9. Faraci M, Lanino E, Dallorso S, et al. Mesial temporal sclerosis—a late complication in four allogeneic paediatric recipients with persistent seizures after an acute episode of cyclosporine— a neurotoxicity. Bone Marrow Transplant. 2003;31:919–22. 10. Gaggero R, Haupt R, Paola Fondelli M, et al. Intractable epilepsy secondary to cyclosporine toxicity in children undergoing
allogeneic hematopoietic bone marrow transplantation. J Child Neurol. 2006;21:861–6. 11. Hori T, Suzuki T, Terashima Y, Kawai N, Shiraishi H, Koi zumi J. Chronic herpes simplex encephalitis with somnambulism: CT, MR, and SPECT findings. Jpn J Psychiatry Neurol. 1990;44:735–9. 12. Sasaguri H, Sodeyama N, Maejima Y, Kanda T, Mizusawa H. Slowly progressive Foix–Chavany–Marie syndrome associated with chronic herpes simplex encephalitis. J Neurol Neurosurg Psychiatry. 2002;73:202–9. 13. Brown WD, Bearer EL, Donahue JE. Chronic active herpes simplex type 2 encephalitis in an asymptomatic immunocompetent child. J Child Neurol. 2010;25:901–8. 14. Conrady CD, Drevets DA, Carr DJ. Herpes simplex type I (HSV1) infection of the nervous system: is an immune response a good thing? J Neuroimmunol. 2010;220:1–9.
13
