Journal of Neuropathology and Experimental Neurology Copyright q 2004 by the American Association of Neuropathologists

Vol. 63, No. 11 November, 2004 pp. 1173 1181

Chronic Granulomatous Herpes Simplex Encephalitis in Children SETH LOVE, PHD, FRCP, FRCPATH, PHILIPP KOCH, MD, HORST URBACH, MD, TIMOTHY P. DAWSON, PHD, MRCPATH

AND

Abstract. Herpes simplex encephalitis is usually a monophasic acute illness but can cause chronic disease, particularly in children. Little information is available as to the histological substrate. We report the findings in 3 children. In 2 children, herpes encephalitis had occurred during the first 2 years, but both later developed intractable epilepsy that led to neurosurgery. The biopsies showed chronic granulomatous inflammation with foci of mineralization. One child made a good post-operative recovery. The other was found post-operatively to have herpes simplex virus type 1 (HSV-1) DNA and elevated titers of HSV IgM antibodies in the CSF. He was given acyclovir but after initial improvement developed hemiparesis, with extensive signal change on MRI. Repeat biopsy revealed florid granulomatous inflammation with necrosis. The third patient was an infant who had had a cutaneous facial HSV-2 eruption soon after birth. This was treated with topical acyclovir, after which she remained well until 2 months, when she presented with a relatively non-specific illness, developed blisters of the right hand and foot, and died a few days later. Necropsy revealed severe granulomatous encephalitis, most extensive in the temporal lobe and insula, and associated with mineralization. Our findings indicate that herpes simplex encephalitis in children can be complicated by chronic granulomatous inflammation with mineralization. This pattern of disease may be an under-recognized complication of herpes simplex infection during the first few years of life. Key Words: Acyclovir; Calcification; Granulomatous inflammation; Herpes encephalitis; Herpes simplex virus; Mineralization; Multinucleated giant cells.

INTRODUCTION Although herpes simplex encephalitis is usually a monophasic acute disease, a small proportion of patients experiences a clinical deterioration or relapse weeks, months or, very rarely, years after the initial illness (1– 16). In some patients, antiviral therapy may have been administered in too small a dose or discontinued too early, but in most cases the reasons for the relapse are unclear. Viral antigen or DNA has occasionally been detected in the brain or CSF during such relapses (5, 8, 12, 13, 17), and patients may respond to a further course of acyclovir. In other patients, culture, immunohistochemical and PCR studies are negative and because of this a post-infectious immune mechanism has been proposed to explain the delayed clinical deterioration (3, 7). Little information is available as to the pathological substrate of the recrudescent disease. The few published descriptions have mostly been of a necrotizing inflammatory process resembling that of classical acute herpes encephalitis (4, 13, 17). Even less common than relapsing acute encephalitis after herpes simplex infection is the development of a chronic progressive encephalitic illness (11, 18–21). This

From the Department of Neuropathology, Institute of Clinical Neurosciences, Frenchay Hospital (SL), Bristol, United Kingdom; Institute of Reconstructive Neurobiology, University of Bonn Medical Center (PK), Bonn, Germany; Department of Radiology, University Bonn (HU), Bonn, Germany; Neuropathology, Lancashire Teaching Hospitals NHS Trust (TPD), Preston, United Kingdom. Correspondence to: Prof. Seth Love, Department of Neuropathology, Institute of Clinical Neurosciences, Frenchay Hospital, Bristol BS16 1LE, United Kingdom. E-mail: [email protected]

usually manifests with a combination of intractable seizures and progressive neurological deficits. Jay et al (19) described the neuropathologic findings in two such patients: both showed chronic inflammation and gliosis, with extensive mineralization of brain tissue. In addition, the sections of temporal lobe from one of the patients included scattered multinucleated giant cells. Other cases have shown chronic inflammation of the brain parenchyma and leptomeninges, microglial nodules, and astrocytic

Fig. 1. Case 1. Axial (A) and coronal (B) FLAIR fast spin echo MRI (TI 2000 ms, TR 6000 ms, TE 120 ms) along or perpendicular to the long axis of the temporal lobes shows atrophy and high-signal change within the medial part of the left temporal lobe and large defects anteriorly and laterally within the lobe. There is also atrophy of the left insular cortex and atrophy and increased signal in the left cingulate gyrus (arrow). The appearances are highly suggestive of herpes encephalitis.

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Fig. 2. Case 1. (A–C) Clusters of lymphocytes and small, discrete, non-necrotizing granulomas within gliotic cerebral cortex and superficial white matter. Several of the multinucleated giant cells have mineralized cytoplasmic inclusions (arrows). D: The multinucleated giant cells (arrows to some) are strongly immunopositive for the macrophage marker CD68, as are the epithelioid mononuclear macrophages. Bars 5 50 mm.

gliosis (11, 20, 21), but no giant cells or other granulomatous features. We describe 3 children in whom an initial herpes simplex infection was followed months or years later by the development of florid granulomatous encephalitis. MATERIALS AND METHODS Three cases of chronic granulomatous inflammation in patients with herpes simplex virus (HSV) infection that had been referred for assessment were reviewed. Clinical, radiological, and therapeutic records and results of laboratory investigations were retrieved from the case notes, and the paraffin sections and blocks from archives. Paraffin sections were stained using conventional tinctorial methods, and a standard streptavidin-biotin-peroxidase method was used to immunostain sections for the following antigens: CD3 (M7524, DakoCytomation, Ely, UK), CD20 (M755, DakoCytomation), CD45 (M0701, DakoCytomation), CD68 (M0814, DakoCytomation), HIV p24

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capsid protein (NCL-HIVp24, Novocastra Laboratories, Newcastle upon Tyne, UK), HSV-1 (Biogenex PU084-UP, A. Menarini Diagnostics, Wokingham, UK), HSV-2 (B116, DakoCytomation), varicella-zoster virus (VZV) (MAB8612, Chemicon Europe, Chandlers Ford, UK), and cytomegalovirus (CMV) (M757, DakoCytomation).

RESULTS Case 1 This male child was born in 1994 after an uneventful pregnancy. His early development was normal but he developed an encephalitic illness at 18 months. MRI revealed abnormal signal in the left cerebral hemisphere, particularly in the temporal lobe (Fig. 1). HSV was detected in his CSF. He was treated with acyclovir and made a good initial recovery but his subsequent psychomotor development was delayed and from 2 years of age

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he experienced frequent complex-partial seizures (up to 25/day) that failed to respond to medication, which included sodium valproate, carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, and combinations of these. At 6 years he underwent a functional hemispherectomy. A block of left temporal lobe was taken for histology. The specimen measured 13 3 8 3 5 mm. It comprised leptomeninges and cortex and a small amount of superficial white matter. Histology showed the leptomeninges to contain an infiltrate of lymphocytes and macrophages. The cerebral cortex included perivascular and parenchymal clusters of lymphocytes and macrophages, and scattered non-necrotizing granulomas that appeared to be separate from blood vessels (Fig. 2). The granulomas consisted of clusters of epithelioid macrophages and large multinucleated giant cells, surrounded by large numbers of small mononuclear inflammatory cells within which plasma cells were quite prominent. Scattered foci of mineralization were present in the adjacent severely gliotic cortex, and small mineral deposits were noted in some of the giant cells. Some of the foci had the appearance of mineralized neurons. No other cytoplasmic or nuclear inclusions were seen. No foreign material was noted on conventional microscopy, and examination of the sections under polarized light did not reveal any birefringence. Stains for bacteria (including acid-fast bacilli) and fungi were negative, as was immunohistochemistry for HSV-1, HSV-2, VZV, CMV, and HIV. The macrophages and giant cells were strongly immunopositive for CD68. The meningeal lymphocytes were predominantly CD3-positive T cells. Most of the lymphocytes within the granulomas were CD20-positive B cells. Post-operatively, he had a right hemiparesis, but this has since largely resolved. His seizures are much less disabling, being confined to occasional twitching of the left hand. Case 2 This male child was born in 1991 after a normal pregnancy. At 4.5 months he developed herpes encephalitis that caused bitemporal cavitation and atrophy, much more pronounced on the right (Fig. 3). His subsequent psychomotor development was delayed and at 2 years he developed simple and complex partial seizures that did not respond to medical treatment. The seizures were frequently nocturnal (2 to 3 seizures/night) but were sometimes precipitated by sounds (e.g. coughing) or by eating. There was a partial response to clobazam, but none to sodium valproate, carbamazepine, phenobarbital, or combinations of these. In August 2002, aged 10, he underwent surgical resection of the seizure focus in the right temporal lobe. The specimen measured 40 3 40 3 25 mm and included leptomeninges, atrophic cortex, and white matter. Histology showed a patchy cortical and leptomeningeal

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Fig. 3. Case 2. Axial (A) and coronal (B) FLAIR fast spin echo MRI (TI 2000 ms, TR 6000 ms, TE 120 ms) along or perpendicular to the long axis of the temporal lobes shows cystic defects and high-signal change within the medial part and poles of both temporal lobes. The changes are more marked in the right lobe. Both hippocampi appear sclerotic.

infiltrate of lymphocytes, macrophages, microglia, and scattered, well-circumscribed granulomas with central epithelioid macrophages and giant cells, and surrounding lymphocytes, macrophages, and plasma cells (Fig. 4). There was no necrosis. Some of the cortical blood vessels were cuffed by lymphocytes and macrophages but the granulomas appeared to be separate from these blood vessels. Foci of mineralization, some of which appeared to be neuronal, were present in the areas of granulomatous inflammation and small, mineralized deposits were present in some of the giant cells. There were no other abnormal cytoplasmic or nuclear inclusions. The adjacent cortex was severely gliotic and depleted of neurons. Stains for bacteria (including acid-fast bacilli) and fungi were negative, as was immunohistochemistry for HSV-1, HSV-2, VZV, CMV, HIV, and JC virus. Culture and PCR for Mycobacterium tuberculosis and atypical mycobacteria were negative, both on CSF and fresh brain tissue. The giant cells and macrophages were strongly immunopositive for CD68. The lymphocytes comprised a mixture of CD3-positive T cells and CD20-positive B cells, with a preponderance of B cells in the granulomas (Fig. 4). Post-operatively, HSV-1 DNA and elevated titers of HSV IgM antibodies were detected in the CSF. Chest Xrays were normal. He was treated with acyclovir, 200 mg, 3 times daily for 10 days. He made a good post-operative recovery and was free of seizures for the next 2.5 months. However, he then developed a left hemiparesis. MRI showed extensive abnormal signal and edema involving the white matter and overlying cortex in the right occipital, posterior temporal, and parietal regions, with some gyriform enhancement and a cystic ring-enhancing lesion J Neuropathol Exp Neurol, Vol 63, November, 2004

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Fig. 4. Case 2. (A, B) The cortex includes a patchy inflammatory infiltrate of lymphocytes, plasma cells, macrophages, microglia, and scattered, well-circumscribed granulomas. The granulomas contain many epithelioid macrophages and a few multinucleated giant cells. Foci of mineralization (B, arrows to some) are present in the gliotic parenchyma and in some of the epithelioid macrophages and giant cells. In (A), lymphocytes are also visible in the leptomeninges. The lymphocytes comprise a mixture of scattered CD3-positive T cells (C) and, especially within the granulomas, CD20-positive B cells (D). The multinucleated giant cells (arrows) and epithelioid macrophages are strongly immunopositive for CD68 (E). Bars 5 50 mm.

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Fig. 5. Case 2. Repeat MRI 3 months following operation reveals marked edema in the right temporal, occipital, and parietal lobes (A). Coronal T1-weighted spin echo slice following Gd-DTPA administration (TR 560 ms, TE 14 ms) (B) shows some gyriform enhancement and ring-like enhancement adjacent to the trigone of the right lateral ventricle. Fig. 6. Case 2. A: The second biopsy shows more extensive granulomatous inflammation than was present in the first biopsy. Again, there are scattered multinucleated giant cells, some with mineralized cytoplasmic inclusions (arrows). Bar 5 100 mm. B: J Neuropathol Exp Neurol, Vol 63, November, 2004

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adjacent to the trigone of the right lateral ventricle (Fig. 5). He had a further right temporal lobe biopsy in December 2002. The specimen measured 15 3 15 3 5 mm and was yellow in color. Histology revealed granulomatous inflammation, much more severe than in the previous biopsy but again with foci of mineralization and scattered multinucleated giant cells (Fig. 6). Some of the giant cells were very large indeed, containing over 50 nuclei. Although most of the granulomas did not contain necrotic tissue, within the biopsy were several large foci of caseous-looking necrosis, surrounded by an inner zone of epithelioid macrophages and fibroblasts, and an outer zone of lymphocytes, plasma cells, and macrophages, separated by strands of collagen. No foreign material was noted on conventional microscopy or examination of the sections under polarized light. Stains, culture, and PCR for M. tuberculosis and atypical mycobacteria were again negative, as were stains and culture for other bacteria and fungi and for HSV. Nonetheless, he was given 200 mg acyclovir 3 times daily for 3 months, and rifampicin and isoniazid for 9 months. Since the second operation he has been free of seizures and his cognitive performance has improved greatly. At his last follow-up visit, in November 2003, he was running around with very little residual hemiparesis. Case 3 This female child was born in 2002 at 34 weeks’ gestation by normal vaginal delivery, after premature rupture of membranes. On day 11 she developed blisters on her lips and forehead from which herpes simplex type 2 was cultured. Topical acyclovir was applied and she was discharged a few days later, apparently well. At 2 months she was seen by the family physician and seemed well. The following day she started wheezing and was prescribed amoxicillin. A week later she developed blisters of the right hand and foot. She seemed otherwise well and it was thought that the blisters had been caused by an allergic reaction to the penicillin. At the age of 11 weeks, 2 weeks after developing the blisters, she awoke at night and was difficult to settle. She eventually went to sleep lying against her mother, who also fell asleep and who on waking found her daughter dead. Necropsy revealed purulent infection of the middle ears, from which Haemophilus influenzae was cultured.

A mild chronic inflammatory cell infiltrate was present in the pharyngeal mucosa and submucosal tissues. No other abnormalities were detected outside of the CNS. The brain weighed 507 g and was fixed by suspension in formalin. Examination after fixation showed the left temporal lobe to be softened and severely atrophic (Fig. 7). Less extensive cavitation and collapse were present in the left insula, right temporal lobe, left caudate nucleus, and both occipital lobes. Histology confirmed the extensive destruction and cavitation of the macroscopically abnormal regions, with associated perivascular and parenchymal infiltration of the brain parenchyma and overlying leptomeninges by T- and B-lymphocytes and macrophages, and widespread mineralization (Fig. 8). The mineralization took the form of large clusters of particulate material, some of which conformed in shape to neurons and their processes. A striking feature was the presence of many multinucleated giant cells. In places, these were associated with mononuclear epithelioid macrophages and lymphocytes to form circumscribed granulomas. The giant cells were particularly numerous in areas of cellular mineralization and some contained fragments of mineralized material. No other abnormal inclusion bodies were identified. However, immunohistochemistry revealed HSV-2 antigen within scattered macrophages and possibly astrocytes in the abnormal tissue. Immunohistochemistry for HSV-1, CMV, VZV, and HIV was negative. DISCUSSION Present findings indicate that herpes simplex infection of the CNS can take the form of chronic granulomatous encephalitis. In two of the patients there was a clear history of herpes simplex encephalitis several years previously. In the third, a neonate, both the initial and the recurrent infection seemed clinically to be solely cutaneous, but the extensive cavitation and mineralization within the brain indicate that the CNS had been infected some weeks prior to death. The ages of the 3 patients are in keeping with previous reports of relapsing or chronic herpes encephalitis in that most patients have been children and several have been infected during the neonatal period. Prematurity is a wellrecognized risk factor for neonatal herpes encephalitis (22, 23) and it is therefore of note that case 3 was delivered at 34 weeks’ gestation after premature rupture of

← Very large multinucleated giant cell within the granulomatous inflammatory infiltrate. Bar 5 50 mm. C: Focus of necrosis (arrows) surrounded by an inner zone of epithelioid macrophages and fibroblasts, and an outer zone of lymphocytes, plasma cells, and macrophages. Bar 5 50 mm. Fig. 7. Case 3. A: External examination of the inferior surface of the fixed brain shows the left temporal lobe (arrows) to have a collapsed appearance. B: A coronal slice through the brain confirms the marked atrophy of the left temporal lobe (arrow), which was reduced to a shriveled strip of gelatinous tissue.

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Fig. 8. Case 3. Low-magnification photomicrographs of the left temporal lobe (A) and insula (B). In affected parts of the brain the white matter is cavitated and the cortex reduced to a layer of gliotic inflammatory tissue containing numerous foci of mineralization. Note the abrupt transition in (B) between an abnormal gyrus (to the left) and a relatively preserved adjacent gyrus (to the right). Bars 5 625 mm. At higher magnification, one can resolve scattered multinucleated giant cells within the residual tissue in the temporal lobe (C) and insula (D). Also visible are the fragments of mineralized tissue (arrows). Some of this appears to be extracellular, some (e.g. arrow in D) is within multinucleated giant cells, and some, particularly in the insula, is associated with capillaries. (E, F) Antibody to HSV-2 labels a few cells (arrows) most of which appear to be macrophages although a few may be astrocytes. The multinucleated giant cells (E) are unlabeled.

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membranes. The mother had no clinical evidence of active genital herpetic disease but in most cases the maternal infection is subclinical (22–24). The distinctive feature of the 3 cases in this series was the granulomatous nature of the cerebral inflammation. As in the patient described by Jay et al (19), the granulomas were associated with foci of mineralization in the adjacent brain tissue, many having the appearance of mineralized neurons or glia. Mineralized cytoplasmic inclusions within giant cells were a prominent finding in all of our cases, raising the possibility that the formation of granulomas may be a reaction to the mineralization. A granulomatous process with some similarity to that in the present series occasionally occurs as a reaction to mineralization of Bowman’s layer in patients with herpetic keratitis (25). However, although this may explain the granulomatous inflammation, it seems less likely to account for the necrosis that developed after the second biopsy in case 2. The pathogenesis of this latter process, which resembled the sort of necrotizing granulomatous inflammation more usually associated with tuberculous or fungal infection, remains unclear. In Case 2, the initial neurosurgery may have caused reactivation of HSV infection within the brain, as evidenced by the presence of HSV-1 DNA and elevated titers of HSV IgM antibodies in the CSF. HSV-1 DNA is demonstrable within the brain long after herpes encephalitis (26, 27). At very low levels, HSV-1 DNA can be found in the CNS even in some people without a history of encephalitis (28, 29). Although the biological significance of HSV-1 DNA in the brain of adults without a history of encephalitis is still unclear (30), reactivation or exacerbation of HSV infection within the CNS has been described in several patients with previous typical herpes encephalitis. In some of these, as possibly in our patient, reactivation was precipitated by surgery for epilepsy (13, 31, 32). In view of this rare but potentially serious complication of neurosurgery, it has been suggested that prophylactic administration of acyclovir should be considered prior to neurosurgical intervention in patients with a history of herpes encephalitis (31). In conclusion, our findings indicate that herpes simplex encephalitis can be complicated by the development of chronic granulomatous inflammation associated with prominent mineralization. Clinicians should be aware of the pathological spectrum of neurologic disease in patients with previous herpes encephalitis and should consider prophylactic administration of acyclovir prior to neurosurgery in such patients, particularly when the initial encephalitis occurred in early childhood. REFERENCES 1. Dankner WM, Spector SA. Recurrent herpes simplex in a neonate. Pediatr Infect Dis 1986;5:582–86

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