e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 4 1 6 e4 1 9
Official Journal of the European Paediatric Neurology Society
Case study
HemiconvulsioneHemiplegiaeEpilepsy syndrome associated with inflammatory-degenerative hystopathological findings in child with congenital adrenal hyperplasia Domenico Serino a,*, Francesca Diomedi Camassei b, Olivier Delalande c, Carlo E. Marras c, Nicola Specchio a, Federico Vigevano a, Lucia Fusco a a
Neurology Unit, Bambino Gesu` Children’s Hospital, Rome, Italy Pathology Unit, Bambino Gesu` Children’s Hospital, Rome, Italy c Neurosurgery Unit, Bambino Gesu` Children’s Hospital, Rome, Italy b
article info
abstract
Article history:
HemiconvulsioneHemiplegia (HH) syndrome represents an uncommon consequence of
Received 25 July 2013
prolonged unilateral clonic or hemiconvulsive status epilepticus in childhood, usually
Received in revised form
occurring during a febrile illness, followed by ipsilateral hemiplegia. The subsequent
16 October 2013
appearance of focal seizures configures the so called HemiconvulsioneHemiplegiaeEpilepsy
Accepted 1 November 2013
(HHE) syndrome. The pathogenesis of HH/HHE syndrome is still unclear. We describe the case of a 4 year-old girl with congenital adrenal hyperplasia (CAH) whom developed HH/HHE
Keywords:
syndrome with drug resistant seizures at the age of 21 months and underwent left cerebral
HemiconvulsioneHemiplegia
hemispherotomy at the age of 3 years and 6 months. Histopathological findings showed the
eEpilepsy
presence of an underlying inflammatory-degenerative process. Disregulation of the in-
Congenital adrenal hyperplasia
flammatory cascade has been proposed as one of the possible pathogenetic mechanisms
Inflammation
underlying HH/HHE syndrome. To our knowledge however, this is the first report of an association with a histologically documented inflammatory process. The clinical and histopathological findings of our reported case lend support to the possible role of inflammation in the pathogenesis of HH/HHE syndrome. ª 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
1.
Introduction
HemiconvulsioneHemiplegia (HH) syndrome, represents an uncommon consequence of prolonged unilateral clonic or hemiconvulsive status epilepticus in childhood, usually
occurring during a febrile illness, followed by ipsilateral hemiplegia. In the acute phase, seizures are characterized by long-lasting hemiclonic seizures with variable topography, inconsistent impairment of consciousness, onset variability and presence of autonomic symptoms, associated with
* Corresponding author. P.zza S. Onofrio 4, 00165 Rome, Italy. Tel.: þ39 0668592731; fax: þ39 0668592463. E-mail addresses: [email protected], [email protected] (D. Serino). 1090-3798/$ e see front matter ª 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejpn.2013.11.001
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 4 1 6 e4 1 9
controlateral rhythmical slow waves at the EEG, sometimes also present, with inferior amplitude, on the ipsilateral hemisphere.1 A stable hemispheric global atrophy follows the acute phase, while focal seizures appear after a period which may be as brief as one month but can last several years depending on the reporting author,1 configuring the so called HemiconvulsioneHemiplegiaeEpilepsy (HHE) syndrome. This phase is mainly characterized by complex partial seizures originating from the temporal lobe, sometimes accompanied by focal motor seizures and/or generalized seizures. The pathogenesis of HH/HHE syndrome is still a matter of debate. So far, the proposed pathogenetic models pointed towards neuronal injury induced by excitotoxicity and/or venous thrombosis,1 however in many patients no cause is obvious and reports on histopathological findings are scarce.2 Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease characterized by impairment of cortisol biosynthesis. The association between CAH and HH/HHE syndrome has been previously reported and a possible link with inflammatory mechanisms has been proposed, however no histopathological evidence supporting such hypothesis was so far available. We describe the clinical characteristics and histopathological findings of a 4 year old girl with CAH whom developed HH/HHE syndrome.
417
evolved towards a stable hemiparesis. After two months the child developed drug-resistant right-sided hemiclonic seizures. Different combinations of antiepileptic drugs (phenitoine and phenobarbital, valproic acid and phenobarbital, valproic acid and levetiracetam, valproic acid and ethosuximide) proved ineffective. EEG at this time showed persisting left-sided depressed background activity associated with multifocal epileptiform anomalies over the left centraleparietal area with controlateral diffusion. A two month seizure free period was later obtained with a 3 day cycle of glucocorticoids. After such period seizures reappeared. They were characterized by clusters of atonic seizures, multiple daily episodes of right upper limb myoclonias or sleep related right-sided tonic seizures. Clobazam was added to valproic acid and ethosuximide, but was ineffective. Serial magnetic resonance scans showed stable atrophy of the left hemisphere (Fig. 1).
2.3.
Presurgical evaluation and follow-up after surgery
N.D. is a 4 year old Caucasian girl with no family history of epilepsy or febrile convulsions. She was born at term. Pregnancy was complicated by threat of miscarriage during the 7th gestational month. At birth, evidence of a hypertrophic clitoris prompted an endocrinological evaluation. Ultrasonography showed hypertrophic surrenal glands. Diagnosis of CAH was made at day 10 and replacement therapy with glucocorticoids was initiated. Corrective surgery of clitoris was performed at age 9 months. Psychomotor development was normal.
N.D. first came to our attention at age 3. Video-EEG monitoring showed asymmetrical background activity, characterized by normal organization of the right hemisphere and by slow thetaedelta rhythms of lower voltage over the left hemisphere. Interictal activity during wake was characterized by asynchronous and arrhythmic medium-voltage spikes over the left hemisphere, which sometimes gave way to brief trains of slow spike-wave complexes at 1 Hz. During sleep, frequent brief trains of polyspike-wave complexes were recorded over the left parietaletemporal area (Fig. 1). Ictal EEG showed brief rhythmic sequences of medium voltage spikes at 8 Hz over the left centraleparietaletemporal area lasting 4e8 s, clinically correlated with right facial and upper limb hypertonus. Neuropsychological testing revealed mild cognitive delay. The child underwent left cerebral hemispherotomy at the age of 3 years and 6 months. Bioptic material was obtained from a left frontal corticectomy. To date, after a 6 month follow-up period, the child is seizure free and undergoing neurorehabilitation. Antiepileptic drug treatment is being gradually withdrawn.
2.2.
2.4.
2.
Case report
2.1.
History of CAH
Acute phase and onset of HHE
Seizure onset was triggered by a febrile episode associated with diarrhea and vomit, at 21 months, and was characterized by right-sided hemiclonic status epilepticus (SE) followed by transitory homolateral hemiplegia. Electroencephalogram (EEG) showed asymmetrical background activity with leftsided depression and sharp waves over the frontal electrodes. The SE lasted several hours and was treated with midazolam, phenobarbital and phenytoin. During the acute phase, brain magnetic resonance with spectroscopy showed cytotoxic edema of the left hemisphere and a peak in lactate levels. Screening for Rotavirus infection was positive in blood and serum, but not in cerebral spinal fluid (CSF). CSF screening (physicalechemical analysis, viral DNA for HSV1, HSV2, HHV6, HHV8, VZV, CMV, EBV, viral RNA for enterovirus) was negative. She was discharged after 5 days of prolonged fever with phenobarbital and phenitoine oral therapy. At discharge, she showed right-sided hemiplegia which progressively
Histopathology
The surgical specimen consisted of a frontal lobe sample of 3.5 2.5 1.5 cm in dimension. The arachnoid membrane was thickened and the parenchyma was edematous. Microscopic evaluation showed a dense inflammatory lymphomonocytic infiltrate of the arachnoid and of the subarachnoidal space with several clusters of perivascular monocytes (anti-CD68 10) (Fig. 1). The cortical tissue was characterized by preservation of the laminar structure, mild increase in glial cells and focal satellitosis. Scattered neurons showed cytoplasmic shrinkage, dismorphism and pyknosis. The cortical-white matter junction was sharp. The white matter presented inflammatory and degenerative features (EE 10 e EE 20) (Fig. 1) characterized by presence of diffuse foamy macrophages, microglial activation, spongiosis and moderate lymphoid infiltration, with perivascular distribution (CD4 20) (Fig. 1). Immunophenotyping showed a mixed population composed of macrophages (50%), T-lymphocytes (30%, with mild
418
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 4 1 6 e4 1 9
Fig. 1 e [A] T2 weighted MRI, coronal plane, no contrast material. Sequence showing significant atrophy of the left hemisphere. [B] EEG recording of interictal activity during phase 2 NREM sleep. Gain 70 uV/mm, timescale 30 s/page. The right hemisphere presents physiological medium voltage thetaedelta background activity, with evident sleep spindles. The left hemisphere presents depressed background activity associated with medium voltage spikes and sharp waves, more evident in the parieto-temporal area. [C] Anti-CD68 immunostaining, 103: Several clusters of perivascular monocytes are evidentiated in lymphomonocytic infiltrate of the meninge. [D] EE staining, 203: presence of diffuse foamy macrophages, microglia activation and spongiosis of the white matter. Perivascular space showed edema and moderate inflammatory infiltrate. [E] Anti-CD4 immunostaining, 203: mild prevalence of CD4-positive cells (T-helper lynphocytes) in perivascular mixed inflammatory population of white matter.
preponderance of CD4þ T-helper compared to CD8þ T-suppressor cells) and B-lymphocytes (20%). Sporadic plasma cells were detected. Vessels were congested and a perivascular edema was present. In order to compare such findings to a control group, we reviewed the data relative to the bioptic specimens taken from five patients with drug resistant epilepsy who underwent hemispherotomy. Epilepsy was secondary to cortical malformation in two patients, to stroke in two patients and to hemimegalenchephaly in one. The arachnoid membrane showed signs of vascular congestion in the patient with hemimegalenchephaly and in one patient with stroke. Alterations of lamination and thickening of cortical layers were found in the patient with hemimegalenchephaly, in one patient with cortical malformation and in one patient with stroke, while the parenchymal architecture appeared preserved in the remaining two cases. Neuronal cells were dismorphic in two cases. Signs of reactive gliosis were found in two cases. In none of the specimens significant inflammatory features were found.
3.
Discussion
In a recent paper, Auvin et al. reviewed the etiologies of 13 reported cases of HH/HHE published in the last 20 years.2 One
had an SCN1A mutation, one a CACNA1A mutation, while the other 11 were reported as idiopathic HH/HHE (IHHS). In a recent review, Nabbout placed IHHS among the so-called “inflammatory epilepsies”, for which an inflammatory pathogenetic mechanism is strongly hypothesized.3 Several elements give credit to this hypothesis, such as the trigger effect played by fever and the influence of amplification or downregulation of the pro-inflammatory cascade on seizures. This said however, among the few published neuropathological findings in relation to IHHS,4e7 our case is the first in which an inflammatory process is histologically documented. The postmortem specimens reported by Mori showed diffuse ipsilateral cortical scarring in the laminae,4 while Auvin reported ipsilateral spongiosis and edema, with axonal damage in the right thalamus5; spongiosis and edema were also reported for Berhouma’s bipotic specimen,6 while a recent work by Jayakodi documented edema, pallor and vacuolation of neurons, neuronal shrinkage with cytoplasmic eosinophilia and nuclear pyknosis.7 The hystopathological evidence obtained from the bioptic specimens of our limited control group, led us to consider seizures as an unlikely cause of the inflammatory findings. Moreover, while a direct role of rotavirus infection in the occurrence of seizures has been supported by different studies8,9 and in both our and other reported cases of HHE10 may have contributed in triggering seizures, negative CSF screening for Rotavirus led us to believe that cerebral infection
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 4 1 6 e4 1 9
would also be an unlikely cause of inflammation. Whether or not the unique nature of our findings may be due to the scarce amount of histopathological data available so far is unclear. However, we discuss the possibility that the peculiar association with CAH may have rendered visible an inflammatory process which is usually limited in time and thus not easily detectable. While the association between CAH and central nervous system (CNS) anomalies such as subclinical whitematter lesions has already been reported,11 to our knowledge there is only one other report of association between CAH and IHHS.12 In such report, the authors hypothesize that endogenous or supplemented glucocorticoids may be insufficient in regulating pro-inflammatory cytokines in some CAH patients and that consequently corticosteroid insufficiency may trigger acute encephalopathy. In this account, it may be possible that the negative feedback exercised by exogenous glucocorticoids on the release and consequent direct immunomodulatory effect of corticotrophin-releasing hormone may contribute in perpetrating an ongoing inflammatory process or maybe act as trigger. This said, it is still of notice that the majority of patients with CAH never develop an acute encephalopathy. A possible explanation discussed by Lee et al.12 is the association between disregulation of the inflammatory process and a genetic predisposition, as supported by the reported higher incidence of the aforesaid combination of CAH and acute encephalopathy found in the Japanese population. Such data seems consistent with a recent work by Shinohara et al. conducted among Japanese patients, in which a variation in the adenosine A2A receptor has been reported as being associated with acute encephalopathy with biphasic seizures and late reduced diffusion.13 In such a light, it may be hypothesized that events such as fever may trigger neuro-modulating processes related to the inflammation cascade which are self-limited and normally harmless. In genetically predisposed subjects, there may be a disregulation of such processes which gives way to a dysfunctional inflammatory response and triggers a vicious circle which eventually leads to IHHS. We believe however, that even in these circumstances inflammation is still a selflimited event. This might explain why, even though the characteristics of IHHS strongly point towards an inflammatory pathogenetic mechanism, no histopathological evidence of inflammation has yet been reported. In our case however, the peculiar conditions associated with CAH may have allowed a normally acute, self-limiting process to acquire the characteristics of a chronic phenomena, thus still visible even after a long time. For this reason, we believe that the clinical and histopathological findings of our reported case lend sup-
419
port to the possible role of inflammation in the pathogenesis of IHHS syndrome.
references
1. Chauvel P, Dravet C. The HHE syndrome. In: Roger J, Bureau M, Dravet C, Genton P, Tassinari C, Wolf P, editors. Epileptic syndromes in infancy, childhood and adolescence. Montrouge: Libbey Eurotext; 2005. pp. 277e93. 2. Auvin S, Bellavoine V, Merdariu D, Delanoe¨ C, ElmalehBerge´s M, Gressens P, et al. Hemiconvulsion-hemiplegiaepilepsy syndrome: current understandings. Eur J Paediatr Neurol EJPN Off J Eur Paediatr Neurol Soc 2012 Sep;16(5):413e21. 3. Nabbout R. Autoimmune and inflammatory epilepsies. Epilepsia 2012 Sep;53(Suppl. 4):58e62. 4. Mori Y. Anatomopathology and pathogeny of the hemiconvulsion-hemiplegia-epilepsy syndrome. Part I. J Neurosurg Sci 1978;22(1):17e28. 5. Auvin S, Devisme L, Maurage CA, Soto-Ares G, Cuisset JM, Leclerc F, et al. Neuropathological and MRI findings in an acute presentation of hemiconvulsion-hemiplegia: a report with pathophysiological implications. Seizure J Br Epilepsy Assoc 2007 Jun;16(4):371e6. 6. Berhouma M, Chekili R, Brini I, Kchir N, Jemel H, Bousnina S, et al. Decompressive hemicraniectomy in a space-occupying presentation of hemiconvulsion-hemiplegia-epilepsy syndrome. Clin Neurol Neurosurg 2007 Dec;109(10):914e7. 7. Jayakody H, Joshi C. Fatal outcome in hemiconvulsionhemiplegia syndrome. J Child Neurol 2012 Dec 26:1e6. http:// dx.doi.org/10.1177/0883073812469053. 8. Iyadurai S, Troester M, Harmala J, Bodensteiner J. Benign afebrile seizures in acute gastroenteritis: is rotavirus the culprit? J Child Neurol 2007 Jul;22(7):887e90. 9. Ben-Ami T, Sinai L, Granot E. Afebrile seizures and rotavirus gastroenteritis: an infrequently recognized association. Clin Pediatr 2007 Mar;46(2):178e80. 10. Sakakibara T, Nakagawa E, Saito Y, Sakuma H, Komaki H, Sugai K, et al. Hemiconvulsion-hemiplegia syndrome in a patient with severe myoclonic epilepsy in infancy. Epilepsia 2009 Sep;50(9):2158e62. 11. Nass R, Heier L, Moshang T, Oberfield S, George A, New MI, et al. Magnetic resonance imaging in the congenital adrenal hyperplasia population: increased frequency of white-matter abnormalities and temporal lobe atrophy. J Child Neurol 1997 Apr;12(3):181e6. 12. Lee S, Sanefuji M, Watanabe K, Uematsu A, Torisu H, Baba H, et al. Clinical and MRI characteristics of acute encephalopathy in congenital adrenal hyperplasia. J Neurol Sci 2011 Jul 15;306(1e2):91e3. 13. Shinohara M, Saitoh M, Nishizawa D, Ikeda K, Hirose S, Takanashi J-I, et al. ADORA2A polymorphism predisposes children to encephalopathy with febrile status epilepticus. Neurology 2013 Apr 23;80(17):1571e6.
Official Journal of the European Paediatric Neurology Society
Case study
HemiconvulsioneHemiplegiaeEpilepsy syndrome associated with inflammatory-degenerative hystopathological findings in child with congenital adrenal hyperplasia Domenico Serino a,*, Francesca Diomedi Camassei b, Olivier Delalande c, Carlo E. Marras c, Nicola Specchio a, Federico Vigevano a, Lucia Fusco a a
Neurology Unit, Bambino Gesu` Children’s Hospital, Rome, Italy Pathology Unit, Bambino Gesu` Children’s Hospital, Rome, Italy c Neurosurgery Unit, Bambino Gesu` Children’s Hospital, Rome, Italy b
article info
abstract
Article history:
HemiconvulsioneHemiplegia (HH) syndrome represents an uncommon consequence of
Received 25 July 2013
prolonged unilateral clonic or hemiconvulsive status epilepticus in childhood, usually
Received in revised form
occurring during a febrile illness, followed by ipsilateral hemiplegia. The subsequent
16 October 2013
appearance of focal seizures configures the so called HemiconvulsioneHemiplegiaeEpilepsy
Accepted 1 November 2013
(HHE) syndrome. The pathogenesis of HH/HHE syndrome is still unclear. We describe the case of a 4 year-old girl with congenital adrenal hyperplasia (CAH) whom developed HH/HHE
Keywords:
syndrome with drug resistant seizures at the age of 21 months and underwent left cerebral
HemiconvulsioneHemiplegia
hemispherotomy at the age of 3 years and 6 months. Histopathological findings showed the
eEpilepsy
presence of an underlying inflammatory-degenerative process. Disregulation of the in-
Congenital adrenal hyperplasia
flammatory cascade has been proposed as one of the possible pathogenetic mechanisms
Inflammation
underlying HH/HHE syndrome. To our knowledge however, this is the first report of an association with a histologically documented inflammatory process. The clinical and histopathological findings of our reported case lend support to the possible role of inflammation in the pathogenesis of HH/HHE syndrome. ª 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
1.
Introduction
HemiconvulsioneHemiplegia (HH) syndrome, represents an uncommon consequence of prolonged unilateral clonic or hemiconvulsive status epilepticus in childhood, usually
occurring during a febrile illness, followed by ipsilateral hemiplegia. In the acute phase, seizures are characterized by long-lasting hemiclonic seizures with variable topography, inconsistent impairment of consciousness, onset variability and presence of autonomic symptoms, associated with
* Corresponding author. P.zza S. Onofrio 4, 00165 Rome, Italy. Tel.: þ39 0668592731; fax: þ39 0668592463. E-mail addresses: [email protected], [email protected] (D. Serino). 1090-3798/$ e see front matter ª 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejpn.2013.11.001
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 4 1 6 e4 1 9
controlateral rhythmical slow waves at the EEG, sometimes also present, with inferior amplitude, on the ipsilateral hemisphere.1 A stable hemispheric global atrophy follows the acute phase, while focal seizures appear after a period which may be as brief as one month but can last several years depending on the reporting author,1 configuring the so called HemiconvulsioneHemiplegiaeEpilepsy (HHE) syndrome. This phase is mainly characterized by complex partial seizures originating from the temporal lobe, sometimes accompanied by focal motor seizures and/or generalized seizures. The pathogenesis of HH/HHE syndrome is still a matter of debate. So far, the proposed pathogenetic models pointed towards neuronal injury induced by excitotoxicity and/or venous thrombosis,1 however in many patients no cause is obvious and reports on histopathological findings are scarce.2 Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease characterized by impairment of cortisol biosynthesis. The association between CAH and HH/HHE syndrome has been previously reported and a possible link with inflammatory mechanisms has been proposed, however no histopathological evidence supporting such hypothesis was so far available. We describe the clinical characteristics and histopathological findings of a 4 year old girl with CAH whom developed HH/HHE syndrome.
417
evolved towards a stable hemiparesis. After two months the child developed drug-resistant right-sided hemiclonic seizures. Different combinations of antiepileptic drugs (phenitoine and phenobarbital, valproic acid and phenobarbital, valproic acid and levetiracetam, valproic acid and ethosuximide) proved ineffective. EEG at this time showed persisting left-sided depressed background activity associated with multifocal epileptiform anomalies over the left centraleparietal area with controlateral diffusion. A two month seizure free period was later obtained with a 3 day cycle of glucocorticoids. After such period seizures reappeared. They were characterized by clusters of atonic seizures, multiple daily episodes of right upper limb myoclonias or sleep related right-sided tonic seizures. Clobazam was added to valproic acid and ethosuximide, but was ineffective. Serial magnetic resonance scans showed stable atrophy of the left hemisphere (Fig. 1).
2.3.
Presurgical evaluation and follow-up after surgery
N.D. is a 4 year old Caucasian girl with no family history of epilepsy or febrile convulsions. She was born at term. Pregnancy was complicated by threat of miscarriage during the 7th gestational month. At birth, evidence of a hypertrophic clitoris prompted an endocrinological evaluation. Ultrasonography showed hypertrophic surrenal glands. Diagnosis of CAH was made at day 10 and replacement therapy with glucocorticoids was initiated. Corrective surgery of clitoris was performed at age 9 months. Psychomotor development was normal.
N.D. first came to our attention at age 3. Video-EEG monitoring showed asymmetrical background activity, characterized by normal organization of the right hemisphere and by slow thetaedelta rhythms of lower voltage over the left hemisphere. Interictal activity during wake was characterized by asynchronous and arrhythmic medium-voltage spikes over the left hemisphere, which sometimes gave way to brief trains of slow spike-wave complexes at 1 Hz. During sleep, frequent brief trains of polyspike-wave complexes were recorded over the left parietaletemporal area (Fig. 1). Ictal EEG showed brief rhythmic sequences of medium voltage spikes at 8 Hz over the left centraleparietaletemporal area lasting 4e8 s, clinically correlated with right facial and upper limb hypertonus. Neuropsychological testing revealed mild cognitive delay. The child underwent left cerebral hemispherotomy at the age of 3 years and 6 months. Bioptic material was obtained from a left frontal corticectomy. To date, after a 6 month follow-up period, the child is seizure free and undergoing neurorehabilitation. Antiepileptic drug treatment is being gradually withdrawn.
2.2.
2.4.
2.
Case report
2.1.
History of CAH
Acute phase and onset of HHE
Seizure onset was triggered by a febrile episode associated with diarrhea and vomit, at 21 months, and was characterized by right-sided hemiclonic status epilepticus (SE) followed by transitory homolateral hemiplegia. Electroencephalogram (EEG) showed asymmetrical background activity with leftsided depression and sharp waves over the frontal electrodes. The SE lasted several hours and was treated with midazolam, phenobarbital and phenytoin. During the acute phase, brain magnetic resonance with spectroscopy showed cytotoxic edema of the left hemisphere and a peak in lactate levels. Screening for Rotavirus infection was positive in blood and serum, but not in cerebral spinal fluid (CSF). CSF screening (physicalechemical analysis, viral DNA for HSV1, HSV2, HHV6, HHV8, VZV, CMV, EBV, viral RNA for enterovirus) was negative. She was discharged after 5 days of prolonged fever with phenobarbital and phenitoine oral therapy. At discharge, she showed right-sided hemiplegia which progressively
Histopathology
The surgical specimen consisted of a frontal lobe sample of 3.5 2.5 1.5 cm in dimension. The arachnoid membrane was thickened and the parenchyma was edematous. Microscopic evaluation showed a dense inflammatory lymphomonocytic infiltrate of the arachnoid and of the subarachnoidal space with several clusters of perivascular monocytes (anti-CD68 10) (Fig. 1). The cortical tissue was characterized by preservation of the laminar structure, mild increase in glial cells and focal satellitosis. Scattered neurons showed cytoplasmic shrinkage, dismorphism and pyknosis. The cortical-white matter junction was sharp. The white matter presented inflammatory and degenerative features (EE 10 e EE 20) (Fig. 1) characterized by presence of diffuse foamy macrophages, microglial activation, spongiosis and moderate lymphoid infiltration, with perivascular distribution (CD4 20) (Fig. 1). Immunophenotyping showed a mixed population composed of macrophages (50%), T-lymphocytes (30%, with mild
418
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 4 1 6 e4 1 9
Fig. 1 e [A] T2 weighted MRI, coronal plane, no contrast material. Sequence showing significant atrophy of the left hemisphere. [B] EEG recording of interictal activity during phase 2 NREM sleep. Gain 70 uV/mm, timescale 30 s/page. The right hemisphere presents physiological medium voltage thetaedelta background activity, with evident sleep spindles. The left hemisphere presents depressed background activity associated with medium voltage spikes and sharp waves, more evident in the parieto-temporal area. [C] Anti-CD68 immunostaining, 103: Several clusters of perivascular monocytes are evidentiated in lymphomonocytic infiltrate of the meninge. [D] EE staining, 203: presence of diffuse foamy macrophages, microglia activation and spongiosis of the white matter. Perivascular space showed edema and moderate inflammatory infiltrate. [E] Anti-CD4 immunostaining, 203: mild prevalence of CD4-positive cells (T-helper lynphocytes) in perivascular mixed inflammatory population of white matter.
preponderance of CD4þ T-helper compared to CD8þ T-suppressor cells) and B-lymphocytes (20%). Sporadic plasma cells were detected. Vessels were congested and a perivascular edema was present. In order to compare such findings to a control group, we reviewed the data relative to the bioptic specimens taken from five patients with drug resistant epilepsy who underwent hemispherotomy. Epilepsy was secondary to cortical malformation in two patients, to stroke in two patients and to hemimegalenchephaly in one. The arachnoid membrane showed signs of vascular congestion in the patient with hemimegalenchephaly and in one patient with stroke. Alterations of lamination and thickening of cortical layers were found in the patient with hemimegalenchephaly, in one patient with cortical malformation and in one patient with stroke, while the parenchymal architecture appeared preserved in the remaining two cases. Neuronal cells were dismorphic in two cases. Signs of reactive gliosis were found in two cases. In none of the specimens significant inflammatory features were found.
3.
Discussion
In a recent paper, Auvin et al. reviewed the etiologies of 13 reported cases of HH/HHE published in the last 20 years.2 One
had an SCN1A mutation, one a CACNA1A mutation, while the other 11 were reported as idiopathic HH/HHE (IHHS). In a recent review, Nabbout placed IHHS among the so-called “inflammatory epilepsies”, for which an inflammatory pathogenetic mechanism is strongly hypothesized.3 Several elements give credit to this hypothesis, such as the trigger effect played by fever and the influence of amplification or downregulation of the pro-inflammatory cascade on seizures. This said however, among the few published neuropathological findings in relation to IHHS,4e7 our case is the first in which an inflammatory process is histologically documented. The postmortem specimens reported by Mori showed diffuse ipsilateral cortical scarring in the laminae,4 while Auvin reported ipsilateral spongiosis and edema, with axonal damage in the right thalamus5; spongiosis and edema were also reported for Berhouma’s bipotic specimen,6 while a recent work by Jayakodi documented edema, pallor and vacuolation of neurons, neuronal shrinkage with cytoplasmic eosinophilia and nuclear pyknosis.7 The hystopathological evidence obtained from the bioptic specimens of our limited control group, led us to consider seizures as an unlikely cause of the inflammatory findings. Moreover, while a direct role of rotavirus infection in the occurrence of seizures has been supported by different studies8,9 and in both our and other reported cases of HHE10 may have contributed in triggering seizures, negative CSF screening for Rotavirus led us to believe that cerebral infection
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 4 1 6 e4 1 9
would also be an unlikely cause of inflammation. Whether or not the unique nature of our findings may be due to the scarce amount of histopathological data available so far is unclear. However, we discuss the possibility that the peculiar association with CAH may have rendered visible an inflammatory process which is usually limited in time and thus not easily detectable. While the association between CAH and central nervous system (CNS) anomalies such as subclinical whitematter lesions has already been reported,11 to our knowledge there is only one other report of association between CAH and IHHS.12 In such report, the authors hypothesize that endogenous or supplemented glucocorticoids may be insufficient in regulating pro-inflammatory cytokines in some CAH patients and that consequently corticosteroid insufficiency may trigger acute encephalopathy. In this account, it may be possible that the negative feedback exercised by exogenous glucocorticoids on the release and consequent direct immunomodulatory effect of corticotrophin-releasing hormone may contribute in perpetrating an ongoing inflammatory process or maybe act as trigger. This said, it is still of notice that the majority of patients with CAH never develop an acute encephalopathy. A possible explanation discussed by Lee et al.12 is the association between disregulation of the inflammatory process and a genetic predisposition, as supported by the reported higher incidence of the aforesaid combination of CAH and acute encephalopathy found in the Japanese population. Such data seems consistent with a recent work by Shinohara et al. conducted among Japanese patients, in which a variation in the adenosine A2A receptor has been reported as being associated with acute encephalopathy with biphasic seizures and late reduced diffusion.13 In such a light, it may be hypothesized that events such as fever may trigger neuro-modulating processes related to the inflammation cascade which are self-limited and normally harmless. In genetically predisposed subjects, there may be a disregulation of such processes which gives way to a dysfunctional inflammatory response and triggers a vicious circle which eventually leads to IHHS. We believe however, that even in these circumstances inflammation is still a selflimited event. This might explain why, even though the characteristics of IHHS strongly point towards an inflammatory pathogenetic mechanism, no histopathological evidence of inflammation has yet been reported. In our case however, the peculiar conditions associated with CAH may have allowed a normally acute, self-limiting process to acquire the characteristics of a chronic phenomena, thus still visible even after a long time. For this reason, we believe that the clinical and histopathological findings of our reported case lend sup-
419
port to the possible role of inflammation in the pathogenesis of IHHS syndrome.
references
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