104
Cerebromeningeal haemophagocytic lymphohistiocytosis We describe 3 children with a progressive encephalopathy that was characterised by irritability, convulsions, cranial nerve palsies, ataxia, nystagmus,
difficulties, delayed walking psychomotor visual hemiplegia/tetraplegia, development, neck and nondisturbance, vomiting, stiffness, specific signs of raised intracranial pressure. A final diagnosis was made in all 3 patients from necropsy material. The clinical features
were
ascribed to
multiple inflammatory, predominantly lymphocytic, reactions and raised intracranial pressure. This condition is an atypical form of haemophagocytic lymphohistiocytosis, which normally presents with fever, hepatosplenomegaly, and cytopenias. By contrast, the disease pattern in our 3 children was dominated by cerebromeningeal involvement, which can precede the typical systemic symptoms of An haemophagocytic lymphohistiocytosis. awareness of this condition is important because treatments are available.
Introduction Childhood disorders of the central nervous system (CNS) have many causes. A child presenting with irritability, convulsions, walking difficulties, ataxia, nystagmus, cranial nerve palsy, hemiplegia/tetraplegia, visual disturbance, vomiting, neck stiffness, or other non-specific signs of raised intracranial pressure or delayed psychomotor development represents a diagnostic and therapeutic challenge. However, the cause of the child’s disease may remain obscure and treatment is rarely specific or effective. Haemophagocytic lymphohistiocytosis (HLH) is an immunological disturbance affecting mainly small children, it is characterised by fever, hepatosplenomegaly, and cytopenias. A familial association is not lIDcommon.12 During a retrospective study to assess the incidence of HLH, 3 children were found who had been admitted to the Department of Paediatrics at St Goran’s/Karolinska Children’s Hospital with predominantly neurological We diagnosed a progressive symptoms (table). immunological encephalopathy from examination of necropsy material. 2 children had a sibling with HLH and histopathological review revealed a common histological picture.12 We describe this condition as cerebromeningeal HLH (CNS-HLH). Cerebral symptoms precede the usual presentation of HLH. Since treatment is available, an awareness of this condition is important. Of these 3 cases, the second is more typical of HLH but is included because of the striking deterioration in neurological signs.
Case reports Case 1 A was
2 -year-old girl with a history of recurrent otitis media
admitted with a two-to-three week history of increasing
fatigue, irritability, and neck stiffness. She had no signs of fever, lymphadenopathy, hepatosplenomegaly, or infection and she was normotensive. She had difficulty walking and held her head tilted to the right; there were no other neurological signs. Papilloedema was present and skull radiographs showed a widening of the coronal and sagittal sutures. Computed tomography (CT) of the brain revealed evidence of increased intracranial pressure. Dexamethasone and acetazolamide were given and the girl- initially recovered; however, a few days later she deteriorated. She became hypotonic in the right side of her neck with a right-sided facial palsy, conjugate deviation of the eyes to the right, and left-sided convulsions especially of the lower extremity. Finally, she became unconscious.
Laboratory investigation revealed no haematological or electrolyte abnormalities. The electroencephalogram (EEG) showed diffuse cortical dysfunction, probably with brainstem involvement, which was consistent with encephalitis. Examination of her cerebrospinal fluid was normal, but five days later a moderate mononuclear pleocytosis (6 x 106 cells/1) was found. The EEG at six and twelve days after onset of unconsciousness showed a slower and more irregular pattern, which later flattened out. No virus was isolated from spinal fluid, the throat, or faeces; viral serology was negative. The patient was hyperventilated for one week and was given dexamethasone, frusemide, and mannitol, together with lignocaine and other anticonvulsant drugs. She was intermittently febrile ( < 38’5°C). When mechanical ventilation was discontinued she was ataxic with generally increased muscle tone, bilateral extensor plantar responses, and seizures, all of which suggested serious brain damage. Five weeks after admission, further febrile episodes ( < 39°C) developed with erythematous skin lesions. She had mild splenomegaly and the bowel was distended. Two weeks later pancytopenia was noted: haemoglobin 79 g/dl, neutrophils (Hx109/1, and platelets 101 x 109/1. She later became jaundiced (conjugated bilirubin 66 umol/1) with hypoalbuminaemia (31 g/1) and moderately increased serum aminotransferases. Serum immunoglobulin concentrations were low: IgM 1 -0 g/l, IgA 04 g/l, and IgG 3-5 g/l. Bone-marrow examination showed hypocellularity and maturity arrest, especially affecting erythropoiesis, but no signs of malignancy. Further spinal fluid examination showed moderate pleocytosis (26 x 106/1) and a protein content of 0-5 g/1. The girl died 2t months after admission. At necropsy, the liver and
spleen (30 g) were reported to gland had been large haemorrhage. Multiple
be of normal size. The left adrenal
completely destroyed by
a
abscesses were found in the liver. There was cerebral oedema and the inferior aspect of the cerebellum showed signs of intracranial herniation with a clear-cut indentation made by the foramen magnum. The inferior aspect of the cerebral hemispheres showed impressions made by the cerebellar tentorium. Histological examination of the heart revealed a myocarditis. Alveolar septa contained collections of ADDRESSES Department of Paediatrics, Karolinska Institute, St Göran’s Children’s Hospital, Stockholm, Sweden (Dr J-I. Henter, MD) and Sachs Children’s Hospital, Stockholm, Sweden (Dr G Elinder, MD). Correspondence to Dr J-I Henter, St Goran’s Children’s Hospital, S-112 81 Stockholm, Sweden
105
CLINICAL FEATURES AND LABORATORY DATA
*Found at necropsy
inflammatory cells, notably lymphocytes, and eosinophilic hyaline membranes lining the alveolar septa were present in abundance. Microscopic examination of the brain showed lymphocyte and histiocyte infiltration of perivascular sites and more generally in brain parenchyma. Confluent areas of inflammation
were
also found and there
was
evidence of
meningitis. The final diagnoses were meningoencephalitis with myocarditis and liver abscesses. Nine years later a younger brother was found to have familial haemophagocytic lymphohistiocytosis (diagnosed by Dr A. Kreuger and Dr A. Jakobson, Uppsala) and a review of his sister showed that she had had the same disease. Re-examination of the bone-marrow specimens revealed haemophagocytosis by histiocytes. In the liver, changes consistent with a mild chronic persistent hepatitis were found, but haemophagocytic activity in the liver and the spleen could not be evaluated because of post-mortem autolysis.
Case 2 A 13-month-old boy was admitted with a three-week history of worsening cough and fever, two days of vomiting, and diarrhoea. He was febrile (39’3°C) and had cervical lymphadenopathy but no neck stiffness or hepatosplenomegaly. He was irritable and had petechiae associated with thrombocytopenia. Cerebrospinal fluid examination was normal. He recovered spontaneously but relapsed with signs of HLH: fever,
anaemia, hepatosplenomegaly, and moderate neutropenia,
thrombocytopenia, increased
serum
aminotransferases. One month after admission, a left abducens nerve palsy was noted with bilateral papilloedema. Within three days he had a bulging fontanelle, vertical nystagmus, and poor balance. The cerebrospinal fluid white cell count was increased with a large proportion of mononuclear cells. Head CT and two bone-marrow examinations were reported as showing no specific abnormality. Intermittent steroid therapy seemed to improve the patient’s general condition. Three months after admission, he deteriorated further, became febrile, had moderate hepatosplenomegaly, seizures, pulmonary oedema, and again became unconscious. He died four months later with thrombocytopenia and severe anaemia together with signs of HLH during the last month. CT of the brain revealed atrophic and low attenuation changes in both occipital lobes. He was blind and irritable, had spastic tetraplegia, nystagmus, and fixed dilated pupils.
Necropsy examination showed a fibrinous exudate in the right pleura with scattered purulent infiltrates especially on the right side. The liver was enlarged (720 g) with fatty change, but with no signs of cirrhosis. The spleen was also enlarged (165 g) and had a poorly developed follicular pattern on its cut surface. Several lymph nodes were enlarged. Cerebral white matter was soft and the cerebral hemispheres showed flattened convolutions with some disintegration, especially on the frontoparietal aspect of the
convex
side.
Histological examination revealed a striking reduction in the amount of white pulp in the spleen, with a corresponding increase in the amount of red pulp. Lymph nodes showed a diffuse infiltration of lymphoid cells. Hepatic parenchymal degenerative changes were found, with vacuolation of hepatocytes and round-cell infiltration in portal zones; this picture suggested a chronic persistent hepatitis. The lungs showed scattered aggregations of bacteria and granulomatous inflammatory changes. Microscopic examination of the brain confirmed severe destruction, primarily of the white matter, but also patchy loss of nerve cell layers in which striking astrogliosis was seen. Some macrophages were present and there was severe inflammation with mononuclear cells, especially lymphocytes, located in perivascular cuffs and more diffusely in the parenchyma of cortex and white matter. We unable to find intranuclear inclusion bodies. The initial diagnosis was an unspecified degenerative cerebral disease on the background of a suspected immunodeficiency. Retrospective review identified haemophagocytic activity in the spleen, liver, and lymph nodes; we believe this patient to have had HLH without any evidence of a family history. were
Case 3 A 15-month-old boy was admitted to hospital because of a disturbance in balance. An elder sister had died suddenly aged 3 years of what was thought to be an acute infectious mononucleosis. This boy had balance difficulties for one day, two months before admission, at which time he could neither stand nor sit, but fell backwards. He made a rapid and spontaneous recovery despite a single short-lasting seizure. Physical examination revealed ataxia but no
hepatosplenomegaly or lymphadenopathy. Fundoscopy was normal. Haematological findings and cerebrospinal fluid examination were normal. EEG showed a moderately diffuse paroxysmal abnormality, with a right-sided predominance, but no definite focal lesion. The preliminary
106
boy,4 familial HLH seems more appropriate because of the presence of haemophagocytic lymphohistiocytosis and a positive family history that was not X-linked. Discussion
Perivascular infiltration with lymphocytes and histiocytes in the cerebral parenchyma of a child with haemophagocytic
lymphohistiocytosis. Courtesy of Dr A Ost, Department of Pathology,
Karolinska hospital,
Stockholm.
diagnosis was encephalitis. CT of the brain was normal but ataxia persisted and he became dyspraxic. Six months after initial admission, his parents noted that his left side was weak. Shortly afterwards he had an episode of vomiting and became unconscious. The left side of his body was weaker, reflexes were increased in the left arm and leg, and he had bilateral upgoing extensor plantar responses. EEG revealed an irregular abnormality in the lateral and dorsal regions, with a left-sided predominance. Extensive neurological and neurometabolic investigations, including angiography of the left vertebral artery, were normal, except for increased attenuation in the region of the sinus transversus on CT. After a further six months, he had now become weak in his right side. He eventually became unconscious and required mechanical ventilation. At 3 years of age he was only able to move his arms slightly and could not move his legs at all. He died at the age of 38 months with a febrile illness and seizures refractory to anticonvulsant
therapy. Necropsy examination showed an enlarged liver (755 g) and spleen (270 g). In the mesentery of the small intestine and the hilus of the liver, several soft lymph nodes up to 2’cm in diameter were seen. The brain was soft with wide flattened gyri and narrow sulci. The subependymal tissue was soft and vascular. Histological examintion of lymph nodes and spleen showed a polymorphic accumulation of lymphocytes, lymphoplasmacytoid cells, and immunoblasts together with-especially in lymph nodes-streaky macrocytic infiltration. A polymorphic cellular accumulation, similar to that seen in lymph nodes, was found in the meninges. Paraventricular tissue in the cerebral hemispheres was characterised by a similar cellular infiltration, with a striking glial cell reaction. The findings in this patient resembled those of his elder sister. The cause of her death was never determined, but she was known to have had cerebral oedema. In both children, polymorphic lymphohistiocytic infiltration was seen in most of the parenchymatous organs studied, together with mixed lymphohistiocytic infiltration in the portal zones, a pattern resembling chronic persistent hepatitis. Moreover, haemophagocytosis was found in the bone marrow of both children. Although a diagnosis of X-linked lymphoproliferativesyndrome was made in the case of the
CNS-HLH is a cerebral disease with a broad range of symptoms. The syndrome seems to be an atypical form of HLH and 2 of our 3 reported patients had a sibling with clinical and histopathological findings consistent with systemic HLH. An important feature of this syndrome is that the cerebromeningeal involvement clearly precedes and dominates the systemic symptoms, which makes it more difficult to establish an early and correct diagnosis. Price and colleaguess described a similar condition in 4 children of a single family. The disease was progressive and characterised by diffuse lymphohistiocytic infiltration of the CNS, erythrophagocytosis, and an overall resemblance to HLH. However, we have now reported two families in whom both cerebral and systemic HLH appeared in the same family, suggesting a common genetic
deficiency. Many children with unexplained cerebral disorders might have CNS-HLH. For instance, unexplained encephalitis, leucoencephalitis, degenerative cerebral disorder, ataxia, non-specific neurometabolic disease, cerebral oedema, cerebral lymphoma, delayed psychomotor development, and sudden unspecified cerebral cause of death could be in this category. CNS-HLH might be misdiagnosed as Reye’s syndrome since encephalopathy and liver involvement are common to both; we have seen such a case.
Familial HLH is an autosomal recessive disorder. However, the hereditary nature of the disease is rarely obvious. Haemophagocytic syndromes have also been in with and described association infection immunodeficiency.6 The upper age limit of those with the disorder is unknown, but HLH has been reported in a 12-year-old patient and even adults cannot be excluded.’ Clinical presentation is highly variable. Some neurological symptoms may be caused by localised CNS inflammation with secondary necrosis (figure). Recurrent or chronic disease activity could produce multiple areas of inflammatory activity. Cranial nerve palsies and opisthotonus might be caused by increased intracranial pressure associated with the inflammatory reaction. Subacute sensorimotor polyneuropathy with a reduction of myelinated fibres and severe axonal lesions has also been associated with HLH 7 The neuropathological findings in our patients are consistent with other reports. 5,8,9 The pathophysiology of HLH is poorly understood. There could be a disorder of immunomodulation with activation and inappropriate lymphohistiocytic hypercytokinaemias.10 Organ involvement is variable: liver and spleen ( > 90%), skin (65%), and lymph nodes are most (50%) frequently affected.1 Pulmonary involvement is also common and can be confirmed by chest
radiography.1 Although an early diagnosis
of CNS-HLH is desirable, clinical feature or test result is absolutely specific. A moderate cerebrospinal fluid pleocytosis (5-50 x 106/1) with mononuclear cell predominance may be present, but this is not an invariable finding (case 1). Evidence of haemophagocytosis in cerebrospinal fluid monocytes/ macrophages is strongly suggestive of CNS-HLH but is present only rarely. Cerebrospinal fluid cytokine
no
107
estimations may be helpful. We have found increases in interferon-gamma and soluble CD8 in patients with active cerebral disease.10 Increased cerebrospinal fluid neopterin concentrations have also been reported in patients with HLH." The diagnostic criteria for systemic HLH are not the same as for CNS-HLH.6 Nevertheless, the presence of any of the following findings could be indicative of this
fever, anaemia, splenomegaly, encephalopathy: neutropenia, thrombocytopenia, hypertriglyceridaemia, hypofibrinogenaemia, evidence of haemophagocytosis, or a 6
familial pttem.
for CNS-HLH is states similar to that used for familial HLH is recommended.12 Since the penetration of etoposide and teniposide across the bloodbrain barrier is limited, steroid treatment is recommended and may need to be prolonged.13 Intrathecal chemotherapy with methotrexate has been difficult to evaluate.12 Bone marrow transplantation is suggested if an HLA-identical sibling is available.14 CNS-HLH imitates several neurological disorders and may be misdiagnosed. An awareness of this condition is important because it is treatable.
Although experience
of
treatment
limited, a regimen for active inflammatory
We thank Dr Ake Ost and Dr Blaise Favara for reviewing the histopathological specimens and Dr Lennart Hedenborg for valuable comments on the manuscript. This work was supported by grants from the Children’s Cancer Foundation of Sweden and the Samariten Foundation.
REFERENCES 1. Henter J-I, Elinder G, Soder O, Öst A. Incidence in Sweden and clinical
features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand 1991; 80: 428-35.
Janka G. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr 1983; 140: 221-30. 3. Britton S, Andersson-Anvert M, Gergely P, et al. Epstein-Barr-virus 2.
immunity and tissue distribution in a fatal case of infectious mononucleosis. N Engl J Med 1978; 298: 89-92 4. Purtilo DT, Sakamoto K, Saemundsen A, et al. Documentation of Epstein-Barr virus infection in immunodeficient patients with lifethreatening lymphoproliferative diseases by clinical, virological and immunopathological studies. Cancer Res 1981; 41: 4226-36. 5. Price DL, Woolsey JE, Rosman NP, Richardson EP. Familial lymphohistiocytosis of the nervous system. Arch Neurol 1971; 24: 270-83. 6. Henter J-I, Elinder
G, Öst A, and the FHL Study Group of the Histiocyte Society. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. Semin Oncol 1991; 18: 29-33. 7. Boutin B, Routin M-C, Rocchccioli F, et al. Peripheral neuropathy associated with erythrophagocytic lymphohistiocytosis. Semin Oncol 1991; 18: 29-33. 8. Rettwitz W, Sauer O, Burow M-M, Lenard H-G, Raute-Kreinsen U, Tomow K. Neurological and neuropathological findings in familial erythrophagocytic lymphohistiocytosis. Brain Dev 1983; 5: 322-27. 9. Akima M, Sumi SM, Neuropathology of familial erythrophagocytic lymphohistiocytosis. Six cases and review of the literature. Hum Pathol 1984; 15: 161-68. 10. Henter J-I, Elinder G, Söder O, Hansson M, Andersson B, Andersson U. Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood 1991; 78: 2918-22. 11. Howells DW, Strobel S, Smith I, Levinsky RJ, Hyland K. Central system involvement in the erythrophagocytic disorders of infancy: the role of cerebrospinal fluid neopterins in their differential diagnosis and clinical management. Pediatr Res 1990; 28: 116-19. 12. Henter J-I, Elinder G. Familial hemophagocytic lymphohistiocytosis: clinical review based on the findings in seven patients. Acta Paediatr nervous
Scand 1991; 80: 267-77. 13. Creaven PJ. The clinical pharmacology of VM26 and VP16-213: a brief overview. Cancer Chemother Pharmacol 1982; 7: 133-40. 14. Blanche S, Caniglia M, Girault D, Landman J, Griscelli C, Fischer A. of Treatment hemophagocytic lymphohistiocytosis with chemotherapy and bone-marrow transplantation. Blood 1991; 78: 51-54.
Parvovirus B19 outbreak in
Parvovirus B19 infection
can
cause
severe
complications in pregnant women, individuals with haemolytic anaemia, and those who are immunocompromised. In a hospital outbreak of this balance should be struck between protection of these individuals and the maintenance of medical services. The index case of an outbreak of parvovirus B19 infection among staff and patients of a paediatric ward was not identified. 58 members of staff were screened for B19 markers and 4 of the 6 susceptible men and 6 of the 24 susceptible women became infected (p = 0·05) as defined by serum IgM and viraemia. 1 of the 11 adults (10 members of staff and 1 parent) infected remained symptom-free. 12 immunocompromised patients were also assessed, and symptom-free infection developed in 2 of these. During the outbreak staff with symptoms were put on sick leave, immunocompromised patients (there were none with haemolytic anaemia) were given normal human immunoglobulin and nursed in single rooms by B19 IgG-positive, IgM-negative staff, and the ward was closed to B19 IgG-negative pregnant women. However, the limitation of spread of
infection,
a
children’s ward
infection cannot be attributed with measures
certainty
to the
taken.
Introduction
a
Parvovirus B19 infection is associated with erythema infectiosum in children, hydrops fetalis and second trimester abortion in pregnant women, aplastic crises in those with underlying haemolytic anaemias, and chronic anaemia in immunocompromised individuals. However, infection is also commonly symptomless, especially in childhood. 40-60% of the adult population have serological evidence of infection, in most cases acquired between the ages of 4 and 10.1 Studies of B19 outbreaks in schools and day-care centres have shown that this virus has high infectivity,2-4 but there are few data on hospital outbreaks5-in which pregnant women, immunocompromised individuals, and those with ADDRESSES Division of Communicable Diseases (D Pillay, PhD, C. C Kibbler, MRCPath, Prof P D. Griffiths, MD), and Occupational Health Unit (S Hurt, OHNCert), Royal Free Hospital and School of Medicine, London NW3 2PF, UK, and Department of Medical Microbiology, University College and Middlesex School of Medicine, London (G Patou, MRCPath). Correspondence to Dr D
Pillay.
Cerebromeningeal haemophagocytic lymphohistiocytosis We describe 3 children with a progressive encephalopathy that was characterised by irritability, convulsions, cranial nerve palsies, ataxia, nystagmus,
difficulties, delayed walking psychomotor visual hemiplegia/tetraplegia, development, neck and nondisturbance, vomiting, stiffness, specific signs of raised intracranial pressure. A final diagnosis was made in all 3 patients from necropsy material. The clinical features
were
ascribed to
multiple inflammatory, predominantly lymphocytic, reactions and raised intracranial pressure. This condition is an atypical form of haemophagocytic lymphohistiocytosis, which normally presents with fever, hepatosplenomegaly, and cytopenias. By contrast, the disease pattern in our 3 children was dominated by cerebromeningeal involvement, which can precede the typical systemic symptoms of An haemophagocytic lymphohistiocytosis. awareness of this condition is important because treatments are available.
Introduction Childhood disorders of the central nervous system (CNS) have many causes. A child presenting with irritability, convulsions, walking difficulties, ataxia, nystagmus, cranial nerve palsy, hemiplegia/tetraplegia, visual disturbance, vomiting, neck stiffness, or other non-specific signs of raised intracranial pressure or delayed psychomotor development represents a diagnostic and therapeutic challenge. However, the cause of the child’s disease may remain obscure and treatment is rarely specific or effective. Haemophagocytic lymphohistiocytosis (HLH) is an immunological disturbance affecting mainly small children, it is characterised by fever, hepatosplenomegaly, and cytopenias. A familial association is not lIDcommon.12 During a retrospective study to assess the incidence of HLH, 3 children were found who had been admitted to the Department of Paediatrics at St Goran’s/Karolinska Children’s Hospital with predominantly neurological We diagnosed a progressive symptoms (table). immunological encephalopathy from examination of necropsy material. 2 children had a sibling with HLH and histopathological review revealed a common histological picture.12 We describe this condition as cerebromeningeal HLH (CNS-HLH). Cerebral symptoms precede the usual presentation of HLH. Since treatment is available, an awareness of this condition is important. Of these 3 cases, the second is more typical of HLH but is included because of the striking deterioration in neurological signs.
Case reports Case 1 A was
2 -year-old girl with a history of recurrent otitis media
admitted with a two-to-three week history of increasing
fatigue, irritability, and neck stiffness. She had no signs of fever, lymphadenopathy, hepatosplenomegaly, or infection and she was normotensive. She had difficulty walking and held her head tilted to the right; there were no other neurological signs. Papilloedema was present and skull radiographs showed a widening of the coronal and sagittal sutures. Computed tomography (CT) of the brain revealed evidence of increased intracranial pressure. Dexamethasone and acetazolamide were given and the girl- initially recovered; however, a few days later she deteriorated. She became hypotonic in the right side of her neck with a right-sided facial palsy, conjugate deviation of the eyes to the right, and left-sided convulsions especially of the lower extremity. Finally, she became unconscious.
Laboratory investigation revealed no haematological or electrolyte abnormalities. The electroencephalogram (EEG) showed diffuse cortical dysfunction, probably with brainstem involvement, which was consistent with encephalitis. Examination of her cerebrospinal fluid was normal, but five days later a moderate mononuclear pleocytosis (6 x 106 cells/1) was found. The EEG at six and twelve days after onset of unconsciousness showed a slower and more irregular pattern, which later flattened out. No virus was isolated from spinal fluid, the throat, or faeces; viral serology was negative. The patient was hyperventilated for one week and was given dexamethasone, frusemide, and mannitol, together with lignocaine and other anticonvulsant drugs. She was intermittently febrile ( < 38’5°C). When mechanical ventilation was discontinued she was ataxic with generally increased muscle tone, bilateral extensor plantar responses, and seizures, all of which suggested serious brain damage. Five weeks after admission, further febrile episodes ( < 39°C) developed with erythematous skin lesions. She had mild splenomegaly and the bowel was distended. Two weeks later pancytopenia was noted: haemoglobin 79 g/dl, neutrophils (Hx109/1, and platelets 101 x 109/1. She later became jaundiced (conjugated bilirubin 66 umol/1) with hypoalbuminaemia (31 g/1) and moderately increased serum aminotransferases. Serum immunoglobulin concentrations were low: IgM 1 -0 g/l, IgA 04 g/l, and IgG 3-5 g/l. Bone-marrow examination showed hypocellularity and maturity arrest, especially affecting erythropoiesis, but no signs of malignancy. Further spinal fluid examination showed moderate pleocytosis (26 x 106/1) and a protein content of 0-5 g/1. The girl died 2t months after admission. At necropsy, the liver and
spleen (30 g) were reported to gland had been large haemorrhage. Multiple
be of normal size. The left adrenal
completely destroyed by
a
abscesses were found in the liver. There was cerebral oedema and the inferior aspect of the cerebellum showed signs of intracranial herniation with a clear-cut indentation made by the foramen magnum. The inferior aspect of the cerebral hemispheres showed impressions made by the cerebellar tentorium. Histological examination of the heart revealed a myocarditis. Alveolar septa contained collections of ADDRESSES Department of Paediatrics, Karolinska Institute, St Göran’s Children’s Hospital, Stockholm, Sweden (Dr J-I. Henter, MD) and Sachs Children’s Hospital, Stockholm, Sweden (Dr G Elinder, MD). Correspondence to Dr J-I Henter, St Goran’s Children’s Hospital, S-112 81 Stockholm, Sweden
105
CLINICAL FEATURES AND LABORATORY DATA
*Found at necropsy
inflammatory cells, notably lymphocytes, and eosinophilic hyaline membranes lining the alveolar septa were present in abundance. Microscopic examination of the brain showed lymphocyte and histiocyte infiltration of perivascular sites and more generally in brain parenchyma. Confluent areas of inflammation
were
also found and there
was
evidence of
meningitis. The final diagnoses were meningoencephalitis with myocarditis and liver abscesses. Nine years later a younger brother was found to have familial haemophagocytic lymphohistiocytosis (diagnosed by Dr A. Kreuger and Dr A. Jakobson, Uppsala) and a review of his sister showed that she had had the same disease. Re-examination of the bone-marrow specimens revealed haemophagocytosis by histiocytes. In the liver, changes consistent with a mild chronic persistent hepatitis were found, but haemophagocytic activity in the liver and the spleen could not be evaluated because of post-mortem autolysis.
Case 2 A 13-month-old boy was admitted with a three-week history of worsening cough and fever, two days of vomiting, and diarrhoea. He was febrile (39’3°C) and had cervical lymphadenopathy but no neck stiffness or hepatosplenomegaly. He was irritable and had petechiae associated with thrombocytopenia. Cerebrospinal fluid examination was normal. He recovered spontaneously but relapsed with signs of HLH: fever,
anaemia, hepatosplenomegaly, and moderate neutropenia,
thrombocytopenia, increased
serum
aminotransferases. One month after admission, a left abducens nerve palsy was noted with bilateral papilloedema. Within three days he had a bulging fontanelle, vertical nystagmus, and poor balance. The cerebrospinal fluid white cell count was increased with a large proportion of mononuclear cells. Head CT and two bone-marrow examinations were reported as showing no specific abnormality. Intermittent steroid therapy seemed to improve the patient’s general condition. Three months after admission, he deteriorated further, became febrile, had moderate hepatosplenomegaly, seizures, pulmonary oedema, and again became unconscious. He died four months later with thrombocytopenia and severe anaemia together with signs of HLH during the last month. CT of the brain revealed atrophic and low attenuation changes in both occipital lobes. He was blind and irritable, had spastic tetraplegia, nystagmus, and fixed dilated pupils.
Necropsy examination showed a fibrinous exudate in the right pleura with scattered purulent infiltrates especially on the right side. The liver was enlarged (720 g) with fatty change, but with no signs of cirrhosis. The spleen was also enlarged (165 g) and had a poorly developed follicular pattern on its cut surface. Several lymph nodes were enlarged. Cerebral white matter was soft and the cerebral hemispheres showed flattened convolutions with some disintegration, especially on the frontoparietal aspect of the
convex
side.
Histological examination revealed a striking reduction in the amount of white pulp in the spleen, with a corresponding increase in the amount of red pulp. Lymph nodes showed a diffuse infiltration of lymphoid cells. Hepatic parenchymal degenerative changes were found, with vacuolation of hepatocytes and round-cell infiltration in portal zones; this picture suggested a chronic persistent hepatitis. The lungs showed scattered aggregations of bacteria and granulomatous inflammatory changes. Microscopic examination of the brain confirmed severe destruction, primarily of the white matter, but also patchy loss of nerve cell layers in which striking astrogliosis was seen. Some macrophages were present and there was severe inflammation with mononuclear cells, especially lymphocytes, located in perivascular cuffs and more diffusely in the parenchyma of cortex and white matter. We unable to find intranuclear inclusion bodies. The initial diagnosis was an unspecified degenerative cerebral disease on the background of a suspected immunodeficiency. Retrospective review identified haemophagocytic activity in the spleen, liver, and lymph nodes; we believe this patient to have had HLH without any evidence of a family history. were
Case 3 A 15-month-old boy was admitted to hospital because of a disturbance in balance. An elder sister had died suddenly aged 3 years of what was thought to be an acute infectious mononucleosis. This boy had balance difficulties for one day, two months before admission, at which time he could neither stand nor sit, but fell backwards. He made a rapid and spontaneous recovery despite a single short-lasting seizure. Physical examination revealed ataxia but no
hepatosplenomegaly or lymphadenopathy. Fundoscopy was normal. Haematological findings and cerebrospinal fluid examination were normal. EEG showed a moderately diffuse paroxysmal abnormality, with a right-sided predominance, but no definite focal lesion. The preliminary
106
boy,4 familial HLH seems more appropriate because of the presence of haemophagocytic lymphohistiocytosis and a positive family history that was not X-linked. Discussion
Perivascular infiltration with lymphocytes and histiocytes in the cerebral parenchyma of a child with haemophagocytic
lymphohistiocytosis. Courtesy of Dr A Ost, Department of Pathology,
Karolinska hospital,
Stockholm.
diagnosis was encephalitis. CT of the brain was normal but ataxia persisted and he became dyspraxic. Six months after initial admission, his parents noted that his left side was weak. Shortly afterwards he had an episode of vomiting and became unconscious. The left side of his body was weaker, reflexes were increased in the left arm and leg, and he had bilateral upgoing extensor plantar responses. EEG revealed an irregular abnormality in the lateral and dorsal regions, with a left-sided predominance. Extensive neurological and neurometabolic investigations, including angiography of the left vertebral artery, were normal, except for increased attenuation in the region of the sinus transversus on CT. After a further six months, he had now become weak in his right side. He eventually became unconscious and required mechanical ventilation. At 3 years of age he was only able to move his arms slightly and could not move his legs at all. He died at the age of 38 months with a febrile illness and seizures refractory to anticonvulsant
therapy. Necropsy examination showed an enlarged liver (755 g) and spleen (270 g). In the mesentery of the small intestine and the hilus of the liver, several soft lymph nodes up to 2’cm in diameter were seen. The brain was soft with wide flattened gyri and narrow sulci. The subependymal tissue was soft and vascular. Histological examintion of lymph nodes and spleen showed a polymorphic accumulation of lymphocytes, lymphoplasmacytoid cells, and immunoblasts together with-especially in lymph nodes-streaky macrocytic infiltration. A polymorphic cellular accumulation, similar to that seen in lymph nodes, was found in the meninges. Paraventricular tissue in the cerebral hemispheres was characterised by a similar cellular infiltration, with a striking glial cell reaction. The findings in this patient resembled those of his elder sister. The cause of her death was never determined, but she was known to have had cerebral oedema. In both children, polymorphic lymphohistiocytic infiltration was seen in most of the parenchymatous organs studied, together with mixed lymphohistiocytic infiltration in the portal zones, a pattern resembling chronic persistent hepatitis. Moreover, haemophagocytosis was found in the bone marrow of both children. Although a diagnosis of X-linked lymphoproliferativesyndrome was made in the case of the
CNS-HLH is a cerebral disease with a broad range of symptoms. The syndrome seems to be an atypical form of HLH and 2 of our 3 reported patients had a sibling with clinical and histopathological findings consistent with systemic HLH. An important feature of this syndrome is that the cerebromeningeal involvement clearly precedes and dominates the systemic symptoms, which makes it more difficult to establish an early and correct diagnosis. Price and colleaguess described a similar condition in 4 children of a single family. The disease was progressive and characterised by diffuse lymphohistiocytic infiltration of the CNS, erythrophagocytosis, and an overall resemblance to HLH. However, we have now reported two families in whom both cerebral and systemic HLH appeared in the same family, suggesting a common genetic
deficiency. Many children with unexplained cerebral disorders might have CNS-HLH. For instance, unexplained encephalitis, leucoencephalitis, degenerative cerebral disorder, ataxia, non-specific neurometabolic disease, cerebral oedema, cerebral lymphoma, delayed psychomotor development, and sudden unspecified cerebral cause of death could be in this category. CNS-HLH might be misdiagnosed as Reye’s syndrome since encephalopathy and liver involvement are common to both; we have seen such a case.
Familial HLH is an autosomal recessive disorder. However, the hereditary nature of the disease is rarely obvious. Haemophagocytic syndromes have also been in with and described association infection immunodeficiency.6 The upper age limit of those with the disorder is unknown, but HLH has been reported in a 12-year-old patient and even adults cannot be excluded.’ Clinical presentation is highly variable. Some neurological symptoms may be caused by localised CNS inflammation with secondary necrosis (figure). Recurrent or chronic disease activity could produce multiple areas of inflammatory activity. Cranial nerve palsies and opisthotonus might be caused by increased intracranial pressure associated with the inflammatory reaction. Subacute sensorimotor polyneuropathy with a reduction of myelinated fibres and severe axonal lesions has also been associated with HLH 7 The neuropathological findings in our patients are consistent with other reports. 5,8,9 The pathophysiology of HLH is poorly understood. There could be a disorder of immunomodulation with activation and inappropriate lymphohistiocytic hypercytokinaemias.10 Organ involvement is variable: liver and spleen ( > 90%), skin (65%), and lymph nodes are most (50%) frequently affected.1 Pulmonary involvement is also common and can be confirmed by chest
radiography.1 Although an early diagnosis
of CNS-HLH is desirable, clinical feature or test result is absolutely specific. A moderate cerebrospinal fluid pleocytosis (5-50 x 106/1) with mononuclear cell predominance may be present, but this is not an invariable finding (case 1). Evidence of haemophagocytosis in cerebrospinal fluid monocytes/ macrophages is strongly suggestive of CNS-HLH but is present only rarely. Cerebrospinal fluid cytokine
no
107
estimations may be helpful. We have found increases in interferon-gamma and soluble CD8 in patients with active cerebral disease.10 Increased cerebrospinal fluid neopterin concentrations have also been reported in patients with HLH." The diagnostic criteria for systemic HLH are not the same as for CNS-HLH.6 Nevertheless, the presence of any of the following findings could be indicative of this
fever, anaemia, splenomegaly, encephalopathy: neutropenia, thrombocytopenia, hypertriglyceridaemia, hypofibrinogenaemia, evidence of haemophagocytosis, or a 6
familial pttem.
for CNS-HLH is states similar to that used for familial HLH is recommended.12 Since the penetration of etoposide and teniposide across the bloodbrain barrier is limited, steroid treatment is recommended and may need to be prolonged.13 Intrathecal chemotherapy with methotrexate has been difficult to evaluate.12 Bone marrow transplantation is suggested if an HLA-identical sibling is available.14 CNS-HLH imitates several neurological disorders and may be misdiagnosed. An awareness of this condition is important because it is treatable.
Although experience
of
treatment
limited, a regimen for active inflammatory
We thank Dr Ake Ost and Dr Blaise Favara for reviewing the histopathological specimens and Dr Lennart Hedenborg for valuable comments on the manuscript. This work was supported by grants from the Children’s Cancer Foundation of Sweden and the Samariten Foundation.
REFERENCES 1. Henter J-I, Elinder G, Soder O, Öst A. Incidence in Sweden and clinical
features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand 1991; 80: 428-35.
Janka G. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr 1983; 140: 221-30. 3. Britton S, Andersson-Anvert M, Gergely P, et al. Epstein-Barr-virus 2.
immunity and tissue distribution in a fatal case of infectious mononucleosis. N Engl J Med 1978; 298: 89-92 4. Purtilo DT, Sakamoto K, Saemundsen A, et al. Documentation of Epstein-Barr virus infection in immunodeficient patients with lifethreatening lymphoproliferative diseases by clinical, virological and immunopathological studies. Cancer Res 1981; 41: 4226-36. 5. Price DL, Woolsey JE, Rosman NP, Richardson EP. Familial lymphohistiocytosis of the nervous system. Arch Neurol 1971; 24: 270-83. 6. Henter J-I, Elinder
G, Öst A, and the FHL Study Group of the Histiocyte Society. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. Semin Oncol 1991; 18: 29-33. 7. Boutin B, Routin M-C, Rocchccioli F, et al. Peripheral neuropathy associated with erythrophagocytic lymphohistiocytosis. Semin Oncol 1991; 18: 29-33. 8. Rettwitz W, Sauer O, Burow M-M, Lenard H-G, Raute-Kreinsen U, Tomow K. Neurological and neuropathological findings in familial erythrophagocytic lymphohistiocytosis. Brain Dev 1983; 5: 322-27. 9. Akima M, Sumi SM, Neuropathology of familial erythrophagocytic lymphohistiocytosis. Six cases and review of the literature. Hum Pathol 1984; 15: 161-68. 10. Henter J-I, Elinder G, Söder O, Hansson M, Andersson B, Andersson U. Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood 1991; 78: 2918-22. 11. Howells DW, Strobel S, Smith I, Levinsky RJ, Hyland K. Central system involvement in the erythrophagocytic disorders of infancy: the role of cerebrospinal fluid neopterins in their differential diagnosis and clinical management. Pediatr Res 1990; 28: 116-19. 12. Henter J-I, Elinder G. Familial hemophagocytic lymphohistiocytosis: clinical review based on the findings in seven patients. Acta Paediatr nervous
Scand 1991; 80: 267-77. 13. Creaven PJ. The clinical pharmacology of VM26 and VP16-213: a brief overview. Cancer Chemother Pharmacol 1982; 7: 133-40. 14. Blanche S, Caniglia M, Girault D, Landman J, Griscelli C, Fischer A. of Treatment hemophagocytic lymphohistiocytosis with chemotherapy and bone-marrow transplantation. Blood 1991; 78: 51-54.
Parvovirus B19 outbreak in
Parvovirus B19 infection
can
cause
severe
complications in pregnant women, individuals with haemolytic anaemia, and those who are immunocompromised. In a hospital outbreak of this balance should be struck between protection of these individuals and the maintenance of medical services. The index case of an outbreak of parvovirus B19 infection among staff and patients of a paediatric ward was not identified. 58 members of staff were screened for B19 markers and 4 of the 6 susceptible men and 6 of the 24 susceptible women became infected (p = 0·05) as defined by serum IgM and viraemia. 1 of the 11 adults (10 members of staff and 1 parent) infected remained symptom-free. 12 immunocompromised patients were also assessed, and symptom-free infection developed in 2 of these. During the outbreak staff with symptoms were put on sick leave, immunocompromised patients (there were none with haemolytic anaemia) were given normal human immunoglobulin and nursed in single rooms by B19 IgG-positive, IgM-negative staff, and the ward was closed to B19 IgG-negative pregnant women. However, the limitation of spread of
infection,
a
children’s ward
infection cannot be attributed with measures
certainty
to the
taken.
Introduction
a
Parvovirus B19 infection is associated with erythema infectiosum in children, hydrops fetalis and second trimester abortion in pregnant women, aplastic crises in those with underlying haemolytic anaemias, and chronic anaemia in immunocompromised individuals. However, infection is also commonly symptomless, especially in childhood. 40-60% of the adult population have serological evidence of infection, in most cases acquired between the ages of 4 and 10.1 Studies of B19 outbreaks in schools and day-care centres have shown that this virus has high infectivity,2-4 but there are few data on hospital outbreaks5-in which pregnant women, immunocompromised individuals, and those with ADDRESSES Division of Communicable Diseases (D Pillay, PhD, C. C Kibbler, MRCPath, Prof P D. Griffiths, MD), and Occupational Health Unit (S Hurt, OHNCert), Royal Free Hospital and School of Medicine, London NW3 2PF, UK, and Department of Medical Microbiology, University College and Middlesex School of Medicine, London (G Patou, MRCPath). Correspondence to Dr D
Pillay.
