Unexplained childhood anaemia: idiopathic pulmonary hemosiderosis

Hong Kong Med J 2015 Apr;21(2):172–4
DOI: 10.12809/hkmj144237
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Unexplained childhood anaemia: idiopathic pulmonary hemosiderosis
KK Siu, MB, ChB, MRCPCH1; Rever Li, MB, ChB, FHKAM (Paediatrics)2; SY Lam, MB, BS, FHKAM (Paediatrics)2
1 Department of Paediatrics, Kwong Wah Hospital, Yaumatei, Hong Kong
2 Department of Paediatrics, Tuen Mun Hospital, Tuen Mun, Hong Kong
 
Corresponding author: Dr KK Siu (skk053@ha.org.hk)
 
 Full paper in PDF
Abstract
This report demonstrates pulmonary haemorrhage as a differential cause of anaemia. Idiopathic pulmonary hemosiderosis is a rare disease in children; it is classically described as a triad of haemoptysis, pulmonary infiltrates on chest radiograph, and iron-deficiency anaemia. However, anaemia may be the only presenting feature of idiopathic pulmonary hemosiderosis in children due to occult pulmonary haemorrhage. In addition, the serum ferritin is falsely high in idiopathic pulmonary hemosiderosis which increases the diagnostic difficulty. We recommend that pulmonary haemorrhage be suspected in any child presenting with iron-deficiency anaemia and persistent bilateral pulmonary infiltrates.
 
 
[Abstract in Chinese]
Case report
We report the case of a 5-year-old boy, who presented with recurrent episodes of unexplained iron-deficiency anaemia in February 2010 since the age of 27 months. Serial chest X-rays (CXRs) showed bilateral reticulonodular haziness. Bronchoalveolar lavage and lung biopsy confirmed the diagnosis of idiopathic pulmonary hemosiderosis (IPH).
 
The patient first presented at 27 months of age in Mainland China with malaise, loss of appetite, and shortness of breath for 10 days. He did not have fever, cough, or haemoptysis. He received two doses of H1N1 vaccination before pallor was noted. There was no history of drug or herb intake.
 
The presenting haemoglobin (Hb) level was 65 g/L (reference range [RR], 115-145 g/L), mean corpuscular volume (MCV) 84.4 fL (RR, 76-90 fL), mean corpuscular haemoglobin (MCH) level 25.8 pg (RR, 25-31 pg), and reticulocyte count 10.4% (reference level [RL], <2%). White cell count and platelet count were unremarkable. Blood smear showed moderate anisopoikilocytosis with polychromasia. Bone marrow aspiration and trephine biopsy revealed active marrow with erythroid preponderance.
 
Other investigations were performed for anaemia. Serum lactate dehydrogenase (LDH) level was elevated to 980 U/L (RL, <615 U/L). Haptoglobin level was reduced (<0.09 g/L; RR, 0.3-2.7 g/L). Direct Coombs test was negative. Bilirubin was normal. Urine for bilirubin and urobilinogen was negative. Haemoglobin pattern, serum vitamin B12, and G6PD activity were unremarkable. Serum ferritin level was 137 pmol/L (RR, 45-449 pmol/L). Antinuclear antibody assay was negative. Flow cytometry showed normal expression of CD55 and CD59 which ruled out paroxysmal nocturnal haemoglobinuria. Donath-Landsteiner antibody assay was negative, which excluded the diagnosis of paroxysmal cold haemoglobinuria.
 
Blood work for viral infection including antibodies to parvovirus, Epstein-Barr virus (EBV), mycoplasma, and viral titres was unremarkable.
 
Screening for blood loss was negative. Stool for occult blood and urine for Hb were negative. Red blood cell scan showed no evidence of haemorrhage.
 
Blood transfusion was given to correct the anaemia. Microcytic hypochromic anaemia was noted at 2 months after presentation. Haemoglobin level was 54 g/L. Mean corpuscular volume dropped from 84.4 fL to 68 fL. Mean corpuscular haemoglobin level was 21.3 pg. Iron profile showed a low serum iron level of 3 µmol/L (RR, 5-20 µmol/L), elevated total iron-binding capacity (TIBC) of 70 µmol/L (RR, 37-68 µmol/L), and iron saturation of 4% (RR, 20-55%). However, the serum ferritin level was normal at 220 pmol/L (RR, 45-449 pmol/L). Iron supplement was started as a therapeutic trial for suspected iron-deficiency anaemia.
 
His Hb level remained stable in the next 2 years. However, in the subsequent 8 months, there were three intermittent episodes of anaemia (lowest Hb level, 60 g/L). The anaemia occurred with fever and cough which were considered symptoms of pneumonia and upper respiratory tract infection. There was no history of haemoptysis.
 
At 36 months after the presentation, he was admitted again for pallor, fatigue, and fever. This time, he needed oxygen therapy. Chest was clear with mild subcostal insucking. Hepatomegaly of 4 cm below the costal margin was noted. Chest X-ray showed bilateral reticulonodular haziness (Fig 1). Haemoglobin level was 61 g/L. Both MCV (78 fL) and MCH level (25 pg) were in the lower normal limits. The serum ferritin level was 879 pmol/L. A diagnosis of pneumonia was made; he was started on oral co-amoxiclav (amoxicillin and clavulanic acid) and azithromycin and given blood transfusion. Fever subsided and oxygen was weaned off. Ultrasonography of abdomen performed 1 month later showed no hepatomegaly; mild hepatic coarsening was suggestive of parenchymal disease. Liver function tests were normal all along. However, the patient tested positive for EBV immunoglobulin (Ig) M antibodies. Thus, he was diagnosed to have pneumonia with EBV infection.
 

Figure 1. A chest X-ray showing bilateral reticulonodular haziness
 
Review of old CXRs showed similar reticulonodular shadows. In view of his history of recurrent iron-deficiency anaemia and CXR findings, pulmonary hemosiderosis was suspected. Flexible bronchoscopy was performed; bronchoscopic lavage over left lingular and right middle lobe showed blood-stained fluid. Bronchoalveolar lavage yielded abundant hemosiderin-laden macrophages (HLM index, 92%). High-resolution computed tomography of thorax showed extensive ground glass opacities and reticular shadows, suggestive of interstitial lung disease. Diffuse visceral pleural brownish deposits were noted over the entire left lung on video-assisted thoracoscopy. Lung biopsy was performed to rule out systemic disorders with pulmonary capillaritis, which could cause diffuse alveolar haemorrhage (DAH). These included Goodpasture’s syndrome, IgA nephropathy, Wegener’s granulomatosis, systemic lupus erythematosus, and antiphospholipid syndrome. Biopsy of lung tissue showed numerous HLM. There was no evidence of capillaritis or vasculitis. Absence of fibrosis and negative exposure history also excluded hypersensitivity pneumonitis. Immunostaining for IgG, IgM, and IgA was negative. The overall picture was compatible with pulmonary hemosiderosis.
 
Further blood investigations were performed to exclude systemic causes of pulmonary haemorrhage as stated above. Antiglomerular basement membrane antibodies, rheumatoid factor, anti-neutrophil cytoplasmic antibodies, antinuclear antibodies, anti-extractable nuclear antibodies, and anti-cardiolipin IgG antibodies were not detected. Furthermore, the patient was negative for anti-transglutaminase antibody for coeliac disease. He tested weakly positive for IgE antibodies against cow’s milk. Immunoglobulin pattern was unremarkable apart from mildly raised IgA antibody level at 2.28 g/L (range, 0.5-1.92 g/L). Renal function and urinalysis were normal.
 
A diagnosis of IPH was made based on the above findings. Oral prednisolone was started after the diagnosis for disease control. Chest X-ray performed after 3 months of prednisolone showed improvement in reticulonodular densities (Fig 2). We plan to monitor the disease with clinical symptoms, Hb levels, LDH levels, CXRs, and spirometry.
 

Figure 2. A chest X-ray performed after 3 months of prednisolone therapy showing improvement in reticulonodular densities
 
Discussion
Idiopathic pulmonary hemosiderosis is a rare disease in children with an unknown aetiology. The estimated yearly incidence among Swedish children from 1960 through 1979 was 0.24 per 1 000 000 children.1 A retrospective review of records from a tertiary paediatric hospital in northern Taiwan noted five cases over 25 years.2 Patients classically presented with a triad of recurrent or chronic pulmonary symptoms (cough, dyspnoea, wheeze, haemoptysis), pulmonary infiltrates on CXR, and iron-deficiency anaemia. Our patient had only anaemia without obvious underlying causes. Subsequent CXR changes led to the suspicion of IPH.
 
Serum ferritin has been traditionally taken as a reliable surrogate marker of body iron stores. Hypoferritinaemia is commonly used as a diagnostic marker for iron deficiency.3 However, as it is an acute-phase reactant, abnormally raised serum ferritin level may be seen during acute infection or liver disease even in the presence of iron deficiency.4 In IPH, iron study usually shows low serum iron with low iron saturation, and microcytosis and hypochromia in the blood picture. However, plasma ferritin level can be normal or elevated in IPH because of alveolar synthesis and release into the circulation and does not reflect the iron deposits in the body.5 This makes the diagnosis of iron-deficiency anaemia in IPH difficult. We recommend the use of serum iron and transferrin saturation (serum iron/TIBC) instead to evaluate suspected iron-deficiency anaemia.4
 
Diagnosis of IPH is based on exclusion of other causes of intrapulmonary haemorrhage and systemic diseases. In the absence of systemic disease, findings of HLM in bronchoscopic lavage or gastric aspirate/sputum along with chronic pulmonary symptoms lead to a diagnosis of IPH. Lung biopsy is the gold standard for diagnosis. We performed lung biopsy to exclude pulmonary capillaritis, which is one of the causes of DAH. Pulmonary capillaritis is a small-vessel vasculitis, which can occur as an isolated condition or in association with multiple systemic vasculitides. Isolated DAH without identifiable causation or associated disease is referred to as IPH.6
 
Daily oral corticosteroids or weekly intravenous pulse methylprednisolone is commonly used in the induction treatment of IPH. Other immunosuppressive agents such as azathioprine, cyclophosphamide, and hydroxychloroquine have also been used alone or in combination with oral corticosteroids.7 8 9 10 11 Low-dose oral corticosteroids, azathioprine, or methotrexate are used in maintenance phase. As there is lack of large patient series and inadequate follow-up in previous studies, the prognosis of IPH remains unclear. However, aggressive treatment with the use of corticosteroids and immunosuppressive agents are associated with a prolonged survival and improved prognosis.12 Long-term low-dose corticosteroid therapy was also reported to result in a milder disease course and prevent bleeding crisis.13
 
In conclusion, iron-deficiency anaemia results from poor dietary intake of iron in infants and toddlers. However, every child older than 24 months presenting with iron-deficiency anaemia should be evaluated for chronic blood loss. In this report, we have illustrated that anaemia without any respiratory symptoms can be the sole presenting feature of IPH, preceding other signs and symptoms, especially in young children. Haemoptysis may not be present in young children with IPH, as they tend to swallow their sputum. We recommend that when children present with unexplained anaemia and bilateral lung infiltrations, pulmonary haemorrhage should be suspected.
 
References
1. Kjellman B, Elinder G, Garwicz S, Svan H. Idiopathic pulmonary haemosiderosis in Swedish children. Acta Paediatr Scand 1984;73:584-8. Crossref
2. Yao TC, Hung IJ, Wong KS, Huang JL, Niu CK. Idiopathic pulmonary haemosiderosis: an Oriental experience. J Paediatr Child Health 2003;39:27-30. Crossref
3. Rybo E. Diagnosis of iron deficiency. Scand J Haematol Suppl 1985;43:5-39.
4. Li CH, Lee AC, Mak TW, Szeto SC. Transferrin saturation for the diagnosis of iron deficiency in febrile anaemic children. Hong Kong Pract 2003;25:363-6.
5. Ioachimescu OC, Sieber S, Kotch A. Idiopathic pulmonary haemosiderosis revisited. Eur Respir J 2004;24:162-70. Crossref
6. Fullmer JJ, Langston C, Dishop MK, Fan LL. Pulmonary capillaritis in children: a review of eight cases with comparison to other alveolar hemorrhage syndromes. J Pediatr 2005;146:376-81. Crossref
7. Milman N, Pedersen FM. Idiopathic pulmonary haemosiderosis. Epidemiology, pathogenic aspects and diagnosis. Respir Med 1998;92:902-7. Crossref
8. Rossi GA, Balzano E, Battistini E, et al. Long-term prednisolone and azathioprine treatment of a patient with idiopathic pulmonary hemosiderosis. Pediatr Pulmonol 1992;13:176-80. Crossref
9. Colombo JL, Stolz SM. Treatment of life-threatening primary pulmonary hemosiderosis with cyclophosphamide. Chest 1992;102:959-60. Crossref
10. Zaki M, al Saleh Q, al Mutari G. Effectiveness of chloroquine therapy in idiopathic pulmonary hemosiderosis. Pediatr Pulmonol 1995;20:125-6. Crossref
11. Bush A, Sheppard MN, Warner JO. Chloroquine in idiopathic pulmonary haemosiderosis. Arch Dis Child 1992;67:625-7. Crossref
12. Saeed MM, Woo MS, MacLaughlin EF, Margetis MF, Keens TG. Prognosis in pediatric idiopathic pulmonary hemosiderosis. Chest 1999;116:721-5. Crossref
13. Kiper N, Göçmen A, Ozçelik U, Dilber E, Anadol D. Long-term clinical course of patients with idiopathic pulmonary hemosiderosis (1979-1994): prolonged survival with low-dose corticosteroid therapy. Pediatr Pulmonol 1999;27:180-4. Crossref
 

From observation to aetiology: a case report of a twin fetus-in-fetu and a revisit of the known rarity

Hong Kong Med J 2015 Feb;21(1):80–3
DOI: 10.12809/hkmj133925
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
From observation to aetiology: a case report of a twin fetus-in-fetu and a revisit of the known rarity
Kristine KY Pang, MB, ChB, MRCSEd1; Nicholas SY Chao, FCSHK, FHKAM (Surgery)1; TK Tsang, FHKAM (Radiology)2; Betty YT Lau, FHKAM (Obstetrics and Gynaecology)3; KY Leung, FHKAM (Obstetrics and Gynaecology)3; SH Ting, MB, BS4; Michael WY Leung, FCSHK, FHKAM (Surgery)1; Kelvin KW Liu, FCSHK, FHKAM (Surgery)5;
1 Division of Paediatric Surgery, Department of Surgery, Queen Elizabeth Hospital, Jordan, Hong Kong
2 Department of Radiology and Imaging, Queen Elizabeth Hospital, Jordan, Hong Kong
3 Department of Obstetrics and Gynaecology, Queen Elizabeth Hospital, Jordan, Hong Kong
4 Department of Pathology, Queen Elizabeth Hospital, Jordan, Hong Kong
5 Division of Paediatric Surgery, Department of Surgery, United Christian Hospital, Kwun Tong, Hong Kong
 
Corresponding author: Dr Nicholas SY Chao (nickchao@yahoo.com)
 
 Full paper in PDF
Abstract
A baby girl presented with an antenatal diagnosis of a retroperitoneal tumour. Postnatal imaging suggested that this mass contained two fetiform structures with spine and long bone formation. This teratomatous mass was completely excised at 3 weeks of age. Histology was consistent with twin fetuses-in-fetu, revealing two fetiform masses each with an umbilical cord connecting to a common placenta-like mass. Despite a difference in the weight of the twin fetuses-in-fetu, the level of organogenesis was identical and corresponded to fetuses of 10 weeks of gestation. Each mass had four limbs, intact skin, rib cage, intestines, anus, ambiguous genitalia, primitive brain tissue and a spine with ganglion cells in the cord. Although considered a mature teratoma in the current World Health Organization classification, the theory of formation from multiple pregnancies has been commonly implied in more recent literature. The true aetiology of this rare condition remains unclear.
 
 
[Abstract in Chinese]
Introduction
Fetus-in-fetu is a rare condition with an estimated incidence of 1 in 500 000 births.1 It was a descriptive term attributed to Meckel circa 1800. The key feature entails well-organised fetal structures in macroscopic pathology, with vertebral columns and, commonly, long bones of the limbs. Variable degree of organogenesis for the lung, liver, intestines, and genitalia has been commonly reported. Although grouped under the entity of teratoma and considered the well-differentiated end of the neoplastic spectrum in the current World Health Organization (WHO) classification,2 the true aetiology remains unclear. The theory of formation from monozygotic twins has been commonly implied in the literature.3 4 5
 
The commonest presentation of this condition was a painless mass lesion with or without pressure symptoms. Prenatal diagnosis was made in nine out of the 88 cases collectively reported by Hoeffel et al.3 We, hereby, report the case of a twin fetus-in-fetu presenting on antenatal ultrasound, and its histopathology.
 
Case report
Clinical course
A Chinese baby girl was admitted to our neonatal unit on the day of birth for antenatal diagnosis of a retroperitoneal mass in November 2010. This was a singleton pregnancy from natural conception, with allegedly normal antenatal ultrasound in early gestation. There were no additional morphology scans during second trimester ultrasound as the mother was a resident of mainland China where she received her obstetric care. Detailed antenatal ultrasound at 37 weeks of maturity showed a 32 mm x 30 mm x 30 mm mass in the left retroperitoneal region of the fetus. There were no other apparent abnormalities, or complicating intestinal or urinary obstruction. The initial differential diagnoses included congenital adrenal tumour and adrenal haemorrhage.
 
The birth weight of the baby was 4.07 kg. Physical examination showed fullness in the left flank. Targeted ultrasound of the retroperitoneal mass was performed immediately after birth. It showed cystic and solid components with areas of ossification within the mass which were suggestive of a teratoma. Abdominal X-ray showed neither dilated bowel nor calcification. Alpha fetoprotein and beta human chorionic gonadotropin levels measured on day 2 of life were normal for age. Clinically, the patient had no evidence of intestinal obstruction and tolerated full feeding soon after birth.
 
A detailed ultrasound of the abdominal region was performed on day 4 and computed tomography on day 7 (Fig 1). These showed a complex cystic mass between the spleen and the left kidney, with a maximal diameter of 47 mm. Within this single thin-walled cyst, there were two heterogeneous solid masses. Each mass contained a well-ossified spine and two ossified long bones at the caudal end, resembling the configuration of fetal femurs; no cardiac or cranial structures were identifiable.
 

Figure 1. Computed tomography showing the spine of each fetus (arrows)
 
To rule out the likelihood of neuroblastoma, urine catecholamine profile was performed which turned out to be normal. While imaging pointed to a likely fetus-in-fetu, the remote possibility of a mature teratoma could not be completely ruled out. Thus, a decision was made to perform an early excision of the mass.
 
Elective laparotomy was performed on day 14. Mobilisation of the colon at the splenic flexure revealed a retroperitoneal mass between the left kidney and left adrenal gland that was supplied by multiple, small feeding vessels from the aorta and left renal artery. After flush-dividing all investing vessels, the mass was resected with an intact capsule. The baby made good recovery from the operation and was discharged uneventfully on postoperative day 22.
 
Histopathology
Pathological section showed two fetiform masses, each with an umbilical cord connecting to a single placenta-like mass (Fig 2). The lengths of the fetuses were 37 mm and 35 mm, respectively. The larger mass contained better developed fetal structures and weighed 14.2 g, while the smaller mass weighed 9.3 g.
 

Figure 2. Fetuses-in-fetu with ‘umbilical cords’; (inset) mid-sagittal section of the fetus-in-fetu: ossified vertebra was seen containing bone marrow (dotted arrow), the spinal cord (white arrow), the non-patent anus (black arrow), and vacuolised intestines (striped arrows)
 
Within each of the ‘fetuses’, vacuolised intestines could be seen in the abdominal cavity but were leading to a non-patent anus (Fig 2, inset). Ambiguous external genitalia were identified in both fetuses. At the cranial end, there was no skull and no skin coverage. The rest of the fetus was covered by intact skin.
 
Regarding the skeletal formation, there was an ossified segmented spine in each fetus. The spinal cord was identified posterior to the vertebral bodies. A well-developed rib cage with bone and cartilage could be seen in the thoracic region. The pelvic bone and the long bones of the lower limbs were ossified with marrow formation in the centre. Two long bones could be identified in the forearm of the larger fetus. Metatarsals could be identified in both fetuses.
 
Microscopic examination revealed striated muscles, bones, and cartilages in the limbs. Ganglion cells were present in the spinal cord. The fetuses were covered by organised skin tissue and appendages. Respiratory mucosa was identified in the thoracic region. The intestines in the abdominal cavity were lined by intestinal mucosa. There was disorganised primitive brain tissue in the cranial end of both fetuses.
 
Discussion
Fetus-in-fetu is rare, with less than 200 cases reported in the literature. Hui et al6 reported, formally, the first regional case only in 2007. Despite the detailed description in literature, its aetiology and relationship with teratoma remains controversial.
 
Fetus-in-fetu is currently classified as a variant of mature teratoma. Previous case reports of recurrence after resection with malignant transformation also support this classification, whereby fetus-in-fetu should be the mature end of the spectrum of teratoma.7 However, the theory of monozygotic diamniotic twins has been increasingly proposed in the recent literature.3 8 Despite the gaining popularity, there is, as yet no concrete evidence to confirm this relationship. Blood group typing, karyotyping, and DNA analysis, when performed in the previously reported cases, always showed identical findings between the fetuses and their hosts. This finding is, however, compatible with both monozygotic multiple pregnancy theory and teratoma theory.
 
If we consider fetus-in-fetu a result of multiple pregnancy with initial normal embryological development, principles of embryological assessment may be considered. By diagnostic criteria, all fetuses-in-fetu possess vertebrae and, therefore, such an embryo should have reached the age of 24 to 25 days, corresponding to a gestational age of 5 weeks. In our case, and indeed in most other reported cases, the caudal neuropores were also closed. This further aged the estimated gestation to 6 weeks before the development was arrested in these presumed parasitic twins. In our case, since digital rays were clearly identified in the hands and feet, the embryonic age should be at least 44 to 46 days, which is 8 weeks by gestation.9 If we consider the abundant length of small bowel within the abdominal cavity, the gestational age had likely reached 10 weeks for both of these twin fetuses.
 
In conventional embryological assessment of aborted products of gestation, size of the fetus can sometimes be smaller than the normal size for embryological age, since the fetuses often undergo a certain period of growth restriction before the actual death. On the other hand, direct measurement of the specimen size may be slightly larger than the ultrasound assessment due to flattening of the tissue after its passage through the cervix.10 Interestingly, in the reported literature, a poor correlation has been observed between the level of organogenesis and size of the parasitic fetus. In a review of 87 cases by Hoeffel et al,3 there were 10 reported parasitic fetuses weighing over 500 g. The level of organogenesis in these fetuses, however, was immature compared to that of a normal 500 g fetus or newborn.3 If these parasitic fetuses were once products of multiple pregnancies, an interesting conclusion would be that these ‘fetuses’ continued to grow in size after their arrest in development or, theoretically, the ‘death’ of fetuses, although the ‘death’ of such fetuses is always difficult to define in view of their ‘acardiac’ nature.
 
With increasing application of assisted reproductive technology, a higher proportion of multiple pregnancies can now be monitored with ultrasound from early gestation. However, to date, there is no longitudinal observation of the evolution of fetus-in-fetu from multiple pregnancies, nor have there been any reported cases arising from assisted pregnancy. Whilst the earliest antenatal diagnosis of this condition in literature was 16 weeks’ gestation,11 no sequential monitoring of the antenatal history of fetus-in-fetu has been published.
 
In our case, both the twin parasitic fetuses had body weights, sizes, and fetal structures that corresponded well with a gestational age of 10 weeks. A normal ultrasound during the early antenatal period rather suggests that they might have been tiny parasitic fetuses that had grown slowly with the ‘patient’ and reached their significant sizes at term, instead of the popular theory of early normal development followed by parasitic inclusion and arrest of growth. Although with limited antenatal documentation, our case report does not support the popular monozygotic multiple pregnancy theory, and favours, by default, the traditional classification into a teratoma.
 
Conclusion
Less than 200 cases of twin fetus-in-fetu have been reported worldwide, and, to date, this was only the second regional case report. Although classified by WHO as a variant of mature teratoma, the theory of demised multiple pregnancy has gained much support recently. More evidence is needed to confirm either theory. The widespread use of antenatal ultrasound in early gestation may provide more concrete evidence from longitudinal observation and give light to the aetiology of this intriguing condition.
 
References
1. Grant R, Pearn JH. Foetus-in-foetu. Med J Aust 1969;1:1016-20.
2. Scully RE, Young RH, Clement PB. Atlas of tumor pathology, 3rd series, fascicle 23. Washington, DC: Armed Forces Institute of Pathology; 1998: ch13.
3. Hoeffel CC, Nguyen KQ, Phan HT, et al. Fetus in fetu: a case report and literature review. Pediatrics 2000;105:1335-44. CrossRef
4. Lewis RH. Foetus in foetu and retroperitoneal teratoma. Arch Dis Child 1961;36:220-6. CrossRef
5. Thrakral CL, Maji DC, Sajwani MJ. Fetus-in-fetu: a case report and review of the literature. J Pediatr Surg 1998;33:1432-4. CrossRef
6. Hui PW, Lam TP, Chan KL, Lee CP. Fetus in fetu—from prenatal ultrasound and MRI diagnosis to postnatal confirmation. Prenat Diagn 2007;27:657-61. CrossRef
7. Hopkins KL, Dickson PK, Ball TI, Ricketts RR, O’Shea PA, Abramowsky CR. Fetus-in-fetu with malignant recurrence. J Pediatr Surg 1997;32:1476-9. CrossRef
8. Mohan H, Chhabra S, Handa U. Fetus-in-fetu: a rare entity. Fetal Diagn Ther 2007;22:195-7. CrossRef
9. O’Rahilly R, Müller F. Developmental stages in human embryos. Carnegie Institute of Washington; 1987: Publication no. 637.
10. Harkness LN, Rodger M, Baird DT. Morphological and molecular characteristics of living human fetuses between Carnegie stages 7 and 23: ultrasound scanning and direct measurements. Hum Reprod Update 1996;3:25-33. CrossRef
11. Khatib MO, Deschamps F, Couture A, Giacalone PL, Boulot P. Early prenatal ultrasonographic diagnosis of fetus in fetu [in French]. J Gynecol Obstet Biol Reprod (Paris) 1998;27:438-40.
 
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Synthetic fibre granuloma of the conjunctiva

Hong Kong Med J 2015 Feb;21(1):77–9
DOI: 10.12809/hkmj144210
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Synthetic fibre granuloma of the conjunctiva
ST Mak, FRCSEd (Ophth), FHKAM (Ophthalmology)1,2; YH Lui, FRCPA, FHKCPath3 #; Kenneth KW Li, FRCS (Ed), FHKAM (Ophthalmology)1,2
1 Department of Ophthalmology, United Christian Hospital, Kwun Tong, Hong Kong
2 Department of Ophthalmology, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
3 Department of Pathology, United Christian Hospital, Kwun Tong, Hong Kong
# YH Lui is now with the Department of Clinical Pathology, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong
 
Corresponding author: Dr ST Mak (dr.makst@gmail.com)
 
 Full paper in PDF
Abstract
Synthetic fibre granuloma of the conjunctiva, sometimes known as ‘teddy bear granuloma’, results from granulomatous foreign body reaction of the conjunctiva to synthetic fibres. It is often an incidental finding, most commonly found in children, is unilateral, and occurs in the lower eyelid. We present here, what we believe is the first reported case of synthetic fibre conjunctival granuloma in Hong Kong, together with a review of the condition. An awareness of this clinical entity allows early and accurate diagnosis and early treatment.
 
 
[Abstract in Chinese]
Introduction
Synthetic fibre granuloma of the conjunctiva, sometimes known as ‘teddy bear granuloma’, was first described by Weinberg et al in 1984.1 It is a rare granulomatous foreign body reaction of the conjunctiva to synthetic fibres. It occurs most commonly in children, and usually presents as a unilateral, inferior conjunctival mass of the lower eyelid. The lesion is known as ‘teddy bear granuloma’ because some cases were caused by materials used in stuffed toy animals.2
 
Seventeen cases of conjunctival synthetic fibre ‘teddy bear granuloma’ have been reported in the literature. To the best of our knowledge, this is the first reported case of this condition in Hong Kong.
 
Case report
A 7-year-old girl with good health presented to the ophthalmology clinic of United Christian Hospital, Hong Kong, in December 2012 with a left lower eyelid conjunctival mass for 1 month. There was no history of trauma. It was an incidental finding by the girl’s mother and the girl did not complain of any pain or discomfort. There was no change in visual acuity.
 
Examination showed a 3.5 mm x 1.5 mm conjunctival mass in the inferior fornix of her left lower eyelid (Fig a). It was embedded with a bunch of hair-like material. The lesion prolapsed easily with gentle pressure over the lower eyelid but could not be removed during slit-lamp examination. The rest of her ophthalmological examination was normal. The girl’s mother was very keen on removal of the mass. Excisional biopsy of the mass was performed under general anaesthesia. The mass was excised and sent for histopathological analysis.
 

Figure. (a) A slit-lamp photograph showing a conjunctival mass (arrows) in the inferior fornix of the left lower eyelid. Histopathological sections of the biopsy specimen: (b) conjunctival mucosal lesion contains numerous synthetic fibres in an inflamed background (H&E; original magnification, x 40); (c) synthetic fibres associated with foreign-body giant cell reaction are seen in an inflamed background (H&E; original magnification, x 100); (d) the synthetic fibres are refractile, colourless, and surrounded by histiocytic giant cells (H&E; original magnification, x 200)
 
Microscopic examination revealed a piece of conjunctival mucosa with stromal granulation tissue showing heavy chronic inflammation, mild activity, and aggregates of foreign body consistent with synthetic fibres, associated with giant cell reaction (Figs b to d). The fibres were refractile and colourless. In another section, scanty hair was seen in the stroma. The picture was compatible with a diagnosis of synthetic fibre granuloma of the conjunctiva.
 
Postoperatively, the wound healed well and there was no recurrence of the lesion at 1.5 years after excision.
 
Discussion
Protective mechanisms of the eye including blinking and tearing normally remove any foreign body that comes into contact with the ocular surface. Occasionally, foreign body may be retained in the eyelid fornix, encapsulated by mucous, embedded in the underlying stroma, and, subsequently, induces a local inflammatory response.2 Synthetic fibre granuloma of the conjunctiva occurs when synthetic fibres are inoculated in the conjunctiva of the eyelid fornix leading to an inflammatory reaction. The lesion is also commonly known as ‘teddy bear granuloma’ because some cases were caused by materials used in stuffed toy animals.2 Various other objects have been suggested as the source of the lesion, including blankets, beddings, and pullover sweaters.2 3 4
 
The majority of patients were brought in by parents or caretakers who identified a mass in the child’s eyelid. The patients were usually asymptomatic, without a history of trauma. Affected children may rarely present with symptoms of ocular irritation and foreign body sensation.5 Synthetic fibre conjunctival granuloma is usually unilateral, and mainly occurs in the inferior eyelid fornix, except in one reported case where it presented superiorly.1
 
Differential diagnoses of synthetic fibre conjunctival granuloma include chalazion, pyogenic granuloma, papillary hyperplasia, sarcoidosis, dermoid, or neoplasm including rhabdomyosarcoma.2 6 7 It has been proposed that the most reliable clinical sign to suggest this diagnosis was the presence of a unilateral inferior conjunctival mass in a child or adolescent.2 In addition, the histological features of synthetic fibre conjunctival granuloma are characteristic and diagnostic. Microscopic examination reveals granulomatous inflammatory cell response with lymphocytes, plasma cells and eosinophils, and foreign-body giant cells surrounding the exogenous synthetic fibres.4 8
 
Treatment of synthetic fibre conjunctival granuloma involves surgical removal of the foreign body and excision of the granuloma.2 Should the granuloma present early and the patient be compliant, it has been suggested to remove the lesion during slit-lamp examination under topical anaesthesia with minimal bleeding and discomfort.9 However, since the granuloma is usually present for a long duration before being noticed, the lesion could be deeply embedded. As a result, excision in the operating theatre under general anaesthesia is often needed, particularly when patients are very young and anxious. Prognosis following surgical excision is excellent.6
 
Although the entity of synthetic fibre conjunctival granuloma was recognised more than two decades ago, clinicians, including ophthalmologists and pathologists, are unfamiliar with this condition.4 While the number of reports in the literature is limited, accurate reporting may actually reveal a higher incidence of this entity.9 An awareness of this condition will allow early and accurate diagnosis and treatment, which subsequently spare the risks and expense associated with general anaesthesia.3
 
Declaration
No conflicts of interests were declared by authors.
 
References
1. Weinberg JC, Eagle RC Jr, Font RL, Streeten BW, Hidayat A, Morris DA. Conjunctival synthetic fiber granuloma. A lesion that resembles conjunctivitis nodosa. Ophthalmology 1984;91:867-72. CrossRef
2. Schmack I, Kang SJ, Grossniklaus HE, Lambert SR. Conjunctival granulomas caused by synthetic fibers: report of two cases and review of literature. J AAPOS 2005;9:567-71. CrossRef
3. Enzenauer RW, Speers WC. Teddy bear granuloma of the conjunctiva. J Pediatr Ophthalmol Strabismus 2002;39:46-8.
4. Ferry AP. Synthetic fiber granuloma. ‘Teddy bear’ granuloma of the conjunctiva. Arch Ophthalmol 1994;112:1339-41. CrossRef
5. Farooq MK, Prause JU, Heegaard S. Synthetic fiber from a teddy bear causing keratitis and conjunctival granuloma: case report. BMC Ophthalmol 2011;11:17. CrossRef
6. Shields JA, Augsburger JJ, Stechschulte J, Repka M. Synthetic fiber granuloma of the conjunctiva. Am J Ophthalmol 1985;99:598-600. CrossRef
7. Lueder GT. Synthetic fiber granuloma. Arch Ophthalmol 1995;113:848-9. CrossRef
8. Batta B, Robin A, George JL, Angioi K. “Teddy bear granuloma”, a rare condition: a case report of a 3-year-old child [in French]. J Fr Ophtalmol 2012;35:117-20. CrossRef
9. Resnick SC, Schainker BA, Ortiz JM. Conjunctival synthetic and nonsynthetic fiber granulomas. Cornea 1991;10:59-62. CrossRef
 
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Magnetic resonance imaging features of vascular leiomyoma of the ankle

Hong Kong Med J 2015 Feb;21(1):73–6
DOI: 10.12809/hkmj144259
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Magnetic resonance imaging features of vascular leiomyoma of the ankle
Alta YT Lai, MB, BS, FRCR1; CW Tam, FRCR, FHKAM (Radiology)1; John SF Shum, FRCR, FHKAM (Radiology)2; Jennifer LS Khoo, FRCR, FHKAM (Radiology)1; WL Tang, FHKCPath, FHKAM (Pathology)3
1 Department of Radiology, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong
2 Radiology Department, Hong Kong Baptist Hospital, Kowloon Tong, Hong Kong
3 Department of Clinical Pathology, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong
 
Corresponding author: Dr Alta YT Lai (altalai@gmail.com)
 
 Full paper in PDF
Abstract
Vascular leiomyoma is a benign soft tissue tumour with a predilection for middle-aged women. It is most often seen in the extremities, particularly in the lower leg. The typical lesion is a small, slow-growing subcutaneous nodule. These tumours are often unexpected or preoperatively confused with other soft tissue tumours including low-grade sarcomas, leading to wide surgical excision. This may partly be due to the relatively few studies delineating the characteristic imaging features of this entity. Here, the imaging findings of a case of vascular leiomyoma in the ankle are presented. Literature review of the magnetic resonance imaging findings of published reports and series of vascular leiomyomas of the extremities is also performed.
 
 
[Abstract in Chinese]
Case report
A 47-year-old previously healthy Hong Kong Chinese man presented in January 2012 with a 2-year history of a slow-growing painless mass over the right medial malleolus. Physical examination showed a soft, well-marginated, non-tender mass measuring 2 cm in diameter over the right medial malleolus. The patient was referred for ultrasound and subsequently magnetic resonance imaging (MRI; Figs a to i). The lesion was excised. Macroscopically, it was a disc-shaped mass with smooth outer surface. Cut section showed a mass with a thin capsule and homogeneous, greyish-to-whitish material without necrosis. Microscopy showed proliferation of smooth muscle cells associated with thick-walled blood vessels without evidence of malignancy. The histopathological diagnosis was vascular leiomyoma (Figs j and k).
 

Figure. A 47-year-old man with a 2-year history of a slow-growing, painless, soft ankle mass
(a) Grey-scale ultrasound and (b) power Doppler study demonstrate a well-circumscribed, mildly compressible, mildly echogenic, subcutaneous lesion adjacent to the right medial malleolus with intralesional slow-flow vessels. No feeding artery, dilated draining vein, or phlebolith is found. Overall features are suggestive of a mildly vascular solid mass. (c, g) It is well-circumscribed and markedly hyperintense with a peripheral hypointense rim (arrows) on axial and coronal T2-weighted images. (d) No susceptibility artefacts are observed in the lesion on gradient echo sequence image, suggesting the absence of intralesional haemorrhage. (e, h) It is slightly hyperintense to muscle on T1-weighted images, with (f, i) homogeneous enhancement upon intravenous administration of gadolinium. The underlying bone, subjacent flexor retinaculum (arrowhead) and medial ankle tendons (arrows) were intact. (j, k) Microscopic pictures of the tumour section include central blood vessels (arrows) surrounded by peripheral smooth muscle. The histopathological diagnosis is vascular leiomyoma (H&E, original magnification: [j] x 5 and [k] x 100)
 
Discussion
Vascular leiomyoma, angiomyoma or angioleiomyoma, is a rare benign smooth muscle tumour that originates in the tunica media of veins and arteries. It can be located in the skin, subcutaneous fat, or superficial fasciae of the extremities. It has a predilection for middle-aged women. It can occur anywhere in the body, but is most often seen in the extremities, particularly in the lower leg.1
 
The most frequent clinical presentation is a mass that enlarges slowly over several years. The size usually ranges from subcentimetre to a few centimetres in diameter, but occasionally may grow larger. They are usually oval or round in shape, and can be located in the skin, subcutaneous fat, or the superficial fasciae of the extremities.
 
Pain, with or without tenderness, has been reported in about 60% of patients, and is thought to be caused by the active contraction of smooth muscles resulting in local ischaemia, and is also suggested to be mediated by intratumoural nerve fibres.2 Treatment usually consists of marginal excision.2
 
Angioleiomyomas are rarely diagnosed preoperatively. In a series of 10 cases by Gupte et al1 in 2008, the preoperative or pre-biopsy imaging diagnoses included sarcoma not otherwise specified, schwannoma, myositis ossificans, synovial sarcoma, and fibroma. This may be partly due to the relatively few studies delineating the characteristic imaging features of this entity. The preoperative differentiation of angioleiomyoma from other soft tissue tumours is of clinical importance, especially sarcomas, since angioleiomyomas are benign and can be treated with simple excision. Literature review of the MRI findings of currently published reports and series of vascular leiomyomas of the extremities is presented below.
 
Literature review
Materials, methods, and patient demographics
A PubMed search of the English literature was performed, using the key words “vascular leiomyoma”, “angioleiomyoma”, and “angiomyoma”. From 1998 to 2011, 36 cases of biopsy-proven vascular leiomyomas in the extremities of adults with detailed descriptions of T1-weighted images (T1WI) and T2-weighted images (T2WI) were found. Articles without detailed descriptions or figures of T1WI and T2WI were excluded. Not all studies in the literature may have been included in this review because of unavailability in PubMed or in English language. After including our case, this review has 37 cases. The mean age of the patients was 51 years (range, 20-72 years). There were 16 male and 17 female patients; the gender of the remaining four patients was not stated.
 
Results
Among the 26 lesions with documented sizes, the mean size of the lesions was 3.2 cm (range, 0.4-12 cm). Overall, 40.5% (15/37) of the lesions were in the upper limb and 59.5% (22/37) were in the lower limb. All of them were located in the subcutaneous layer, were well-defined, and round, oval or disc-shaped. On T1WI, 91.9% (34/37) of the tumours showed isointense–to–slightly high signal intensity, 5.4% were heterogeneous, and 2.7% showed low signal intensity. On T2WI, all the cases demonstrated high signal intensity. Signal voids were seen in 10.8% (4/37) of the tumours, either on T1WI or T2WI. Among the 33 cases in which contrast was administered, only two (6.1%) cases showed no or poor enhancement, 93.9% (31/33) showed enhancement, 42.4% (14/33) were homogeneous, and 39.4% (13/33) were described as showing heterogeneous enhancement. One case showed peripheral enhancement, one showed central enhancement. One case showed rapid enhancement and one case demonstrated slow enhancement. Among the cases in which the presence or absence of peripheral hypointense rim was recorded, a hypointense rim was found on T2WI in 85.2% of cases (23/27; Table1 2 3 4 5 6 7 8 9 10 11 12 13 14).
 

Table. Magnetic resonance imaging findings in 37 patients with vascular leiomyomas in extremities1 2 3 4 5 6 7 8 9 10 11 12 13 14
 
Vascular leiomyomas often show similar signal intensity to that of muscle on T1WI. A T2WI is expected to demonstrate mixed areas that are hyper- and isointense to muscle. A well-defined peripheral T2-hypointense rim may be seen, representing the fibrous capsule. It has been reported that T2-hyperintense areas correlated with strong contrast enhancement, whereas isointense areas did not show enhancement after intravenous administration of contrast material.3 It was suggested that the smooth muscle and numerous vessels corresponded to the hyperintense areas, and the fibrous tissue appeared isointense on T2WI. Tortuous vascular structures with signal void may also be seen.
 
Imaging differentials
The differentials of a well-defined, enhancing, subcutaneous nodule or mass with T2-hyperintense signals include synovial sarcoma, other low-grade soft tissue sarcomas, haemangioma, neurogenic tumour, and nodular fasciitis.
 
Low-grade sarcomas such as synovial sarcoma and low-grade myxofibrosarcoma may be slow-growing and appear well-circumscribed on MRI, giving the misleading impression that the lesion is well-localised. Haemorrhage may be present in synovial sarcomas, which may be seen as fluid-fluid levels, T2 hypointensity, or “triple signal intensity”, namely areas of hyperintensity, isointensity and hypointensity relative to fat, due to presence of cystic, solid and fibrous elements with haemorrhage. It is unknown whether the absence of haemorrhage, a more homogeneous appearance, and the presence of a peripheral hypointense rim are reliable distinguishing features favouring angioleiomyoma over otherwise benign-appearing, soft tissue sarcomas; this may be a potential knowledge gap that future prospective comparison studies may serve to fill.
 
Haemangiomas may show homogeneous signals if these are small, making it challenging to differentiate from angioleiomyomas. Phleboliths can be sought for on plain radiographs. Fatty and serpentine vascular elements may be identified in haemangiomas, which are pathognomonic. The classical ‘target’ sign, ‘split-fat’ sign, and fusiform tumour shape demonstrated in neurogenic tumours are not found in angioleiomyomas. Although nodular fasciitis demonstrates similar shape and size as angioleiomyomas, linear extension along the fascia, surrounding oedema, low T1 signal, heterogeneous T2 signal, and non-homogeneous enhancement are features that differ from characteristic imaging features of angioleiomyoma.15
 
On microscopic examination, the presence of tortuous vascular channels surrounded by smooth muscle bundles and areas of myxoid change may be seen. This explains the heterogeneity of signal intensity in the tumour on T2WI. Magnetic resonance imaging–histopathological correlation published by Hwang et al2 stated that the smooth muscle and numerous vessels within each type of vascular leiomyoma corresponded with the hyperintense areas on T2WI, and the tough fibrous tissue appeared isointense on T2WI. In addition, a well-defined peripheral hypointense area on T2WI correlated with the fibrous capsule, and the interlacing isointense areas within the tumour correlated with the various quantity of connective tissue and intravascular thrombus.3
 
Conclusions
Vascular leiomyoma should be considered a possible diagnosis when a well-demarcated oval or round subcutaneous mass with T1-isointense–to–slightly high signal, T2-high signal intensity, hypointense rim, and intense enhancement is seen in the soft tissue of the extremities. It is unknown whether the absence of haemorrhage, a more homogeneous appearance, and the presence of a peripheral hypointense rim are reliable distinguishing features favouring angioleiomyoma over otherwise benign-appearing soft tissue sarcomas; this may be a potential knowledge gap that future prospective comparison studies may serve to fill.
 
References
1. Gupte C, Butt SH, Tirabosco R, Saifuddin A. Angioleiomyoma: magnetic resonance imaging features in ten cases. Skeletal Radiol 2008;37:1003-9. CrossRef
2. Hwang JW, Ahn JM, Kang HS, Suh JS, Kim SM, Seo JW. Vascular leiomyoma of an extremity: MR imaging–pathology correlation. AJR Am J Roentgenol 1998;171:981-5. CrossRef
3. Yoo HJ, Choi JA, Chung JH, et al. Angioleiomyoma in soft tissue of extremities: MRI findings. AJR Am J Roentgenol 2009;192:W291-4. CrossRef
4. Kinoshita T, Ishii K, Abe Y, Naganuma H. Angiomyoma of the lower extremity: MR findings. Skeletal Radiol 1997;26:443-5. CrossRef
5. Turhan-Haktanir N, Haktanir A, Demir Y, Tokyol C, Acar M. Toe leiomyoma: A case report with radiological correlation. Acta Chir Belg 2006;106:92-5.
6. Nagata S, Nishimura H, Uchida M, Hayabuchi N, Zenmyou M, Fukahori S. Giant angioleiomyoma in extremity: report of two cases. Magn Reson Med Sci 2006;5:113-8. CrossRef
7. Hamoui M, Largey A, Ali M, et al. Angioleiomyoma in the ankle mimicking tarsal tunnel syndrome: a case report and review of the literature. J Foot Ankle Surg 2010;49:398.e9-15.
8. Shafi M, Hattori Y, Doi K. Angioleiomyoma of distal ulnar artery of the hand. Hand (N Y) 2010;5:82-5. CrossRef
9. Gulati MS, Kapoor A, Maheshwari J. Angiomyoma of the knee joint: value of magnetic resonance imaging. Australas Radiol 1999;43:353-4. CrossRef
10. Kugimoto Y, Asami A, Shigematsu M, Hotokebuchi T. Giant vascular leiomyoma with extensive calcification in the forearm. J Orthop Sci 2004;9:310-3. CrossRef
11. Waldt S, Rechl H, Rummeny EJ, Woertler K. Imaging of benign and malignant soft tissue masses of the foot. Eur Radiol 2003;13:1125-36.
12. Sookur PA, Saifuddin A. Indeterminate soft-tissue tumors of the hand and wrist: a review based on a clinical series of 39 cases. Skeletal Radiol 2011;40:977-89. CrossRef
13. Okahashi K, Sugimoto K, Iwai M, Oshima M, Takakura Y. Intra-articular angioleiomyoma of the knee: a case report. Knee 2006;13:330-2. CrossRef
14. Stock H, Perino G, Athanasian E, Adler R. Leiomyoma of the foot: sonographic features with pathologic correlation. HSS J 2011;7:94-8. CrossRef
15. Walker EA, Fenton ME, Salesky JS, Murphey MD. Magnetic resonance imaging of benign soft tissue neoplasms in adults. Radiol Clin North Am 2011;49:1197-217. CrossRef
 
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Xanthogranulomatous inflammation of terminal ileum: report of a case with small bowel involvement

Hong Kong Med J 2015 Feb;21(1):69–72
DOI: 10.12809/hkmj134103
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Xanthogranulomatous inflammation of terminal ileum: report of a case with small bowel involvement
KC Wong, MCSHK, MRCSEd1; Wilson MS Tsui, FIAC, FRCPath2; SJ Chang, FRCS, FRCSEd1
1 Department of Surgery, Caritas Medical Centre, Shamshuipo, Hong Kong
2 Department of Pathology, Caritas Medical Centre, Shamshuipo, Hong Kong
 
Corresponding author: Dr KC Wong(kamkam44@gmail.com)
 
 Full paper in PDF
Abstract
Xanthogranulomatous inflammation is a rare pathological condition most frequently detected in the kidney and gallbladder. Reported herein is a case of xanthogranulomatous inflammation in a 51-year-old male presenting as a mass-forming lesion in the terminal ileum with mucosal ulceration. Diagnostic laparoscopy followed by ileocecectomy was performed due to intra-operative suspicion of carcinoma of appendix. This is a report of the condition involving the terminal ileum with mucosal ulceration and full-thickness involvement of bowel wall which are uncommon features of xanthogranulomatous inflammation in previously reported lower gastro-intestinal tract lesions.
 
 
[Abstract in Chinese]
Introduction
Xanthogranulomatous inflammation (XGI) is a rare but well-defined disease, first reported by Oberling in 1935.1 The disease process was most frequently reported in the kidney and gallbladder. Rare occurrence in the gastro-intestinal tract was illustrated in only one recently reported case in the terminal ileum,2 four reported cases in the colon,3 4 5 6 eight cases in a series of interval appendicectomy specimens,7 and eight cases with gastric involvement.8 9 10 11 12 13 Of the four cases with colonic involvement, two involved the sigmoid colon,3 4 one involved the caecum,5 and one involved the ascending colon.6 Most of these colonic lesions presented with a mass-forming lesion with predominant submucosal involvement, while primary mucosal involvement was only reported in the last case involving the ascending colon. We, herein, report the second case of XGI in the terminal ileum with mucosal ulceration and full-thickness involvement of the bowel wall, presenting as a painful right-lower-quadrant abdominal mass.
 
Case report
A 51-year-old Chinese male presented to the Emergency Department on 2 December 2012. He was a chronic smoker and alcoholic. He complained of right-sided abdominal pain for the past 2 weeks. The pain was not associated with nausea, vomiting, constipation, or diarrhoea. There was no anorexia or weight loss. There was no history of melaena. His medical history included diabetes, hypertension, and gout. There was no history of tuberculosis.
 
He was admitted to a hospital in Mainland China 10 days before the index admission for the same problem. While in that hospital, he had raised white cell count of 16.2 x 109 /L, and an ultrasound of abdomen revealed a gallstone and a renal stone. There was no hydronephrosis. A course of antibiotics was given, but the symptoms persisted. The patient returned from Mainland China on 2 December 2012, and attended our Emergency Department for further management.
 
On admission, the physical examination of the respiratory, cardiovascular, and central nervous systems was unremarkable. Abdominal examination revealed tenderness in the right lower quadrant. Per rectal examination revealed no blood, melaena, or mass. Abdominal X-ray showed no specific abnormalities.
 
His blood tests revealed mildly elevated white cell count of 10.6 x 109 /L (reference range [RR], 3.7-9.2 x 109 /L), haemoglobin level of 137 g/L (RR, 134-171 g/L), normal amylase level of 57 U/L (RR, 30-128 U/L), and normal electrolytes and liver enzymes. An urgent ultrasound of the abdomen and pelvis raised suspicion of acute appendicitis, with a tubular, non-peristaltic, non-compressible structure measuring 1.55 cm in diameter at the appendicular region, with small amount of loculated fluid around the lesion (Fig 1), corresponding with the site of maximum tenderness. The distal end of the lesion was obscured by bowel gas; it could not be ascertained whether it was blind-ended. The same study also revealed the presence of a gallstone and a right lower pole renal stone.
 

Figure 1. An ultrasound image of the right-lower-quadrant mass showing a tubular, non-peristaltic, non-compressible structure in the appendicular region with small amount of loculated free fluid (arrow) around the lesion. The distal end of the lesion is obscured by bowel gas; it could not be ascertained whether it was blind-ended
 
With a preliminary diagnosis of acute appendicitis, diagnostic laparoscopy was performed on 3 December 2012. There was an ileocaecal mass fixed to the posterior abdominal wall, which was difficult to mobilise despite an open approach via gridiron incision. Upon conversion to midline laparotomy, a large inflammatory mass was found at the ileocaecal junction, compatible with an infiltrative tumour. The mass demonstrated through-and-through invasion into the ileal mesentery, involving several loops of the ileum. Ileocaecal lymph node enlargement was noted. The appendix was not identified. There was no gross cavity or pus. With the suspicion of carcinoma of appendix, limited right hemicolectomy with en-bloc resection of the mass together with 65 cm of the terminal ileum, caecum, and proximal ascending colon was performed. Primary sub-end to sub-end, side-to-side anastomosis was fashioned.
 
The postoperative course of the patient was complicated by on-and-off fever with elevated white cell count of up to 22.5 x 109 /L. Blood culture taken on postoperative day 2 yielded no bacterial growth. Erythema and serous discharge were noted in the paraumbilical region of the laparotomy and gridiron wounds, which were managed with dressing and packing. Wound swab yielded scanty growth of Escherichia coli. The fever responded to a 10-day course of cefuroxime and metronidazole. He was discharged on postoperative day 10.
 
A colonoscopy done 4 months after the operation in April 2013 revealed no abnormalities.
 
Pathological examination
Gross examination of the ileocolectomy specimen revealed a 0.5-cm ileal mucosal ulcer, which was 1.5 cm proximal to the ileocaecal valve. The periappendicular mass was haemorrhagic and covered with exudate, within which was a retrocaecal appendix, measuring 5 cm in length and 1 cm in diameter, surrounded by necrotic and yellowish tissue. Cut surface of the appendix was unremarkable. A few lymph nodes were found in the ileocaecal fossa.
 
Microscopic examination of the appendicular mass showed abscess, haemorrhage, and XGI which consisted predominantly of foamy histiocytes, scattered neutrophils, lymphoplasmacytic cells, a few multinucleated giant cells, and congested capillaries with surrounding fibrosis (Fig 2). The foamy histiocytes were positive for CD68 on immunostaining, confirming their histiocytic origin. No Michaelis-Gutmann bodies were detected. The terminal ileum ulcer revealed similar XGI which extended through the bowel wall to involve the mesentery. The appendicular mucosa showed no neutrophilic infiltrate. A few reactive lymph nodes were noted. There was no evidence of malignancy or granuloma.
 

Figure 2. Microscopic examination of the appendicular mass. (a) Terminal ileum featuring ulceration (arrow) and underlying inflammation (H&E; original magnification, x 10). (b) Appendix buried in the inflammatory mass but showing intact muscle wall and non-inflamed mucosa (H&E; original magnification, x 10). (c) Xanthogranulomatous inflammation comprising mainly foamy histiocytes (arrows), scattered neutrophils, a few lymphoid cells, and congested capillaries (H&E; original magnification, x 100). (d) High-power view to reveal the lipid-laden foamy histiocytes (arrows) [H&E; original magnification, x 400]
 
Discussion
Xanthogranulomatous inflammation is a form of chronic inflammatory condition characterised macroscopically by mass-forming golden yellow tumours and microscopically by aggregation of lipid-laden foamy histiocytes including multinucleated giant cells, with a minor component of chronic and acute inflammatory cells and fibrous reaction. It was first described by Oberling in 1935 in three cases of retroperitoneal xanthogranulomas.1 Its occurrence in the endometrium, ovary, fallopian tubes, vagina, testis, epididymis, stomach, bone, skin (as fistulation secondary to inflammation primarily involving another internal organ),14 appendix,7 15 urinary bladder, thyroid, and adrenal glands has been reported, with the highest prevalence reported in the kidney and gallbladder. A majority of XGI cases present as a mass-like lesion with an extension of fibrosis and inflammation to the surrounding tissues, leading to diagnostic difficulties in differentiating them from infiltrative malignant tumours.
 
Pathological differential diagnoses bearing similar histological features include malakoplakia, which is characterised by an inflammatory and destructive xanthomatous proliferation with the presence of Michaelis-Gutmann bodies, which are intracytoplasmic laminated concretions usually positive for periodic acid–Schiff, von Kossa, and Prussian blue stains. Macrophages known as von Hansemann cells are more granular and eosinophilic and have less vacuolated cytoplasm than ordinary histocytes. Other differential diagnoses include localised xanthoma deposits without parenchymal destruction or xanthomas with prominent foam cell features.
 
Although the pathological features of XGI are well described, its exact pathogenesis is not well established.
 
Various proposed mechanisms include chronic recurrent infection, obstruction, immunological disorders, and defective lipid transport. It is generally believed that the localised proliferation of lipid-laden foamy histiocytes in XGI represents chronic suppurative inflammation secondary to interaction between the host and micro-organisms. Examples of immunological disorders include disrupted chemotaxis of polymorphs and macrophages, which is a specific immune response toward Proteus and Escherichia infections. A recently reported case2 involving the terminal ileum proposed a possible mechanism of perforation due to an ingested foreign body. However, none of the above hypotheses were able to fully explain the anatomical distribution of the condition, which is most common in the appendix where neither perforation due to ingested foreign bodies nor chronic suppurative inflammation is most often found. In this reported case, infected laparotomy wound swab yielded E coli, while there were no symptoms to suggest pre-existing chronic suppurative inflammation. There was no evidence of a penetrating foreign body on history or gross examination of the pathological specimen.
 
Rare occurrence of XGI in the lower gastro-intestinal tract is illustrated by only one reported case in the terminal ileum,2 four reported cases in the colon with two involving the sigmoid colon,3 4 one involving the caecum,5 and one involving the ascending colon.6 However, a histopathological review of 22 interval appendicectomy specimens by Guo and Greenson7 in 2003 reported presence of XGI in eight cases (36.4%) of interval appendicectomy versus none in the 44 matched patients receiving acute appendicectomy, suggesting XGI may be underreported as a delayed consequence of acute inflammation and that these histological changes are secondary to the time interval of inflammation rather than intrinsic factors specific to the patient or disease.
 
Due to endoscopic, radiological, and the intra-operative macroscopic resemblance to infiltrative malignant neoplasms, these lesions warrant excision with a wide margin, similar to treatment of locally advanced malignancies.
 
However, there has been inadequate evidence to suggest association between XGI and gastro-intestinal malignancies. Of the eight cases of XGI of the stomach reported in the literature,8 9 10 11 12 13 co-existence of XGI with gastric cancer was reported in three cases. Histological examination of these cases did not support continuity between the xanthogranuloma and adenocarcinoma. In the other case of XGI in the terminal ileum reported by Yoon et al,2 preoperative endoscopy and biopsy showed ulcers with acute and chronic inflammation only. However, surgical resection was considered unavoidable in view of the radiological findings highly suggestive of appendiceal cancer. While preoperative endoscopic biopsy may not be helpful to exclude malignancy as most of the lesions are submucosal, intra-operative frozen section may be helpful to avoid unnecessary radical surgery.
 
Conclusion
We report a case of XGI with full-thickness involvement of the terminal ileum presenting with a tender intraperitoneal mass. This report aimed to emphasise ileal involvement of XGI, although rare, as one of the differential diagnoses of mass lesions in the small bowel mimicking malignant neoplasms.
 
Declaration
No conflicts of interest were declared by the authors.
 
References
1. Oberling C. Retroperitoneal xanthogranuloma. Am J Cancer 1935;23:477-89. CrossRef
2. Yoon JS, Jeon YC, Kim TY, et al. Xanthogranulomatous inflammation in terminal ileum presenting as an appendiceal mass: case report and review of the literature. Clin Endosc 2013;46:193-6. CrossRef
3. Lo CY, Lorentz TG, Poon CS. Xanthogranulomatous inflammation of the sigmoid colon: a case report. Aust N Z J Surg 1996;66:643-4. CrossRef
4. Oh YH, Seong SS, Jang KS, et al. Xanthogranulomatous inflammation presenting as a submucosal mass of the sigmoid colon. Pathol Int 2005;55:440-4. CrossRef
5. Anadol AZ, Gonul II, Tezel E. Xanthogranulomatous inflammation of the colon: a rare cause of cecal mass with bleeding. South Med J 2009;102:196-9.
6. Dhawan S, Jain D, Kalhan SK. Xanthogranulomatous inflammation of ascending colon with mucosal involvement: report of a first case. J Crohns Colitis 2011;5:245-8. CrossRef
7. Guo G, Greenson JK. Histopathology of interval (delayed) appendectomy specimens: strong association with granulomatous and xanthogranulomatous appendicitis. Am J Surg Pathol 2003;27:1147-51. CrossRef
8. Zhang L, Huang X, Li J. Xanthogranuloma of the stomach: a case report. Eur J Surg Oncol 1992;18:293-5.
9. Guarino M, Reale D, Micoli G, Tricomi P, Cristofori E. Xanthogranulomatous gastritis: association with xanthogranulomatous cholecystitis. J Clin Pathol 1993;46:88-90. CrossRef
10. Lespi PJ. Gastric xanthogranuloma (inflammatory malignant fibrohistiocytoma). Case report and literature review [in Spanish]. Acta Gastroenterol Latinoam 1998;28:309-10.
11. Lai HY, Chen JH, Chen CK, et al. Xanthogranulomatous pseudotumor of stomach induced by perforated peptic ulcer mimicking a stromal tumor. Eur Radiol 2006;16:2371-2. CrossRef
12. Kubosawa H, Yano K, Oda K, et al. Xanthogranulomatous gastritis with pseudosarcomatous changes. Pathol Int 2007;57:291-5. CrossRef
13. Kinoshita H, Yamaguchi S, Sakata Y, Arii K, Mori K, Kodama R. A rare case of xanthogranuloma of the stomach masquerading as an advanced stage tumor. World J Surg Oncol 2011;9:67. CrossRef
14. Rogers S, Slater DN, Anderson JA, Parsons MA. Cutaneous xanthogranulomatous inflammation: a potential indicator of internal disease. Br J Dermatol 1992;126:290-3.
15. Chuang YF, Cheng TI, Soong TC, Tsou MH. Xanthogranulomatous appendicitis. J Formos Med Assoc 2005;104:752-4. CrossRef
 
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Generalised involuntary limb twitching after ingestion of Mesobuthus martensii Karsch (Quanxie) powder

Hong Kong Med J 2014 Dec;20(6):552–5
DOI: 10.12809/hkmj134091
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Generalised involuntary limb twitching after ingestion of Mesobuthus martensii Karsch (Quanxie) powder
PK Lam, FHKAM (Emergency Medicine), Dip Clin Tox1; TW Wong, FRCSEd, FHKAM (Emergency Medicine)1; YC Chan, FRCSEd, FHKAM (Emergency Medicine)2; Tony WL Mak, FRCPath, FHKAM (Pathology)3
1 Department of Accident and Emergency, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong
2 Hong Kong Poison Information Centre, United Christian Hospital, Kwun Tong, Hong Kong
3 Hospital Authority Toxicology Reference Laboratory, Princess Margaret Hospital, Laichikok, Hong Kong
 
Corresponding author: Dr PK Lam (lampkrex@hotmail.com)
 
 Full paper in PDF
Abstract
Mesobuthus martensii Karsch, commonly known as the Chinese scorpion or Manchurian scorpion, has been used in traditional Chinese medicine as Quanxie to treat chronic pain, tetanus, tremors, convulsion, and paralysis for more than a thousand years. We report a case of poisoning after ingestion of a teaspoon of Quanxie powder. The patient presented with chest pain, dizziness, diaphoresis, generalised involuntary limb twitching, and hypertonia around 15 minutes post-ingestion. The patient recovered uneventfully after supportive management. Intravenous diazepam appeared to be effective in alleviating limb twitching. Failure to accurately measure the dose and to boil before consumption may have contributed to his clinical toxicities.
 
 
[Abstract in Chinese]
Case report
A 63-year-old man complained of chest pain, dizziness, and generalised tremors 15 minutes after ingestion of a teaspoon of herbal powder with water in September 2012. He had started taking herbal decoctions prescribed by a registered Chinese medicine doctor 1 month ago because of suboptimal pain control of his trigeminal neuralgia with western medicine. He presented around 2 to 3 hours post-ingestion to our emergency department because of persistent symptoms. He was fully conscious but the limb tremor was so severe that he could barely walk. There was no numbness, headache, or any gastro-intestinal (GI) symptom. Apart from trigeminal neuralgia, he also had a history of ischaemic heart disease and hypercholesterolaemia. The medication on-hand included aspirin, famotidine, simvastatin, metoprolol, isosorbide mononitrate, diclofenac, dihydrocodeine, tramadol, and carbamazepine but he denied overdosing of any of those drugs. He had not taken any other herbs, over-the-counter medicines, or other suspicious foods such as coral reef fish and shellfish.
 
On arrival he was fully conscious with a Glasgow Coma Scale score of 15/15. His vital signs were as follows: blood pressure 126/95 mm Hg, pulse rate 66 beats/min, respiratory rate 18 breaths/min, oxygen saturation by pulse oximetry (SaO2) 99% on supplemental oxygen 2 L/min via a nasal cannula, and tympanic temperature 36.6°C. He appeared nervous with diaphoresis. Both his pupils were 2 mm in size and reactive to light. Cranial nerve examination was unremarkable but generalised involuntary limb twitching with hypertonia was evident. The muscle power in his four limbs was 5/5. Hyperreflexia and bilateral upgoing plantar reflexes were noted; there was no ankle clonus. Cardiovascular examination was unremarkable and his chest was clear. No distended urinary bladder or abnormal bowel sounds were noted. Repeated electrocardiograms showed sinus rhythm with normal axis. First-degree heart block was noted but there were no definite ischaemic changes. The QRS duration and the corrected QT interval were 89 ms and 431 ms, respectively. Chest X-ray revealed marginal cardiomegaly with clear lung field. The spot haemostix level was 6.2 mmol/L. Other blood tests including a complete blood picture, urea and electrolytes, serum calcium level, liver function tests, troponin-I, and arterial blood gas were essentially unremarkable, except a slightly raised creatine kinase (CK) level of 408 IU/L (reference range, 24-180 IU/L), which was likely due to generalised muscle twitching.
 
His chest pain decreased after administering 3 mg of intravenous (IV) morphine. Subsequently, his blood pressure dropped to 66/48 mm Hg but responded to fluid challenge with 500 mL of IV 0.9% normal saline. Less limb twitching was noted after administering 5 mg of IV diazepam. The provisional diagnosis was suspected Chinese herbal medicine (CHM)–related neurotoxicity but at the time of presentation, the formula of the herbal decoction was not available for identifying the culprit. The patient was admitted to the intensive care unit (ICU) for close monitoring in view of the unstable haemodynamic status upon presentation, which may have been the result of CHM toxicity or hypotensive effect of morphine.
 
Seven sheets of CHM prescription formula were subsequently traced back by the patient’s son 3 hours after admission. The Hong Kong Poison Information Centre was consulted for opinion. Multiple ingredients, including Quanxie (全蝎, Mesobuthus martensii Karsch), were prescribed according to the formula. However, the patient had remained free of side-effects in the previous month when he took the herbal decoctions as instructed. Further questioning revealed that the patient had found his pain control unsatisfactory even after taking the herbal decoctions. After receiving verbal advice from his Chinese medicine doctor, he took a few pieces of scorpion from the herb package and put them into a food blender. He took a teaspoon of the powder directly with water; this was the first time he took the herb in this form and fashion. He developed symptoms soon after ingestion.
 
The patient’s twitching decreased gradually after ICU admission but he remained hypertonic, which warranted administering another dose of IV diazepam 2 mg 10 hours after admission. Otherwise, he was fully conscious with a stable haemodynamic status. Computed tomography of the brain was unremarkable. His symptoms gradually resolved and he was discharged from the ICU and transferred to the Emergency Medicine Ward 16 hours after admission. His CK level peaked to 413 IU/L and normalised on day 2. He was discharged 36 hours after admission, and was totally asymptomatic on follow-up 5 days later.
 
The patient’s serum and urine samples, together with the unused herbs and herbal powder, were sent to the Hospital Authority Toxicology Reference Laboratory for further analysis. Poisoning due to other toxic herbs, such as aconitine, strychnine, and matrine was ruled out by liquid chromatography-mass spectrometry of the leftover herbal powder. However, detection of the toxic peptides of M martensii was not possible as the laboratory was not equipped to test for these toxins. The patient’s urine sample revealed the presence of diclofenac, dihydrocodeine, carbamazepine metabolite, salicylic acid and famotidine but these were the usual medications taken by the patient. The serum salicylate level was far below the toxic level. Judging from the history and absence of other toxic alkaloids to explain the symptoms, the diagnosis of this case was compatible with neurotoxicity associated with the consumption of M martensii powder, even though it could not be directly confirmed by chemical analysis.
 
Discussion
Mesobuthus martensii Karsch (synonym: Buthus martensii Karsch), commonly known as Chinese scorpion or Manchurian scorpion (東亞鉗蝎 or 馬氏鉗蝎), belongs to the Buthidae family, and is widely distributed in China. The whole body of the scorpion has been used in traditional Chinese medicine as Quanxie for more than a thousand years (Fig). It functions through the liver meridian, extinguishing wind, and stopping tremors and convulsion. According to the literature in traditional Chinese medicine, common indications include chronic pain, tetanus, tremors, acute/chronic childhood convulsions, paralysis, cerebral vascular accident, and fire toxic nodules.1 Its use is contra-indicated during pregnancy and should be avoided in cases of internal wind with blood deficiency. The recommended dose is 3 to 6 g for herbal decoction2 and 0.5 to 1 g for herbal powder.3
 

Figure. Quanxie (dried Mesobuthus martensii)
 
The venom of M martensii is complex. At least 51 long-chain peptides related to the sodium (Na+) channel toxin family and 18 peptides related to the potassium (K+) channel toxin family have been described4 and more have yet to be discovered. Neurotoxins affecting the Na+ channel consist of α (highly active in mammalian brain) and β (highly active in insects) toxins. Many β toxins, which are not noxious to mammals, were found to have analgesic properties in animal models without the risk of dependence.5 Recently, a novel peptide, BmK-YA, was found to contain an enkephalin-like sequence and can activate the mammalian δ opioid receptor.6 Novel peptides with antiepileptic (eg BmK AEP),7 antitumour (BmK AGAP),8 and antibacterial (BmKn2-7)9 effects in animal models have also been identified in the venom. These findings provide molecular evidence to support its traditional use in Chinese medicine, but relevant clinical studies are still lacking.
 
Although known to be toxic in traditional Chinese medicine, so far, literature on Quanxie poisoning has been rather limited. Many of the reported cases were due to therapeutic overdose,10 which might be related to the way the scorpions are processed. Traditionally, the captured scorpions are put into water for a few hours to allow them to spit out soil from gut, pass retained faeces, and clean the dirt over their bodies. Thereafter they are either boiled with plain water or salt water, resulting in ‘plain’ Quanxie (淡全蝎) and ‘salted’ Quanxie (鹽全蝎), respectively. Boiling kills the scorpion and decreases its toxicity. The addition of salt serves to preserve the processed scorpions for prolonged periods. The majority of the processing is undertaken in scorpion farms and there is a lack of standardised protocol.11 The details of processing vary from place to place, resulting in variable therapeutic effects, even with the same dose. Moreover, many merchants try to add more salt when processing salted Quanxie to increase its weight, for more profit in sale. The salt content in salted Quanxie could be up to 44.82% in the market,12 resulting in inadequate therapeutic effects with the recommended dose. Therefore, many traditional Chinese medicine doctors may opt to use a higher-than-recommended dose to achieve the targeted effect, thus increasing the risk of clinical toxicities.10
 
In our case, it is difficult to estimate the amount of Quanxie actually consumed as the powder had not been accurately weighed before consumption. With a standard teaspoon, the patient could have taken 5 to 6 g of the powder, which is higher than the recommended dose. Failure to boil before ingestion might also have contributed to his clinical toxicities.
 
The clinical features of M martensii (Quanxie) poisoning are summarised in the Table.10 13 14 15 There is no specific antidote, such as anti-venom, for this condition. The mainstay of treatment is supportive. The toxicokinetics of Quanxie have not yet been thoroughly studied. Judging from the rapid onset of clinical symptoms after oral ingestion, we believe that GI absorption is rapid. Gastro-intestinal decontamination with gastric lavage or activated charcoal can be considered if the patient presents within 1 hour of ingestion and has a protected airway. Such a time frame for GI decontamination has also been recommended for other toxic herbs with rapid GI absorption, such as aconitine. Clinicians may choose to consider GI decontamination in patients presenting beyond 1 hour after ingestion but the benefit and risk should be carefully weighed on a case-to-case basis. The benefit would certainly decline with time, which may not justify the risk of aspiration, especially when neurotoxic features such as generalised twitching have already set in, making the administration of activated charcoal further difficult. As Quanxie has not been shown to have enterohepatic circulation or prolonged GI absorption, multi-dose activated charcoal is not recommended. Benzodiazepines appeared effective in alleviating limb twitching muscle spasm in our case but its role in the management of M martensii poisoning remains to be elucidated.
 

Table. Clinical features of Mesobuthus martensii (Quanxie) poisoning10 13 14 15
 
Declaration
No conflicts of interests were declared by authors.
 
References
1. Li N, Yu M, Hu LN, Lin J. Collation of animal drugs — Quanxie [in Chinese]. Jilin J Tradit Chin Med 2009;29:805-6.
2. Committee of National Pharmacopoeia. Chinese pharmacopoeia [in Chinese]. Vol 1. Beijing: Chemical Industry Press; 2010: 133-4.
3. The editorial committee of “Chinese Herbals”, State Administration of Traditional Chinese Medicine. Chinese Materia Medica [in Chinese]. Vol 9. Shanghai: Shanghai Science & Technology Press; 1999: 129-35.
4. Goudet C, Chi CW, Tytgat J. An overview of toxins and genes from the venom of the Asian scorpion Buthus martensii Karsch. Toxicon 2002;40:1239-58. CrossRef
5. Shao JH, Zhang R, Ge X, Yang B, Zhang JH. Analgesic peptides in Buthus martensii Karsch: a traditional Chinese animal medicine. Asian J Tradit Med 2007;2:45-50.
6. Zhang Y, Xu J, Wang Z, Zhang X, Liang X, Civelli O. Bmk-YA, an encephalin-like peptide in scorpion venom. PLoS One 2012;7:e40417. CrossRef
7. Zhou XH, Yang D, Zhang JH, Liu CM, Lei KJ. Purification and N-terminal partial sequence of anti-epilepsy peptide from venom of the scorpion Buthus martensii Karsch. Biochem J 1989;257:509-17.
8. Liu YF, Zhang ZG, Mao YZ, et al. Production and antitumor efficacy of recombinant Buthus martensii Karsch AGAP. Asian J Tradit Med 2009;4:228-33.
9. Cao L, Dai C, Li Z, et al. Antibacterial activity and mechanism of a scorpion venom peptide derivative in vitro and in vivo. PLoS One 2012;7:e40135. CrossRef
10. Chang JM. Adverse effects of Quanxie [in Chinese]. J China Pharm 2003;14:484-5.
11. Gao ZJ. Brief review of the processing methods of Quanxie [in Chinese]. J Community Med 2006;4:59-60.
12. Shao XH, Kong XS, Fang LH. Processing of Quanxie and its clinical application [in Chinese]. Lishizhen Med Materia Medica Res 2006;17:232-3.
13. Chen XM. Analysis of adverse effects of Quanxie [in Chinese]. Lishizhen Med Materia Medica Res 2003;14:635.
14. Xiao YC. A case report of neurotoxicity induced by centipede and Quanxie [in Chinese]. China J Chin Materia Medica 1996;21:634.
15. Dai Y. A case report of free decoction for treatment of Quanxie [in Chinese]. J Jilin Med Coll 2009;3:342.

An outbreak of refrigerant-induced acute hepatitis in Hong Kong

Hong Kong Med J 2014 Dec;20(6):548–51
DOI: 10.12809/hkmj134012
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
An outbreak of refrigerant-induced acute hepatitis in Hong Kong
YM Kan, MB, BS, FHKAM (Medicine); CF Lau, MRCP, FHKAM (Medicine); WC Chan, MRCP; WS Chan, MB, BS, FHKAM (Medicine); YM Tung, MRCP, FHKAM (Medicine); CK Loo, MRCP, FHKAM (Medicine)
Department of Medicine and Geriatrics, Kwong Wah Hospital, Yaumatei, Hong Kong
 
Corresponding author: Dr YM Kan (kanym@ha.org.hk)
 
 Full paper in PDF
Abstract
We report a cluster of acute hepatitis in five air-conditioning maintenance workers following accidental exposure to 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123). They presented to us with complaints of feverishness, generalised malaise, and epigastric discomfort. Their blood biochemistry tests were compatible with acute hepatitis. Viral hepatitis serology, tests for autoimmune hepatitis, and analyses for drugs and alcohol consumption were all negative. No focal hepatic lesion was detected by ultrasound imaging. Percutaneous liver biopsy samples were taken from two of them. The patients were managed with supportive treatment. All had spontaneous, but slow, recovery. Their liver function tests returned to normal after 4 months and their outcomes were favourable. Physicians should be aware of this occupational disease entity.
 
 
[Abstract in Chinese]
Case report
A 30-year-old air-conditioning maintenance worker presented to the Accident and Emergency Department in September 2010 with complaints of feverishness, dry cough, general malaise, poor appetite, and epigastric discomfort for 1 week. His initial symptoms 1 week before included feverishness and dry cough. He took paracetamol (500 mg, 4 times a day for 2 days) after consulting a general practitioner and diagnosed as having acute upper respiratory tract infection. Two days after visiting the general practitioner, he developed general malaise, nausea, and epigastric bloating. He had good past health and his family history was unremarkable. He was a social drinker and his last drink was almost 3 months ago. On physical examination, he was febrile and showed a tinge of jaundice. He was conscious and well-oriented. His pulse rate was 140 beats/min, the blood pressure was 130/75 mm Hg, and his body temperature was 39.3°C. Abdominal examination showed right upper quadrant tenderness but no other sign of acute abdomen; Murphy’s sign was negative.
 
Initial investigation showed elevated blood leukocyte count and mild thrombocytopenia (Table). His liver function tests were deranged and clotting profile was impaired. Serology for hepatitis A, B, C and E, Epstein-Barr virus, and cytomegalovirus was negative. Tests for antinuclear antibodies and anti-smooth muscle antibodies were also negative.
 

Table. Progression of the patient
 
His toxicology screening was negative, except for a serum paracetamol level of 77 mmol/L (taken 6 hours after the last dose of paracetamol). Ultrasound of the abdomen was unremarkable. His liver function tests further deteriorated after admission (Table) and he remained febrile. Computed tomography of the abdomen was then performed, which revealed minimal amount of ascites and non-specific pericholecystic fluid collection.
 
He received intravenous hydration and vitamin K as supportive treatment for his acute hepatitis. He remained fully oriented, and his serum ammonia level was normal.
 
Upon further enquiry, the patient recalled that he experienced dizziness, drunk feeling, and unsteady gait after exposure to a refrigerant during maintenance of an air-conditioning system in a computer server room with an area of around 200 m2. His job was to flush the air-conditioning system and pipeline with a cleansing refrigerant. He said he was not provided with any protective gear. He was, therefore, asked to call his co-workers to see if they had developed similar symptoms.
 
Eight workers worked in rotation for 2 weeks. They were posted to clean and repair the air-conditioning system in an enclosed area without any local exhaust ventilation system. In the first week, they were not provided with any effective protective gears. They worked for 6 hours a day in the first week. In the next week, they were provided with 3M face masks and their work duration shortened to 3 hours a day because they felt dizzy during work and needed to leave the room for a rest. Thus, exposure to leaked refrigerant was estimated to be high in such an enclosed workplace in the absence of effective protective gear. All workers experienced headache, dizziness, unsteady gait, and drunk feeling 15 minutes after exposure to the chemical released. They also had symptoms of dry cough, runny nose, fever, malaise, and loss of appetite a few days later. One of them also noticed passing tea-coloured urine and two had epigastric bloating.
 
Four among his seven co-workers agreed to undertake laboratory investigations. They were all found to have deranged liver function tests compatible with acute hepatitis. All investigations including viral hepatitis serology, tests for autoimmune hepatitis, and analyses for drugs and alcohol consumption were found to be negative. The circumstantial evidence, together with the clinical and laboratory findings, made refrigerant-induced acute hepatitis highly likely in this group of air-conditioning maintenance workers.
 
Percutaneous liver biopsy in one of the affected patients revealed the presence of hepatocytic dropouts and mitotic figures in perivenular distribution. There was moderate lymphocytic infiltrate with scattered eosinophils in the portal areas with mild bile duct proliferation. Perivenular hepatocytic cholestasis was also evident (Fig). These features, coupled with the clinical history and laboratory findings, were in keeping with a diagnosis of hydrochlorofluorocarbons-related hepatitis.
 

Figure. Liver biopsy: hepatocytic dropouts and mitotic figures in perivenular distribution (H&E; original magnification, x 40)
 
However, urine analysis of volatile organic hydrocarbons, metabolites of 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123), on day 4 after admission of the index patient, turned out to be negative.
 
Over the following days, our index patient’s symptoms improved progressively. His liver function tests, serum platelet count, and prothrombin time (given by the international normalised ratio) started to improve since day 5 of admission (Table). His coworkers’ symptoms also improved gradually.
 
Four months later, the health conditions of all the workers were confirmed to be normal. Their liver function tests had normalised. All had favourable outcomes.
 
We reported the cases to the Labour Department and the Department of Health since poisoning by halogen derivatives of hydrocarbon of the aliphatic series (ie HCFC-123) is a notifiable occupational disease in Hong Kong.
 
Discussion
HCFC-123 is a common refrigerant. It is one of the major substitutes for ozone-depleting chlorofluorocarbons used mainly as a refrigerant in chillers for industrial air-conditioning and in other applications such as foam blowing, cleansing agents, and industrial solvents. It is a colourless liquid with a light ether-odour and a boiling point of 27.6°C.1
 
Acute exposure to HCFC-123 has been shown to produce severe hepatotoxicity in guinea pigs.2 A single acute exposure to 1000 ppm of HCFC-123 for 4 hours can cause increases in aspartate aminotransferase and alanine aminotransferase levels compatible with hepatocellular necrosis. Increased liver weight, focal liver necrosis, induction of peroxisomal activity and hepatocellular adenomas have been found in subchronic studies in rats and dogs.3
 
The mechanism of hepatotoxicity of HCFC-123 was believed to be similar to that of 1-bromo-1-chloro-2,2,2-trifluoroethane (halothane). Halothane is metabolised to form reactive trifluoroacetyl halide intermediates that can react with water to form trifluoroacetyl haptens which result in direct hepatotoxicity. Since HCFC-123 is metabolised in the same oxidative way as halothane, HCFC-123 exposure might result in direct hepatotoxicity. In animal studies, the relative concentrations of trifluoroacetyl-protein adducts formed in the liver after administration of halothane and HCFC-123 were found to be similar.4 Alternatively, in-vitro metabolic studies of the human liver cytochrome P450 2E1 showed that exposure of human beings to HCFC-123 might result in higher concentrations of trifluoroacetyl-adducted liver proteins than those produced by halothane. The development of autoantibodies against P450 2E1 or P58 arising from immune reactions induced by trifluoroacetyl-adducted liver protein indicates that HCFC-related hepatotoxicity might also be immune-related.3
 
Takebayashi et al1 reported a cluster of acute liver dysfunction among workers exposed to HCFC-123 for less than 5 hours. Nine out of 14 workers developed impairment of liver function tests and symptoms of poor appetite and abdominal pain. Alanine aminotransferase level went up to more than 1700 U/L in these patients, but all had a favourable outcome. By the end of 2 months after HCFC-123 exposure, their liver function tests had returned to normal. This revealed that the incidence of liver dysfunction after HCFC-123 exposure is high.
 
Hoet et al3 investigated an epidemic of liver disease in nine industrial workers who had repeated accidental exposure to a mixture of HCFC-123 and HCFC-124. The results of this study also showed that repeated exposure of humans to HCFCs can result in serious liver injury in a high proportion of the exposed population. The liver biopsy showed hepatocellular necrosis which was prominent in perivenular zone 3, and extended focally across portal tracts and to centrilobular areas. The hepatocyte dropout was well-developed. The leukocytic inflammatory infiltrates in the zones of necrosis were mononuclear. Trifluoroacetyl-adducted proteins were detected in surviving hepatocytes by immunohistochemical staining. Serum autoantibodies against P450 2E1 or P58, which are associated with halothane hepatitis, were also detected. In our index patient, the presence of hepatocytic dropouts, increased mitotic figures and eosinophils might suggest acute hepatitis and liver regeneration after a short period of refrigerant exposure.
 
At moderate levels of exposure to HCFC-123, such as in some occupational accidents or prolonged exposure in poorly ventilated areas, respiratory effects (cough, dyspnoea, and tachypnoea), central nervous system effects (dizziness, drowsiness, weakness, fatigue, numbness, and coma), and gastro-intestinal upsets are characteristic. Hepatic injury (with elevated liver enzymes) and rhabdomyolysis might also rarely occur.5 A retrospective study showed that workers who had exposure to HCFC-123 experienced symptoms related to the central nervous system, gastro-intestinal upset, and irritation of mucous membrane.6 These may include headache, dizziness, abdominal pain, nausea, vomiting, dyspepsia, irritating smell, and eye or throat irritation.6 The prevalence of these symptoms also increased in the high-exposure group. Moreover, the degree and prevalence of liver dysfunction were higher in the high-exposure group.7
 
Urinary concentration of trifluoroacetic acid (TFA), which is a major metabolite of HCFC-123, can be used to determine the degree of HCFC exposure in air. However, in our case, urinary concentration of HCFC metabolite was negative. A small-scale human study found that the concentration of TFA in the urine peaked at 20 to 30 hours, and returned to zero by 96 hours post-exposure.8 Since the urine sample of our index case was collected 4 days after exposure, a positive test would not be expected.
 
There is no specific antidotal treatment for liver injury related to HCFC exposure. Supportive treatment of liver dysfunction is recommended. Fortunately, the outcome of HCFC-related liver dysfunction is usually favourable. All our patients had spontaneous recovery after cessation of exposure. To our knowledge, there is no report of death or liver transplant due to HCFC-123–induced hepatitis.
 
Poisoning by HCFC exposure is a notifiable occupational disease in Hong Kong. We reported this outbreak to the Labour Department and the Department of Health so that the related parties could conduct investigations and recommend appropriate modifications in the relevant working environment. It is essential to implement strict measures to prevent HCFC exposure, and physicians should be aware of the potential toxicities following HCFC exposure.
 
References
1. Takebayashi T, Kabe I, Endo Y, et al. Acute liver dysfunction among workers exposed to 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123): a case report. J Occup Health 1998;40:169-70. CrossRef
2. Marit GB, Dodd DE, George ME, Vinegar A. Hepatotoxicity in guinea pigs following acute inhalation exposure to 1,1-dichloro-2,2,2-trifluoroethane. Toxicol Pathol 1994;22:404-14. CrossRef
3. Hoet P, Graf ML, Bourdi M, et al. Epidemic of liver disease caused by hydrochlorofluorocarbons used as ozone-sparing substitutes of chlorofluorocarbons. Lancet 1997;350:556-9. CrossRef
4. Harris JW, Poul LR, Martin JL, Anders MW. Tissue acylation by the chlorofluorocarbon substitute 2,2-dichloro-1,1,1-trifluoroethane. Proc Natl Acad Sci USA 1991;88:1407-10. CrossRef
5. Concise International Chemical Assessment Document No. 23. Available from: http://www.inchem.org/documents/cicads/cicads/cicad23.htm. Accessed Jun 2014.
6. Takebayashi T, Kabe I, Endo Y, et al. Exposure to 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123) and acute liver dysfunction: a causal interference. J Occup Health 1998;40:334-8. CrossRef
7. Boucher R, Hanna C, Rusch GM, Stidham D, Swan E, Vazquez M. Hepatotoxicity associated with overexposure to 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123). AIHA J (Fairfax, Va) 2003;64:68-79. CrossRef
8. Tanaka S, Kabe I, Takebayashi T, et al. Environmental and biological monitoring of 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123). J Occup Health 1998;40:348-9. CrossRef

Fluoroquinolone-induced Achilles tendinitis

Hong Kong Med J 2014 Dec;20(6):545–7
DOI: 10.12809/hkmj134105
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Fluoroquinolone-induced Achilles tendinitis
PK Tam, MB, BS, FHKAM (Medicine); Carmen TK Ho, MB, BS, FHKAM (Medicine)
Department of Medicine, Tung Wah Hospital, 12 Po Yan Street, Sheung Wan, Hong Kong
 
Corresponding author: Dr PK Tam (alvintam@graduate.hku.hk)
 
 Full paper in PDF
Abstract
We report a case of Achilles tendinitis after intake of ciprofloxacin for treatment of respiratory tract infection. Fluoroquinolone-induced tendinopathy is an uncommon but increasingly recognised adverse effect of this antibiotic class. Most of the cases occur in the Achilles tendon and may lead to tendon rupture. Possible predisposing risk factors include use of steroid, patients with renal impairment or renal transplant, old age, and being an athlete. The drug should be stopped once this condition is suspected. Symptomatic treatment should be given and orthopaedic referral is desirable if tendon rupture occurs.
 
 
[Abstract in Chinese]
Case report
A 59-year-old woman with good past health, except for post-radioiodine hypothyroidism on T4 replacement, had a 3-week history of cough with yellowish sputum but no fever. She visited a general practitioner and was prescribed a course of ciprofloxacin for possible respiratory tract infection. Three days after starting the drug, she noticed pain and swelling over the left heel. She was not on any other medications including steroid. She went hiking regularly and there was no history of trauma. There was no history of joint or tendon problems. On presentation in May 2012, physical examination revealed tenderness and swelling over the left Achilles tendon (Fig 1). Ultrasound revealed Achilles tendinitis with increased flow on power Doppler signal. There were no signs of tear or calcium deposition (Fig 2). Due to the temporal relationship and the absence of other obvious causes, the diagnosis was ciprofloxacin-induced Achilles tendinitis (the Naranjo Scale was 7, ie probable adverse drug reaction).1 Ciprofloxacin was stopped and the patient was advised to avoid hiking until symptoms subsided completely. She recovered fully 2 weeks later.
 

Figure 1. Swollen left Achilles tendon (arrow)
 

Figure 2. Ultrasound shows thickened Achilles tendon (arrow) with increased flow on colour Doppler examination
 
Discussion
Fluoroquinolone-induced tendinopathy was first reported in 19832 and, since then, more than 100 cases have been reported in the literature. A case-control study from Italy found that use of fluoroquinolone was associated with higher risk of tendon disorders as well as Achilles tendon rupture (odds ratios, 1.7 and 4.1, respectively) compared with the control population.3 Another case-control study done in the United Kingdom estimated the risk to be 3.2 cases per 1000 patient-years.4
 
The commonest fluoroquinolones in the reported cases included ciprofloxacin and pefloxacin but, essentially, all the commonly used fluoroquinolones such as levofloxacin, ofloxacin, and norfloxacin have been associated with this adverse event.
 
Achilles tendon is the commonest affected site, accounting for nearly 90% of the reported cases. Other tendons like quadriceps tendon, rotator cuff tendon, as well as the site of tendon insertion may also be affected (there were two cases of epicondylitis reported after quinolone use).5 Tendinitis was the commonest pathology, present in 83.7% of the cases. Tendon rupture occurred in about 40% of the patients.6 A case-control study found that patients taking fluoroquinolones had a 4-fold increased risk of Achilles tendon rupture compared with the general population.3 Other complications related to tendinitis, such as carpal tunnel syndrome, are also possible.7
 
The mean time of symptom onset was about 2 weeks after initiation of the culprit medication, although it could range from 2 hours to as long as 6 months and, in 50% of the cases, it started within 6 days of drug intake. The mean age of affected subjects was 59 years.6
 
Several risk factors have been identified in the development of tendinopathy in patients taking fluoroquinolones. Among them, steroid use was the most significant risk factor. Most of the time, this was related to long-term use of systemic steroids, although even inhaled steroids were thought to be associated with the development of quinolone-induced tendinopathy.8 Other risk factors include old age (>60 years old), haemodialysis, renal impairment, renal transplant recipients, participation in sports activities, and history of rheumatic disorders.6 9 One previous review stated that males were more likely to develop this side-effect.6 One more recent case-crossover study, however, found that the association of tendinopathy and fluoroquinolone use was stronger in females, although not statistically significant.10 Therefore, it is not sure whether a particular gender is more likely to have this problem.
 
The underlying pathophysiology of the tendinopathy is not entirely known. A number of possible mechanisms have been proposed in animal and in-vitro studies. Ciprofloxacin could affect the metabolism of fibroblasts in tendon structures by reducing collagen synthesis and increasing extracellular matrix degradation.11 The chelating property of fluoroquinolones may also disturb the physiological interaction between cells and extracellular matrix.12 There was also evidence that fluoroquinolone increased apotosis in human tenocytes.13 In renal transplant recipients, the clearance of the drug may be impaired resulting in elevated concentrations in the tendon structures. Other risk factors like age, repeated trauma due to sports activities, or steroid therapy may impair the repair process of the tendon, thus, increasing the risk of tendinopathy in this group of patients.6 14
 
The tendinopathy usually presents with acute or subacute onset of pain and swelling over the tendon. Together with a history of recent consumption of fluoroquinolones and absence of other obvious causes of the tendinopathy, the diagnosis can be established. Imaging like ultrasound or magnetic resonance imaging is not mandatory but can aid in diagnosis, especially for visualising deep structures. Typical ultrasound findings of tendinopathy include thickened tendon with increased flow on colour Doppler examination.
 
The most important step in management is to stop the culprit drug. Appropriate rest and pain control are important. Pain can be well-controlled by non-steroidal anti-inflammatory agents; non-pharmacological treatments include ice therapy and therapeutic ultrasound. In case of tendon rupture, early referral to orthopaedic surgeon is desirable. Treatment options include immobilisation with casting or operative repair.
 
Prevention is also very important. One should only use fluoroquinolones when really necessary. Our patient’s symptoms did not suggest genuine lower respiratory tract infection; therefore, prescription of antibiotics was indeed not indicated. Moreover, quinolone is not the recommended first-line empirical antibiotic for treatment of chest infection in Hong Kong (it should only be considered in patients who are sensitive to penicillin or macrolide group of antibiotics). When use of antibiotics is really deemed necessary, fluoroquinolones should be avoided in patients with risk factors. Those with a history of fluoroquinolone-related tendinopathy should not be prescribed drugs of this class. We should also avoid co-prescription with steroid. If no better alternative is available, patients should be warned of this potential adverse effect and advised to stop the drug and seek medical advice if there are symptoms suggestive of tendinopathy. Athletes who are prescribed with fluoroquinolones should be advised to alter their training regimen (reduction in high-intensity and ballistic activities, decrease in total training volume) during the course of the antibiotics.14
 
References
1. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45. CrossRef
2. Bailey RR, Kirk JA, Peddie BA. Norfloxacin-induced rheumatic disease. N Z Med J 1983;96:590.
3. Corrao G, Zambon A, Bertù L, et al. Evidence of tendinitis provoked by fluoroquinolone treatment: a case control study. Drug Saf 2006;29:889-96. CrossRef
4. van der Linden PD, Sturkenboom MC, Herings RM, Leufkens HG, Stricker BH. Fluoroquinolones and risk of Achilles tendon disorders: case-control study. BMJ 2002;324:1306-7. CrossRef
5. Le Huec JC, Schaeverbeke T, Chauveaux D, Rivel J, Dehais J, Le Rebeller A. Epicondylitis after treatment with fluoroquinolone antibiotics. J Bone Joint Surg Br 1995;77:293-5.
6. Khaliq Y, Zhanel GG. Fluoroquinolone-associated tendinopathy: a critical review of the literature. Clin Infect Dis 2003;36:1404-10. CrossRef
7. Liang VY, Ghearing GR, Zivkovic SA. Carpal tunnel syndrome after ciprofloxacin-induced tendinitis. J Clin Neuromuscul Dis 2010;11:165-6. CrossRef
8. Schwald N, Debray-Meignan S. Suspected role of ofloxacin in a case of arthralgia, myalgia, and multiple tendinopathy. Rev Rhum Engl Ed 1999;66:419-21.
9. Tsai WC, Yang YM. Fluoroquinolone-associated tendinopathy. Chang Gung Med J 2011;34:461-7.
10. Wise BL, Peloquin C, Choi H, Lane NE, Zhang Y. Impact of age, sex, obesity, and steroid use on quinolone-associated tendon disorders. Am J Med 2012;125:1228.e23-1228.e28.
11. Williams RJ 3rd, Attia E, Wickiewicz TL, Hannafin JA. The effect of ciprofloxacin on tendon, paratenon and capsular fibroblast metabolism. Am J Sports Med 2000;28:364-9.
12. Shakibaei M, Pfister K, Schwabe R, et al. Ultrastructure of Achilles tendons of rats treated with ofloxacin and fed a normal or magnesium-deficient diet. Antimicrob Agents Chemother 2000;44:261-6. CrossRef
13. Sendzik J, Shakibaei M, Schäfer-Korting M, Stahlmann R. Fluoroquinolones cause changes in extracellular matrix, signalling proteins, metalloproteinases and caspase-3 in cultured human tendon cells. Toxicology 2005;212:24-36. CrossRef
14. Hal MM, Finnoff JT, Smith J. Musculoskeletal complications of fluoroquinolones: guidelines and precautions for usage in the athletic population. PM R 2011;3:132-42. CrossRef

Post-transplantation primary central nervous system lymphoma in a patient with systemic lupus erythematosus and prolonged use of immunosuppressant

Hong Kong Med J 2014 Dec;20(6):541–4
DOI: 10.12809/hkmj134095
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Post-transplantation primary central nervous system lymphoma in a patient with systemic lupus erythematosus and prolonged use of immunosuppressant
Teresa PK Tse, MB, ChB; Allan NL Chan, FHKCEM, FHKAM (Emergency Medicine); Tony KT Chan, FCSHK, FHKAM (Surgery); YC Po, FCSHK, FHKAM (Surgery)
Department of Neurosurgery, Princess Margaret Hospital, Lai Chi Kok, Hong Kong
 
Corresponding author: Dr Teresa PK Tse (teresapoki@hotmail.com), (tpk730@ha.org.hk)
 
 Full paper in PDF
Abstract
Post-transplantation primary central nervous system lymphoma is an uncommon and fatal post-transplant lymphoproliferative disorder. Such lymphomas have been described in only a few case series in the literature. The incidence of this condition is rising with improved survival after organ transplantation. A case of post-transplantation primary central nervous system lymphoma in a young Chinese woman with systemic lupus erythematosus is described here. She presented with right-sided weakness and memory loss after tooth extraction 2 weeks before admission. Contrast computed tomography of the brain demonstrated a contrast rim-enhancing lesion over the left frontal lobe. With a history of recent dental procedure, long-term immunosuppressive therapy and computed tomography findings, cerebral abscess was highly suspected. Emergency operation was performed. Histopathology showed post-transplantation primary central nervous system lymphoma, with cells positive for B-cell marker CD20. Immunosuppressant was stopped and she was treated with radiotherapy and rituximab (anti-CD20 monoclonal antibody). She remained disease-free at 16 months. Post-transplantation primary central nervous system lymphoma is rare with variable presentation and radiological features. We believe rituximab may have a role in the treatment of such lymphomas.
 
 
[Abstract in Chinese]
Introduction
Post-transplant lymphoproliferative disorder (PTLD) is a rare neoplastic complication of solid organ transplantation, affecting less than 2% of post-transplant patients. It includes a spectrum of diseases ranging from Epstein-Barr virus (EBV)–driven polyclonal lymphoid proliferation to EBV-positive or -negative malignant lymphoma. Post-transplantation primary central nervous system lymphoma (PT-PCNSL) is an uncommon and potentially fatal PTLD that develops in post-transplantation patients with the tumours confined to the brain and spinal cord, affecting 10% of patients with PTLD, which in turn affects only 1% of patients with kidney transplantation. The most common form of PCNSL is diffuse large B-cell lymphoma.1 2 To date, PT-PCNSL has been described in only case reports and a few case series in the literature.3 4 The exact incidence of PT-PCNSL is unknown, but it is expected to be rising in the future with improving survival for patients with organ transplant.5 Clinical presentation and radiological features of PT-PCNSL can vary. Here we describe a case of PT-PCNSL in a Chinese woman with systemic lupus erythematosus (SLE) and prolonged use of immunosuppressant.
 
Case report
A young woman with a known history of SLE underwent cadaveric renal transplantation for end-stage renal failure at the age of 28 years. She developed a complication of moderate cellular rejection postoperatively and was placed on mycophenolate mofetil (MMF) 750 mg every morning and 500 mg in the afternoon, and prednisolone 5 mg daily since 2000. Her renal function worsened after an episode of acute pyelonephritis in 2010 with creatinine level rising to 210 mg/dL from 150 mg/dL. She remained well afterwards until December 2011 when she was admitted to our hospital for progressive right-sided weakness and memory loss after tooth extraction 2 weeks before admission. On physical examination, she was found to have expressive dysphasia and right-sided weakness. Urgent contrast computed tomography (CT) of the brain demonstrated a 3.9 cm x 6.4 cm x 4.7 cm multilobulated contrast rim-enhancing lesion in the left frontal region with perifocal oedema and midline shift (Fig 1). With a history of recent dental procedure, long-term immunosuppressive therapy, and CT findings, cerebral abscess was highly suspected. Emergency operation was arranged and intravenous antibiotics were started immediately.
 

Figure 1. (a) Contrast and (b) plain computed tomography of the brain showing a multilobulated lesion in the left frontal region, measuring 3.9 cm x 6.4 cm x 4.7 cm, causing significant mass effect with perifocal oedema, effacement of adjacent sulcal spaces, and resultant right-sided midline shift. It has thin contrast-enhancing rims and non-enhancing central areas. No significant enhancing soft tissue component was associated
 
Operation
Burr hole for tapping of abscess was planned initially. Intra-operative ultrasound revealed an isodense lesion underneath the dura. Tapping was performed thrice but no fluid was aspirated. As frozen section was unavailable during non-office hours, we decided to perform left frontal craniotomy. Frontal lobectomy with partial excision of lesion was done. The lesion was found to be rubbery, lobulated, and non-vascular.
 
Pathological findings
Pathological examination revealed a lympho-proliferative lesion characterised by extensive infiltration by abnormal medium–to–large-sized lymphoid cells with large areas of necrosis. The abnormal lymphoid cells were monomorphic with vesicular nuclei and small nucleoli. The neoplastic cells were strongly positive for B-cell marker CD20. They were also positive for BCL2 and CD30, but negative for CD10 and T-cell marker CD3. In addition, the tumour cells were positive for EBV-encoded early RNAs (EBER) and EBV LMP-1. The Ki-67 proliferation index was estimated at 40% to 50%. The morphological findings, supported by immunohistochemical studies, were consistent with monomorphic PTLD, primary diffuse large B-cell lymphoma of the central nervous system (CNS) [Fig 2].
 

Figure 2. Various findings are shown: (a) tumour cells with prominent perivascular pattern on haematoxylin and eosin staining (x 20), (b) positive results for in-situ hybridisation for Epstein-Barr virus (x 20), and (c) aberrant expression of T-cell marker CD43 (x 20), and (d) positive staining for B-cell marker (x 20)
 
Postoperative course
Further workup showed that the patient had isolated CNS lymphoma. Bilateral bone marrow biopsies were done which showed no evidence of lymphoproliferative disease. Postoperative positron emission tomography–computed tomography (PET-CT) revealed residual hypermetabolic left frontal lymphomatous deposits but there were no hypermetabolic foci in the neck, thorax, abdomen, and pelvis. Serology was negative for EBV all along.
 
Postoperatively, the patient was continued on prednisolone and her antibiotics were discontinued. Mycophenolate mofetil was stopped and she was started on everolimus 0.25 mg daily. In view of suboptimal Karnofsky Performance Score and deteriorating renal function, she was treated with whole-brain radiotherapy (WBRT) alone (40 Gy/20 fr) followed by rituximab consolidation therapy (500 mg, once every 3 week, for 4 weeks). Five months after surgery, PET-CT showed complete resolution of the left frontal hypermetabolic foci; PET-CT 16 months after surgery showed stable disease. She is currently doing well 30 months after operation.
 
Discussion
Post-transplantation PCNSL is a rare neoplasm. Its clinical presentation and radiological features can vary. In a case series that involved 33 patients with PT-PCNSL imaged by contrast magnetic resonance imaging (MRI), 41% had homogeneously enhanced lesions, while 29% had ring enhancement and 61% had multiple lesions.6 In a review involving 221 patients with ring-enhancing lesions on MRI, 40% were gliomas, 30% were brain metastases, 12% were brain abscesses, 6% were multiple sclerosis plaques, and 2% were lymphomas.7 Imaging modalities such as magnetic resonance spectroscopy (MRS) may aid in differentiating PCNSL from brain abscess. In MRS, PCNSL typically demonstrates a lipid peak with raised choline to N-acetylacetate (NAA) ratio; while abscess typically demonstrates a lactate peak with reduced choline and NAA. Both PCNSL and abscess demonstrate restricted diffusion in diffusion-weighted imaging. Nuclear imaging such as PET scan may also help by showing high uptake in PCNSL while the uptake is low in abscess. However, urgent MRI, MRS, and PET scan were not readily available in our centre during non-office hours. In our case, the patient presented with focal neurological deficit with a history of recent dental procedure, use of long-term immunosuppressive therapy, and contrast rim-enhancing lesion on CT. The overall picture was suggestive of cerebral abscess, which warranted urgent surgical drainage.
 
Systemic lupus erythematosus is associated with an increased risk of haematological cancer, mainly non-Hodgkin’s lymphoma, while association with PCNSL is very rare with only few case reports on the condition in the literature. Moreover, most of these cases were associated with serious immunosuppressive therapy. Possible risk factors of PT-PCNSL include high-dose immunosuppressant and negative EBV serology in the transplant recipient.8 Our patient developed PT-PCNSL after kidney transplantation with prolonged use of MMF, and her EBV serology was also negative. It is postulated that EBV seronegativity and immunosuppression may predispose the transplant recipient to a novel EBV infection and, thus, the development of PT-PCNSL. However, the association of PT-PCNSL and SLE remains unclear.
 
The best treatment of PT-PCNSL has not been established. Reduction of immunosuppressive therapy, WBRT, and chemotherapy with agents like methotrexate and rituximab have been used for treating patients with PT-PCNSL. Whole-brain radiotherapy induced complete response by neuroimaging in 60% of patients with PCNSL but the median overall survival was only 12 months.9 High-dose intravenous methotrexate is now the standard of care for PCNSL with reported overall survival of up to 60 months.10 Rituximab, an anti-CD20 monoclonal antibody, has been used to treat patients with systemic PTLD. As rituximab does not penetrate the blood-brain barrier effectively, its effectiveness in treating PT-PCNSL is doubtful.11 Only three studies involving 10 patients with PT-PCNSL treated with intravenous rituximab have been reported with overall survival of at least 20 months.6 12 13 Resection of PCNSL has been discouraged as it causes significant neurological deficit without any survival benefit. In our case, after partial resection of tumour, WBRT and rituximab were used to treat PT-PCNSL. The patient remained disease-free at 16 months with MRI showing complete resolution of the lesions; she remains asymptomatic at 30 months after operation. It is believed that rituximab may have a role in the management of patients with PT-PCNSL by achieving adequate drug penetration into the brain parenchyma through leaky lymphomatous vasculature. We propose reconsidering the statement that efforts at resection of PCNSL should be discouraged, at least if resection seems safe. Yet, further studies are required to determine the best treatment for PT-PCNSL.
 
Conclusion
Post-transplantation PCNSL is a rare neoplasm with variable clinical presentation and radiological features. Possible risk factors include EBV seronegativity and prolonged use of immunosuppressive therapy. We believe rituximab and tumour resection may have a role in the treatment of PT-PCNSL.
 
Acknowledgement
We would like to express our special thanks to Dr WL Lam for the pathological examination of the specimen.
 
Declaration
No conflicts of interest were declared by authors.
 
References
1. Castellano-Sanchez AA, Li S, Qian J, Lagoo A, Weir E, Brat DJ. Primary central nervous system posttransplant lymphoproliferative disorders. Am J Clin Pathol 2004;121:246-53. CrossRef
2. Vaglio A, Manenti L, Mancini C, et al. EBV-associated leukoencephalopathy with late onset of central nervous system lymphoma in a kidney transplant recipient. Am J Transplant 2010;10:947-51. CrossRef
3. Phan TG, O’Neill BP, Kurtin PJ. Posttransplant primary CNS lymphoma. Neuro Oncol 2000;2:229-38. CrossRef
4. Snanoudj R, Durrbach A, Leblond V, et al. Primary brain lymphomas after kidney transplantation: presentation and outcome. Transplantation 2003;76:930-7. CrossRef
5. Wolfe RA, Roys EC, Merion RM. Trends in organ donation and transplantation in the United States, 1999-2008. Am J Transplant 2010;10:961-72. CrossRef
6. Cavaliere R, Petroni G, Lopes MB, Schiff D; International Primary Central Nervous System Lymphoma Collaborative Group. Primary central nervous system post-transplantation lymphoproliferative disorder: an International Primary Central Nervous System Lymphoma Collaborative Group Report. Cancer 2010;116:863-70. CrossRef
7. Schwartz KM, Erickson BJ, Lucchinetti C. Pattern of T2 hypointensity associated with ring-enhancing brain lesions can help to differentiate pathology. Neuroradiology 2006;48:143-9. CrossRef
8. Caillard S, Dharnidharka V, Agodoa L, Bohen E, Abbott K. Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression . Transplantation 2005;80:1233-43. CrossRef
9. Nelson DF, Martz KL, Bonner H, et al. Non-Hodgkin’s lymphoma of the brain: can high dose, large volume radiation therapy improve survival? Report on a prospective trial by the Radiation Therapy Oncology Group (RTOG): RTOG 8315. Int J Radiat Oncol Biol Phys 1992;23:9-17. CrossRef
10. Thiel E, Korfel A, Martus P, et al. High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial. Lancet Oncol 2010;11:1036-47. CrossRef
11. Ruhstaller TW, Amsler U, Cerny T. Rituximab: active treatment of central nervous system involvement by non-Hodgkin’s lymphoma? Ann Oncol 2000;11:374-5. CrossRef
12. Traum AZ, Rodig NM, Pilichowska ME, Somers MJ. Central nervous system lymphoproliferative disorder in pediatric kidney transplant recipients. Pediatr Transplant 2006;10:505-12. CrossRef
13. Kordelas L, Trenschel R, Koldehoff M, Elmaagacli A, Beelen DW. Successful treatment of EBV PTLD with CNS lymphomas with the monoclonal anti-CD20 antibody rituximab. Onkologie 2008;31:691-3. CrossRef

Spontaneous intracranial hypotension: improving recognition and treatment strategies in the local setting

Hong Kong Med J 2014 Dec;20(6):537–40
DOI: 10.12809/hkmj133996
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
CASE REPORT
Spontaneous intracranial hypotension: improving recognition and treatment strategies in the local setting
Gregory KY Lee, MB, BS1; Jill M Abrigo, MD1; Tom CY Cheung, FRCR, FHKAM (Radiology)1; Deyond YW Siu, FRCR, FHKAM (Radiology)1; Danny TM Chan, FRCS, FHKAM (Surgery)2
1 Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
2 Department of Neurosurgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
 
Corresponding author: Dr Gregory KY Lee (greglee011@gmail.com)
 
 Full paper in PDF
Abstract
We report a case of spontaneous intracranial hypotension with classic symptoms of orthostatic headache and acute presentation of subdural haematoma on computed tomographic scan. Conventional approach with conservative treatment was initially adopted. The patient’s condition, however, deteriorated after 2 weeks, requiring surgical evacuation of the intracranial haemorrhage. We reviewed the clinical features of this disease and the correlated magnetic resonance imaging findings with the pathophysiological mechanisms, and described treatment strategies in the local setting. Subtle findings on initial computed tomographic scan are also reported which might improve pathology recognition. Spontaneous intracranial hypotension is not uncommonly encountered in Hong Kong, and physicians must adopt a high level of clinical suspicion to facilitate early diagnosis and appropriate management. In addition, novel therapeutic approaches may be required in those with recurrent symptoms or who are refractory to current treatment strategies.
 
 
[Abstract in Chinese]
Case report
A 54-year-old man with no history of trauma was admitted to the Prince of Wales Hospital for headache of progressive severity accompanied by dizziness in August 2012. He had consulted the emergency room 4 weeks earlier for neck pain, and had an unremarkable computed tomographic (CT) scan of the brain (CTB). Further enquiry revealed an orthostatic component within the headache (worse in upright position and relieved within minutes of assuming supine posture), while admission CTB revealed interval development of bilateral 5 mm–thick frontoparietal subacute subdural haematomas (SDHs) with disproportionate tightness of the basal cisterns.
 
Cerebral magnetic resonance imaging (MRI) additionally demonstrated compression of the midbrain, but no caudal herniation of the cerebellar tonsils beyond the foramen magnum. Contrast study showed diffuse pachymeningeal enhancement, venous sinus distension, and prominent pituitary gland. Spinal MRI was unremarkable and MRI cisternography/myelography was negative for cerebrospinal fluid (CSF) leakage.
 
The patient was advised complete bed rest with adequate hydration. His neurological status was intact all along. However, he reported persistent, severe bifrontal headache which, after 2 weeks, was accompanied with repeated projectile vomiting. Computed tomographic scan of the brain at this juncture revealed enlargement of the SDH with development of acute haemorrhage. Emergency evacuation of subdural blood was performed with development of low intracranial pressure during the evacuation process.
 
The patient’s symptoms improved markedly thereafter, and CTB reassessment showed minor residual blood. The patient was discharged in a neurosurgically stable condition, and currently remains asymptomatic.
 
Discussion
Intracranial hypotension is traditionally attributed to leakage of CSF from a dural defect along the craniospinal axis, which can occur spontaneously, such as due to rupture of Tarlov cyst1 or dural weakness in connective tissue disorder.2 Intracranial hypotension can also be precipitated by direct trauma or iatrogenic causes such as a lumbar puncture. The commonest cause, however, is a spontaneous defect of the dura (spontaneous intracranial hypotension [SIH]), though a trivial traumatic event can be elicited retrospectively in around one third of such patients.3 4 The most common sites of leakage identified were at the cervicothoracic junction and thoracic region of the spinal canal.1 5 In the absence of a dural defect, a recent alternative hypothesis proposes increased CSF absorption from negative pressure gradient in the inferior vena cava.6 In both instances, CSF hypovolaemia is the main feature and primary cause of the related clinical and imaging findings.
 
Spontaneous intracranial hypotension is an increasingly diagnosed cause of headache, with an incidence of one in 50 000 individuals.7 The female-to-male incidence ratio of SIH is 2:1, with a peak incidence occurring around the age of 40 years.3 7
 
The typical clinical feature of SIH is orthostatic headache, which, according to the International Headache Society, should occur or worsen within 15 minutes in an upright posture together with at least one feature of meningeal irritation (neck stiffness, tinnitus, hypacusia, photophobia, nausea) in addition to imaging features of SIH.8 With chronicity, the postural component may become less prominent.3 Other clinical manifestations include disappearance of or improvement in the headache within 30 minutes after lying supine, and cranial nerve palsies related to traction from caudal displacement of the brainstem.9 Severe midbrain compression may result in nigral dopaminergic dysfunction and manifest as parkinsonism.9 Coma occurs from delayed decompression of brainstem descent.4
 
Subdural haematoma is a late finding and occurs in around 10% of patients with SIH,3 commonly seen in males and those older than 35 years.10
 
Computed tomography is the frontline imaging workup for headache. Typically, SIH is not considered unless patients present with non-traumatic SDH in the setting of a normal clotting profile. The proposed mechanism involves rupture of bridging veins in expanding subdural hygromas which, in turn, results from brain sagging due to CSF hypovolaemia.
 
On CT, SIH in the absence of SDH can be easily interpreted as being unremarkable. With high level of clinical suspicion, however, subtle imaging features may suggest the diagnosis. For instance, the initial CTB of our index patient showed paucity of CSF for his age (Fig 1). On follow-up CTB, the tightness of the basal cisterns appeared rather disproportionate to the small amount of SDH. Thus, it may be possible to detect CSF hypovolaemia on CT if these subtle findings are sought and the diagnosis is borne in mind.
 

Figure 1. (a) Computed tomography of the brain (axial view) showing a normal brain with adequate space over the midbrain and basal cisterns. (b) Our patient’s scan at similar axial level showing disproportionate tightness around the midbrain and basal cistern
 
The MRI findings of SIH are well-described in the literature. This preferred modality of imaging depicts characteristic features which may obviate the need for lumbar tap.4 Additionally, the cause or site of dural defect can be investigated.
 
The MRI appearances are mainly attributed to CSF hypovolaemia, or represent secondary reactive changes following the Monro-Kellie doctrine. Briefly, decrease in CSF volume prompts an increase in dural blood flow and causes venous engorgement. The latter, when prolonged, incites surrounding fibro-proliferation that in turn accounts for diffuse dural thickening and intense enhancement with gadolinium on MRI. Such explanation is confirmed by meningeal biopsy showing proliferation of fibroblasts without inflammation.11 12
 
The primary feature of brain sagging is a very specific MRI finding in SIH. It is a collaboration of features, including decreased dimension of the suprasellar cistern, bowing of optic chiasma, flattening of the pons against the clivus, effacement of the perimesencephalic cistern and hindbrain herniation (Fig 2a).11 12 A quantitative measurement of brain sagging has been described10 although the degree of descent may be underestimated since patients are scanned in the recumbent position.
 

Figure 2. Magnetic resonance imaging of our patient showing typical features of spontaneous intracranial hypotension (SIH). (a) Brain sagging, best appreciated by the mammillary body, which normally lies on, but currently is, below the line between tentorial apex and tuberculum sella. (b) Classical diffuse dural enhancement seen in SIH
 
Secondary and less-specific signs of SIH are more readily appreciated but represent a later stage of the disease. Findings of MRI in the brain classically show diffuse pachymeningeal thickening which has a sensitivity of up to 94% (Fig 2b).9 The venous distention sign may also be seen and is best appreciated in the mid-portion of the dominant transverse sinus12; on sagittal sections, the sinus, which normally adopts a concave or straight inferior border, bulges with a convex contour. Venous engorgement at the dura mater across the sella turcica could produce reactive hyperaemia and possible increase in size of the pituitary gland. In the spine, MRI findings mirror those of the brain with diffuse dural enhancement, engorgement of venous plexus and extrathecal CSF collection.3
 
Magnetic resonance imaging cisternography or myelography can be easily added to routine MRI examination. Using a heavy T2-weighted sequence with fat signal suppression, spinal fluid outside the craniospinal axis may be detected with equal or improved accuracy than CT myelography.5 Radiological improvement lags behind clinical recovery. Meningeal enhancement resolves considerably earlier than brain sagging.12 13
 
Computed tomography myelography and radionuclide cisternography are available locally but seldom performed. These are more invasive and time-consuming to perform, and entail intrathecal injection of contrast/radioisotope label, with fluoroscopic screening or serial imaging with gamma cameras to visualise extrathecal contrast/tracer activity.
 
Conservative management of SIH includes Trendelenburg positioning, aggressive hydration, caffeine intake and abdominal binder, and has been reported to be successful in most cases. In those patients with increased persistent headache or neurological deterioration, CTB should be immediately performed to rule out expanding SDH.
 
The timing of active surgical drainage is controversial. In a particular series, surgical drainage was advised in those with focal neurological deficits, decreased level of consciousness, or subdural collection of >1 cm.4 Most surgically managed patients show transient improvement but have high likelihood of re-accumulation of subdural fluid.13
 
A more active strategy that is gaining international acceptance is epidural blood patch (EBP), which aims at sealing off the spinal leak3 but appears to be useful in those without a definite dural defect.6 The treatment involves placing 10 to 20 mL of autologous blood in the epidural space at the thoracolumbar level. As the patient is put in Trendelenburg position, the blood patch distributes along the epidural space and clots at the site of leakage.
 
The overall success rate for headache improvement is 30% to 70% after the first EBP and 30% to 50% for the remainder with repeated EBP.10 Epidural blood patch has a success rate of 85% in reverting patients who were comatose due to SIH.13 Under fluoroscopic guidance, EBP may yield a high rate of pain relief and is preferred for those with altered anatomy or failure in the initial attempt.14 A novel technique of multisite EBP via continuous infusion has been described.15
 
The newest treatment approach developed at the Stanford University recommends emergency subdural clot evacuation in the absence of improvement in Trendelenburg positioning, presence of dilated pupils, and large SDH with mass effect. Otherwise, EBP is the treatment of choice.13
 
In those with initial improvement with EBP, studies have shown concomitant spontaneous resolution of significant SDH.13 Epidural blood patch may even be performed after surgical evacuation, and has been proven to further reduce the recurrence of headache and SDH.13 16 As the brain has a tendency to sag downwards in SIH, pneumocephalus during clot evacuation may cause further downward herniation of the brain. Hence, surgical evacuation after EBP may not be advisable. Most of these patients, like our index case, have shown low-pressure subdural collection during craniotomy.
 
Conclusion
The diagnosis of SIH should be considered for any patient presenting with headache and neck pain. A high level of clinical suspicion could assist identification of subtle signs on initial CT which could facilitate early recognition and prompt treatment and, consequently, improve outcomes. However, MRI remains an important, highly sensitive, and specific method for depicting imaging markers that allow confident clinical diagnosis. Further, MRI cisternography/myelography for CSF leak localisation can be added with ease. Currently, the medical practice in Hong Kong for SIH predominantly comprises conservative treatment and symptomatic clot evacuation. More novel interventions that have been successfully employed overseas may need to be reconsidered to improve current therapeutic strategies.
 
References
1. Cheng MF, Pan MH, Wu YE, Tsai WC, Yen RF, Tzen KY. Radionuclide cisternography in diagnosing spontaneous intracranial hypotension. Ann Nucl Med Sci 2004;17:167-72.
2. Schievink WI, Gordon OK, Tourje J. Connective tissue disorders with spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension: a prospective study. Neurosurgery 2004;54:65-70; discussion 70-1. CrossRef
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