Volume 18, number 3, 2007
PEDIATRIC CLINICS AMSTERDAM Pediatric Clinics Amsterdam is an edition from Emma Kinderziekenhuis AMC Visit adress: Meibergdreef 9 1105 AZ Amsterdam Post adress: Postbus 22660 1100 DD Amsterdam Editorial Board
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Pediatric Clinics Amsterdam was first published in 1990 with the aim to offer young pediatricians and residents the opportunity to publish remarkable cases they encountered in their clinical work. In the years since, it has grown and flourished, and many of us have published our first paper in Pediatric Clinics Amsterdam. During the last six years Dr. Koert M. Dolman has been a highly inspiring and professional Editor in Chief of the journal. On behalf of the editorial board I would like to express our gratitude for his great dedication during these years.
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Symptoms of tetany in a girl treated with methotrexate
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C.T. Jagt1, H. van den Berg1, A. C. Verschuur1 Case report A 9-year-old girl from Aruba (Netherlands Antilles) was diagnosed as having an osteosarcoma in her left distal femur. In accordance with the European Osteosarcoma Intergroup (EOI) osteosarcoma protocol the girl was treated with preoperative chemotherapy for 8 weeks after which local therapy was provided consisting of left upper leg amputation. Histological evaluation of the resected tumour tissue showed >10% viable tumour cells, which is considered a poor response to the preoperative chemotherapy. Consequently the girl was treated in accordance with the high risk arm of the protocol and MAPIE (methotrexate, adriamycin, cisplatin, ifosfamide, and etoposide) was given as postoperative chemotherapy. 1
Department of Pediatric Oncology, Emma Children’s Hospital AMC, Amsterdam
This protocol consists amongst others of seven courses of high dose methotrexate (MTX), 12 g/m2 to be given during a period of 40 weeks. MTX administration is always paralleled by standard hyperhydration and alkalisation to increase urinary elimination of MTX. After the fourth dose of MTX, the girl developed symptoms of tetany of both hands (‘main d’accoucheur’). During this tetany period the lab results showed the following levels: calcium 2.37 mmol/L (normal range: 2.15-2.75 mmol/L), ionized calcium 1.16mmol/L (normal range 1.20-1.38 mmol/L). Urinary pH was at this time 8.5-9.0, while blood gas analysis revealed a blood pH of 7.38, which means no alkalosis was present at the time of measurement. Forty-eight hours after administration the MTX level was 0.41µmol/L, which is within the normal range. The tetany was treated with diazepam 10 mg by rectal administration (without improvement), followed after 1½ hours by calcium
Fig 1. The girl’s hands during the second period of tetany.
PEDIATRIC CLINICS AMSTERDAM - PAGE 2
gluconate. The tetany disappeared 1¼ hour after that administration. The fifth dose of MTX was given without any complications. When the girl woke up the morning after having received the sixth dose of MTX, she again developed tetany in both hands. This time, both hands (Fig. 1) and her right foot were affected. The lab results again showed a low level of ionized Ca. The lab investigations were repeated throughout the day of tetany and showed the following results. The calcium ranged from 2.38-2.93 mmol/L, the ionized calcium was 1.22 mmol/L and at one moment even 1.01mmol/L and urinary pH was 7.5-8.5. The MTX level was measured again 48 hours after administration and was once again within the normal range. The tetany was treated the same way as the first episode and disappeared. It was decided to cancel the last two doses of metho trexate. So far, complete remission was achieved and is still persisting 2 years after diagnosis. Comment According to most treatment protocols, osteosarcoma is treated with MTX-containing multidrug regimens. Studies have shown that the elimination of MTX is increased by urine alkalisation and increased urinary flow.1,2 Urine alkalisation is known to cause complications such as hypokalaemia and hypocalcaemia.1 One clinical sign of hypocalcaemia is the development of tetany as described in our case report. However, in the literature no cases of tetany related to urine alkalisation were reported. The only similar cases described are hypocalcaemic tetany complaints not related to urine alkalisation, such as the case described by Edmondson et al.4 This case report is about a 4-yearold boy who developed tetany after being treated with sodium phosphate enemas. This resulted in hypocalcaemia because the calcium binds to phosphate. The pathophysiology of tetany during a MTX-course seems to indicate that the symptom is a complication of urine alkalisation. Urine alkalisation is defined as a therapeutic measure that increases chemotherapy elimination by the administration of intravenous sodium bicarbonate in order to produce urine with a pH >7.5.1 Alkalisation of the urine increases urinary excretion of methotrexate. Cell membranes are more permeable to substances in the non-ionized form than those in the ionized form. Since MTX is a weak acid (pH 4.8), the drug will be maximally ionized in an alkaline en-
vironment. As a result reabsorption over the tubular membrane is diminished and the agent is trapped in the urine. Increasing urinary pH also prevents the development of crystalluria.1,2 Calcium exists in the circulation in three forms: ionized Ca2+ (50%), protein-bound mainly to albumin (40%) and complexed to substances such as citrate and phosphate (10%). The physiologically active form is ionized Ca2+, which stabilizes/triggers muscle contraction by maintaining a muscle potential. Albumin is a plasma protein which functions as a transport protein and an acid-base buffer.3 Albumin is negatively charged so it has the opportunity to bind positively charged ions such as Ca2+ and H+. In an acidic environment, albumin will bind more H+ ions to increase the pH. In an alkaline environment this mechanism is reversed and albumin will release H+ ions to bring the pH back to 7.4. To remain in a stable position, albumin must compensate the negative charge by binding to positively charged ions, mainly Ca2+. In an alkaline environment this results in a shift from ionized Ca2+ to albumin-bound calcium.4 This results in a relative hypocalcaemia. The decrease of ionized calcium in the blood results in higher muscle activity.5 In our case the girl developed a relative hypocalcaemia according to the pathophysiology described above. In conclusion, this case of tetany is a result of the alkalisation concomitant to methotrexate administration and this uncommon complication may arise when continuous alkalisation is required. Early detection could be achieved by monitoring the ionized calcium. References 1. Proudfoot AT et al. Position paper on urine alkalisation. J. of. Toxicology. Clinical Toxicology. 2004; 42:1-26 2. Sand TE and Jacobsen S. Effect of Urine pH and Flow on Renal Clearance of Methotrexate. Eur. J. Clin. Pharmacol. 1981;19:453-6 3. Bouman LN. Medische fysiologie. Houten: Bohn Stafleu Van Loghum 2002: 649 4. Edmondson S, Almquist TD. Iatrogenic hypocalcemic tetany. Annals of emergency medicine. 1990; 19.8 :134-6 5. James W et al. Tetany : quantitative interrelationships between calcium and alkalosis. Am. J. of Physiology. 1975; 228:1082-6
Intractable neonatal seizures: Don’t forget pyridoxine-dependent seizures T.G.J. de Meij1, A.J.M. van den Broek2, E.E.O Hagebeuk3 Case report We present a Caucasian girl who was born at 41 5/7 weeks of gestation by caesarean section as the first child of unrelated healthy parents. The mother reported repetitive intrauterine fetal movements during the last trimester of pregnancy. The child had Apgar scores of 9 and 10, after 1 and 5 minutes, respectively, and a birth weight of 3790 grams (p75-90). She was irritable, jittery, and hypertonic and showed no spontaneous movements. Besides this, physical examination showed no abnormalities. Five minutes after birth she developed symmetric generalized tonic seizures of arms and legs, which responded only temporarily to phenobarbital and continuous parenteral administration of midazolam. An electroencephalogram (EEG) performed at that moment exhibited suppression burst pattern and frequent epileptic discharges. A single dose of pyridoxine (vitamin B6) 100 mg intravenous was given according to the neonatal seizures protocol, upon which the seizures ceased. After three days, the EEG showed a slow background pattern without epileptiform activity. Midazolam could be stopped; maintenance monotherapy with phenobarbital was continued. Pyridoxine was also discontinued, because the diagnosis pyridoxine-dependent seizures was not proven yet. Ultrasound examination of the cerebrum, routine investigation, and investigation into the presence of pathogens in blood and cerebrospinal fluid revealed no abnormalities in our patient. Cultures of blood, urine and liquor were negative, as was the Herpes Simplex PCR. Metabolic investigations were pending. Diffusion-weighted MRI of the cerebrum showed bilateral frontal vasogenic oedema of unknown cause and no signs of bleeding. It follows that the cause of the seizures remained unknown at that moment.
1
Departments of Pediatrics, Neonatology and 3 Neurology, Emma Children’s Hospital AMC, Amsterdam
2
Two weeks later she was readmitted because of status epilepticus, this time unresponsive to conventional anticonvulsants such as midazolam, phenytoin and clonazepam. Therefore, 100 mg pyridoxine was administered via the parenteral route, during simultaneous EEG recording, resulting in the resolution of clinical and electrographic seizure activity within minutes (Fig. 1). The clinical diagnosis pyridoxine-dependent epilepsy was made and pyridoxine supplementation was started in a daily dose of 45 mg. All other anticonvulsants were sequentially withdrawn without recurrence of the seizures. The clinical diagnosis was confirmed by metabolic tests and genetic testing. In the follow-up period, seizures regularly reoccurred during high fever and after vaccination. Apart from that, she is free of seizures. The daily dose of pyridoxine was increased to 100 mg. To date, she manifests delayed psychomotor development. At the age of 22 months, she started walking without support and only speaks a single word. Comment The main causes of neonatal seizures are perinatal asphyxia, infarction, intracranial haemorrhage, meningitis, congenital abnormalities of the brain, inborn errors of metabolism, acquired hypoglycaemia, hypo calcaemia or hypomagnesaemia and occasionally epileptic syndrome. Pyridoxine-dependent epilepsy has been recognized as a cause of intractable seizures in neonates and infants for more than 50 years.1 The birth incidence of this autosomal recessive disorder in the Netherlands is 1 in 396 000 for definite and probable cases, and 1 in 252 000 if possible cases are included.2 It is characterized by various types of seizures, including myoclonic or atonic seizures, partial and generalized events and infantile spasms. Usually children present in the first hours after
birth, but late-onset pyridoxine-dependent seizures in children up to 3 years of age have been reported.3,4 The mean age at the time of diagnosis is 3.5 months.5 Seizures are intractable to conventional anticonvulsants, but will cease within several minutes after parenteral administration of a single dose of 100 mg pyridoxine. Maintenance treatment of pyridoxine is 15 mg/kg/day. These doses far exceed the recommended daily need of 0.5 mg for children or 2 mg for adults.6 Diagnosis is confirmed by recurrence of seizures after withdrawal of pyridoxine, which cease again after a second trial of pyridoxine. Pyridoxine-dependent epilepsy used to be a clinical diagnosis. Many studies concerning the genetic and biochemical aspects of this disorder have been performed to facilitate its diagnosis. It has been demonstrated that these patients show a 4 to 15-fold elevation of the pipecolic acid level in their plasma and even higher in CSF, although the specific biochemical relation of pipecolic acid to the pyridoxine metabolism remains unclear.7 Recently, an increased level of (alpha)-aminoadipic semialdehyde (αAASA) in various body fluids (including urine) of affected patients has been found, which can serve as a biomarker for the disorder. Besides this, a variety of mutations in the antiquitin (ALDH7A1) gene (located at 5q31) have been discovered in patients with pyridoxine-dependent epilepsy. In a recent study concerning 13 patients with a definite clinical diagnosis of pyridoxine-dependent epilepsy, sequencing of ALDH7A1 revealed homozygous and compound heterozygous mutations in all cases.8 In our patient increased levels of αAASA were found in urine, plasma and liquor as well as increased levels of pipecolic acid in plasma and liquor. Genetic testing showed the mutation of ALDH7A1. Reports concerning the developmental outcome of patients with pyridoxine-dependent epilepsy show that most patients have at least some degree of cognitive impairment, particularly in expressive language.5,9 Intrauterine foetal seizures, such as those the mother of our patient probably noticed, are described in almost 20% of reported cases and seem to be related to a poor outcome.5,10 It has been suggested that this might be prevented by maternal pyridoxine supplementation (50-100
mg per day) during the final half of the gestation period.10 Confirmation of the diagnosis may warrant pyridoxine administration to the mother in a future pregnancy. In conclusion, pyridoxine-dependent epilepsy should always be considered in a case of neonatal seizures of unknown origin. The discovery of the metabolic marker αAASA and the disease-causing gene is of great importance for genetic counselling and early diagnosis.2 Trial withdrawal of pyridoxine, to prove the clinical diagnosis of pyridoxinedependent seizures, is unnecessary nowadays. References 1. Hunt AD, Stokes I, McCrory WW, Stroud HH. Pyridoxine dependency: report of a case of intractable convulsions in an infant controlled by pyridoxine. Pediatrics. 1954 Feb;13(2):140-5 2. Been JV, Bok LA, Andriessen P, Renier W O. Epidemiology of pyridoxine dependent seizures in the Netherlands. Arch Dis Child 2005; 90: 1293-6 3. Sidney M, Gospe SM. Current perspectives on pyridoxine-dependent seizures. Eur J Pediatrics 1991;150:452-5 4. Goutiéres F, Aicardi J. Atypical presentations of pyridoxine-dependent seizures: a treatable cause of intractable epilepsy in infants. Ann Neurol 1985;17: 117–20 5. Haenggeli CA, Girardin E, Paunier L. Pyridoxine-dependent seizures: clinical and therapeutic aspects. Eur J Pediatr 1991;150:452–5 6. Sidney M, Gospe SM. Pyridoxine-dependent seizures: findings from recent studies pose new questions. Pediatric Neurology 2002;26:181-5 7. Plecko B, Hikel C, Korenke GC, Schmitt B, Baumgartner M, Baumeister F, Jakobs C, Struys E, Erwa W, Stöckler-Ipsiroglu S. Pipecolic Acid as a Diagnostic Marker of Pyridoxine-Dependent Epilepsy. Neuropediatrics 2005;36: 200-5 8. Mills P, Struys E, Jakobs C, Plecko B, Baxter P, Baumgartner M, Willemsen M, Omran H, Tacke U, Uhlenberg B, Weschke B, Clayton P. Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nature Medicine 2006;12:307-9 9. Ohtsuka Y, Hattori J, Ishida T, Ogino T, Oka E. Long-term follow-up of an individual with vitamin B6-dependent seizures. Dev Med Child Neurol 1999;41:203-6 10. Nabbout R, Soufflet C, Plouin P, Dulac O. Arch Dis Child Fetal Neonatal Ed 1999;81:F125-9
Wegener’s granulomatosis in two adolescents: a treacherous pulmonary presentation L.B. van der Aa1, M. van der Heide1, A.B. Sprikkelman2, G. Brinkhorst3, G.A.M. Tytgat4,
Abstract In two teenagers Wegener’s granulomatosis was diagnosed. In both patients the symptoms and initial additional tests suggested an infectious disease, but antibiotic therapy had no effect. An elevated ANCA titre with a cytoplasmic pattern and an elevated PR3ELISA led to the diagnosis. Both patients recovered after aggressive immunosuppression. Wegener’s granulomatosis is a systemic necrotizing vasculitis, mainly localized in the airways and kidneys. The disease is very rare in children, and can be life-threatening. Therefore, in children with pulmonary problems resistant to antibiotics, it is important to consider the diagnosis Wegener’s granulomatosis and perform the appropriate tests. Patient A, a previously healthy, 17-year-old boy, presented with pain in his right flank, which had existed for several weeks. He also suffered from spiking fever, night sweats, weight loss, headache and epistaxis. There were no complaints of dyspnoea or coughing. The physical examination revealed no abnormalities. Laboratory tests showed a mild anaemia, leucocytosis, thrombocytosis and increased inflammatory parameters (CRP 185 mg/L; ESR 91 mm/hr). The renal function was normal and urinalysis showed no abnormalities. Imaging studies of the thorax showed a round lesion in the lower lobe of the right lung (Figs. 1 and 2). Cultures of blood, sputum, pleural effusion and bronchial lavage fluid did not reveal a microbial cause and treatment with several antibiotics had no effect. The lesion was biopsied by thoracotomy. Pathology showed a granulomatous inflammation with necrosis and vasculitis, without signs of (myco)bacterial or fungal infection. As Wegener’s granulomatosis was suspected, antineutrophil cytoplasmic antibodies (ANCA) were measured and the patient was transferred to an academic hospital. By that time he had developed a 1
Emma Children’s Hospital AMC, Amsterdam Department of Pediatric Pulmonology, Emma Children’s Hospital AMC, Amsterdam 3 Department of Pediatrics, Medical Centre Alkmaar, Alkmaar 4 Department of Pediatrics, Zaans Medical Centre, Zaandam 5 Dept of Pediatric Haematology, Immunology and Infectious Diseases, Emma Children’s Hospital AMC, Amsterdam 2
productive cough with haemoptysis. Shortly after transferral the ANCA-immunofluorescence turned out positive (titre 1:320, cytoplasmic pattern). Further specification of the ANCA with ELISA showed a raised anti-proteinase-3 (PR3) (260 kAU/L, normally 0-30). These results confirmed the diagnosis Wegener’s granulomatosis. The patient was considered to have the limited form, since the kidneys were not involved. He was treated with prednisone and methotrexate and was discharged after three weeks, in relatively good condition. Ten days later he was readmitted because of malaise, severe coughing and haemoptysis. In addition, there was a dehiscence of the thoracotomy wound. Imaging studies showed substantial expansion of the pulmonary lesions. Haematuria and proteinuria indicated renal involvement, although renal function was still normal. The medication was changed into cyclophosphamide and methylprednisolone pulse therapy, after which the new lesions disappeared. The large initial lesion resolved after discharge of large amounts of pus through the scar of a previous chest drain. A culture showed Staphylococcus aureus, which was treated with antibiotics. After four weeks the patient was discharged in good clinical condition. At present, one year later, the thoracotomy wound has closed spontaneously. The immunosuppressive medication has been changed to azathioprine, with cotrimoxazole prophylaxis. The lung function is normal and all laboratory tests have normalized. The patient feels healthy and performs at his previous level. A few weeks after patient A, patient B, a 16-year-old boy, presented with progressive dyspnoea, haemoptysis, malaise and headache, of three weeks duration. A chest X-ray showed bilateral consolidations, and treatment with antibiotics was started. However, the patient’s clinical condition rapidly deteriorated and he was transferred to an academic hospital two days later. By that time he ran a fever, and severe dyspnoea and tachypnoea were present, which were treated with oxygen therapy. Physical examination revealed rhonchi in the basal areas of both lungs, as well as a dull percussion. He had an enlarged spleen, while the size of the liver was normal.
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Figure 2. CT-thorax of patient A at admission shows the granuloma in the right lung.
Laboratory tests showed normal blood gases, anaemia and raised inflammatory parameters (ESR 66 mm/ hr; CRP 244 mg/L). Haematuria and proteinuria were present, but there were no erythrocyte casts or leucocyturia and the creatinine clearance was normal. Cultures of sputum, blood, urine and bronchial lavage fluid showed no microbial cause. Repeated chest x-rays showed rapidly progressive consolidations in all lung fields (Fig. 3). A biopsy of the nasal mucosa showed an ulcerating, granulomatous inflammation. Extensive screening for autoantibodies showed a slightly raised ANCA titre (1:80, cytoplasmic pattern). The PR3-ELISA, however, was very high (2500 kAU/L). The latter, in combination with the clinical and radiological findings, confirmed the diagnosis classic Wegener’s granulomatosis. A few hours after admission the patient developed respiratory insufficiency, which eventually made extracorporeal membrane oxygenation (ECMO) unavoidable. Therefore, he was transferred to an ECMO centre the next day. Treatment with methylprednisolone, cyclophosphamide and plasmapheresis had been started just before transferral. This resulted in normalization of the c-ANCA titre as well as clinical improvement. After two weeks, ECMO and plasmapheresis could be stopped and the patient, who was still mechanically ventilated, was transferred back. Nine weeks after the initial admission he was discharged, in reasonable clinical condition, to a rehabilitation centre, with oral cyclophosphamide as maintenance therapy. At present, nine months later, the patient is in reasonably good condition. He experiences no limitations in his daily life and has started college. However, lung function tests show persistent restriction. There is intermittent, minimal haematuria, and the PR3 ELISA remains slightly elevated. Cyclophosphamide has been replaced by azathioprine, in combination with low dose prednisolone and co-trimoxazole prophylaxis. Pathogenesis Wegener’s granulomatosis is a systemic vasculitis of
the small and medium-sized blood vessels. The aetiology is unknown, but the presence of autoantibodies (ANCA) directed against PR3, is essential. PR3 is a proteolytic enzyme present in neutrophilic granulocytes. Binding of ANCA to neutrophilic granulocytes appears to be necessary for the inflammatory response that leads to vasculitis.1 Another hallmark of Wegener’s granulomatosis is the formation of granulomas, mostly in the respiratory tract, the pathogenesis of which is also unknown. A combination of genetic predisposition and an external (microbial) agent is considered to cause the disease. It has been shown that nasal carriage of Staphyloccus aureus increases the chance of an exacerbation of Wegener’s granulomatosis. Antibiotic prophylaxis substantially diminishes this risk.2 It is unknown whether infection with S. aureus plays a part in the origin of the disease. Epidemiology The estimated incidence of Wegener’s granulomatosis varies from 0.5/million/ year3 to 3/ 100.000/year.4 The male-female ratio is 1:1. The disease is so rare in childhood that it is not possible to give a reliable estimate of the incidence in children.5-7 The incidence appears to increase with age, although the disease has been reported in infants only a few weeks old.
Figure 3. Chest X-ray of patient B at admission. The X-ray shows extensive bilateral consolidations.
PEDIATRIC CLINICS AMSTERDAM - PAGE 7
Figure 1. Chest X-ray of patient A at admission in the academic hospital. The x-ray shows a round consolidation in the lower lobe of the right lung and atelectasis/pleural fluid.
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Clinical manifestations There are two forms of Wegener’s granulomatosis: the ‘limited form’, which affects only the airways and the ‘classic form’, in which the kidneys are also involved. Renal problems vary from slight haematuria and/or proteinuria, to glomerulonephritis and even renal failure. At diagnosis, 20% of the patients have renal involvement, progressing to 80% with time. This systemic disease can also involve joints, eyes, skin, nervous system and the heart. Usually patients present with general complaints such as fever, night sweats, weight loss and malaise, in combination with tracheobronchial symptoms (sinusitis, rhinorrhoea, otitis, oral ulcers, coughing, dyspnoea, haemoptysis and thoracic pain caused by pleuritis). Imaging of the lungs often shows consolidations and noduli. However, 30% of the patients with radiological abnormalities do not have pulmonary symptoms. Glomerulonephritis is also often asymptomatic.5 Affected organs and symptoms are generally similar in children and adults.5-7 However, in children the disease is complicated by subglottic tracheostenosis in 50% of the patients, while this occurs only in 10% of adults. In addition, children frequently develop nasal deformations.5,6 Diagnosis As these cases illustrate, Wegener’s granulomatosis initially often mimics a pulmonary infection. The diagnosis can be made after infectious causes, such as (myco)bacteria and fungi, have been excluded. If there is any doubt, invasive procedures such as an open lung biopsy should not be avoided. Immunosuppressive therapy during an unrecognized infection can be life-threatening. The presence of ANCA strongly supports the diagnosis Wegener’s granulomatosis. ANCA can be demonstrated microscopically by immunofluorescent labelling of antibodies in patients’ serum to neutrophilic granulocytes on a slide. There are two immunofluorescence patterns: a cytoplasmic pattern (c-ANCA) and a perinuclear pattern (p-ANCA). A cytoplasmic pattern corresponds with ANCA directed at PR3, which is characteristic for Wegener’s granulomatosis. A p-ANCA pattern is seen with other types of vasculitis, for instance polyarteritis nodosa.8 A more delicate, quantitative test is the ELISA.9 A rise in PR3 ELISA can be used to anticipate an exacerbation of Wegener’s granulomatosis in a patient who has no clinical symptoms as yet.10 It is recommended to obtain a biopsy of an affected organ, which may show a necrotizing, granulomatous vasculitis. With a positive immuno fluorescence, a positive ELISA and, if possible, a tissue biopsy, the chances of a false-positive diagnosis are very small. Therapy Because of the small number of paediatric patients, randomized controlled trials that compare the current therapy of Wegener’s disease with other treatment strategies are not possible. Therefore, out of necessity, the current protocol for adults is also used in children. However, in children the desired strong immunosuppression has to be weighed even more critically against serious side effects. The induction therapy that is used most often is a combination of oral cyclophosphamide and prednisone. The most important side effects are possible infertility and induction of malignancies caused by cyclophosphamide, and obesity and growth retardation caused by corticosteroids. If possible, cyclophosphamide is replaced by the less toxic agent azathioprine after three months. Azathioprine is then continued for at least one year. Corticosteroids are started at a high dose, then weaned and, if possible, stopped after six months.11 The ‘limited form’ of Wegener’s disease is treated with methotrexate instead of cyclophosphamide, sometimes in combination with prednisone. Plasmapheresis effectively removes the ANCA 12, but is used only when renal dialysis is also necessary, as this strategy requires a central line. Besides immunosuppressive therapy, long-term antibiotic prophylaxis (co-trimoxazole) is given to prevent exacerbations.2
Prognosis Before the introduction of immunosuppressive therapy the prognosis of Wegener’s granulomatosis was poor (median survival 5 months).13 Nowadays 80% of the patients, children and adults, achieve complete remission after a median treatment period of 12 months. Fifty percent of all patients experience a relapse.5 In children, a mortality rate of 0-10% has been reported.5-7 In 85% of patients permanent morbidity is observed, for instance nasal deformities, subglottic stenosis, renal failure (35-50%, 10% develops end-stage renal disease), pulmonary disease and chronic sinusitis. Malignancies caused by treatment have been reported in 11% of the adult patients, but not in children.5 Discussion In conclusion, Wegener’s granulomatosis is very rare in childhood. However, if the disease is diagnosed too late it may lead to permanent morbidity and even mortality. The cases reported here illustrate the fulminating course this disease may follow, also in childhood. In both patients aggressive therapy was necessary. Therefore, in spite of the low incidence, it is recommended to test ANCA and perform urinalysis in a case of pneumonia resistant to antibiotic therapy. It is essential to not only carry out an ANCA immunofluorescence, but also an ELISA for PR3. The case history of patient B shows that a quick diagnosis can be life-saving. This case also shows the discrepancy between ANCA immunofluorescence and PR3 ELISA, as only the latter provided reliable information on the nature and severity of the disease. Although the almost simultaneous presentation of this rare disease in two teenagers living in the same region suggests a common causative agent, this has not been confirmed. As with all autoimmune diseases, there is much uncertainty about the pathogenesis, which hampers an effective search for this putative infectious agent. Acknowledgements We thank Prof. Dr. T.W. Kuijpers for critical revision of the manuscript. The Dutch version of this article was published as ‘De ziekte van Wegener bij twee adolescenten’ in Ned. Tijdschr Geneeskd 2007;151(27):1522-6 References 1. Von Vietinghoff S, Schreiber A, Otto B, Choi M, Gobel U, Kettritz R. Membrane proteinase 3 and Wegener’s granulomatosis. Clin Nephrol 2005;64(6):453-9 2. Stegeman CA, Tervaert JW, de Jong PE, Kallenberg CG. Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener’s granulomatosis. Dutch Co-Trimoxazole Wegener Study Group. N Engl J Med 1996;335(1):16-20 3. Scott DG, Bacon PA, Elliott PJ, Tribe CR, Wallington TB. Systemic vasculitis in a district general hospital 1972-1980: clinical and laboratory features, classification and prognosis of 80 cases. Q J Med 1982;51(203):292-311 4. Cotch MF, Hoffman GS, Yerg DE, Kaufman GI, Targonski P, Kaslow RA. The epidemiology of Wegener’s granulomatosis. Estimates of the five-year period prevalence, annual mortality, and geographic disease distribution from populationbased data sources. Arthritis Rheum 1996;39(1):87-92 5. Rottem M, Fauci AS, Hallahan CW et al. Wegener granulomatosis in children and adolescents: clinical presentation and outcome. J Pediatr 1993;122(1):26-31 6. Belostotsky VM, Shah V, Dillon MJ. Clinical features in 17 paediatric patients with Wegener granulomatosis. Pediatr Nephrol 2002;17(9):754-61 7. Stegmayr BG, Gothefors L, Malmer B, Muller Wiefel DE, Nilsson K, Sundelin B. Wegener granulomatosis in children and young adults. A case study of ten patients. Pediatr Nephrol 2000;14(3):208-13 8. Schonermarck U, Lamprecht P, Csernok E, Gross WL. Prevalence and spectrum of rheumatic diseases associated with proteinase 3-antineutrophil cytoplasmic antibodies (ANCA) and myeloperoxidase-ANCA. Rheumatology (Oxford) 2001;40(2):178-84 9. Savige J, Gillis D, Benson E et al. International Consensus Statement on Testing and Reporting of Antineutrophil Cytoplasmic Antibodies (ANCA). Am J Clin
Pathol 1999;111(4):507-13 10. Sanders JS, Huitma MG, Kallenberg CG, Stegeman CA. Prediction of relapses in PR3-ANCA-associated vasculitis by assessing responses of ANCA titres to treatment. Rheumatology (Oxford) 2006;45(6):724-9 11. Guillevin L, Cordier JF, Lhote F et al. A prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized Wegener’s granulomatosis. Arthritis Rheum 1997;40(12):2187-98
12. Klemmer PJ, Chalermskulrat W, Reif MS, Hogan SL, Henke DC, Falk RJ. Plasmapheresis therapy for diffuse alveolar hemorrhage in patients with small-vessel vasculitis. Am J Kidney Dis 2003;42(6):1149-53 13. Walton EW. Giant-cell granuloma of the respiratory tract (Wegener’s granulomatosis). Br Med J (Clin Res Ed) 1958;265-70
Pediatric Pictures
A neonate with thickened, curved nails L.C. Delemarre1 and B. Boersma1
Figure 1 and 2: A neonate with remarkably shaped, thickened, yellow-brownish nails. Mother has pachyonychia congenita, and wears acrylic nails. Case A 5-day-old female neonate was referred to our outpatient clinic because of excessive crying due to feeding problems. Physical examination showed, besides a white tongue, remarkable curved, thickened, yellowbrownish nails (Figs. 1 and 2). Her mother was known was known with pachyonychia congenita (PC). The white tongue was considered to be oral candidiasis and disappeared after antimycotic treatment. After a few months, she developed a hyperkeratotic plaque on the head, which only partially responded to retinoids. PC is an autosomal dominant keratin disorder, caused by a mutation in one of the keratin genes (12q11q-14, 17q12-q21). PC is characterized by hypertrophic nail dystrophy: hyperkeratosis of the nail bed, and thickening and distortion of the nail plate. PC is associated with palmoplantar keratosis and hyperhidrosis, oral or laryngeal hyperkeratosis, which probably predisposes to candidiasis, and hair and teeth abnormalities.1 In our patient no oral hyperkeratosis has been seen after treatment of the candidiasis. Two phenotypes have been described. PC-1 1
Department of Pediatrics, Medical Centre Alkmaar, Alkmaar
is characterized by more prominent oral leukokeratosis, whereas in PC-2 pilosebaceous cysts, hair abnormalities and natal teeth are more frequently seen. In this case, the symptoms are limited to hypertrophic nail dystrophy and a hyperkeratotic plaque on the head, which makes the distinction between the different phenotypes difficult. In general, there is considerable variability between symptoms and mutation status.2 PC is a clinical diagnosis, which can be confirmed by genetic analysis.2 Treatment is symptomatic by mechanical or pharmacological removal of keratin, surgical excision of the nails, and treatment of pain and secondary infections.3 References 1. Leachman SA et al. Clinical and pathological features of pachyonychia congenita. J Invest Dermatol Symp Proc. 2005;10:3-17 2. Smith FJD et al. The genetic basis of pachyonychia congenita. J Invest Dermatol Symp Proc. 2005;10:21-30 3. Milstone LM et al. Treatment of pachyonychia congenita. J Invest Dermatol Symp Proc. 2005;10:18-20
DE BRUG TUSSEN IDEE EN REALISATIE Nederlands Tijdschrift voor Obstetrie & Gynaecologie
Osteoporose Journaal huisartseneditie
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Verkort IB-tekst:
Primaire (systemische) carnitine deficiëntie. Aanbevolen wordt de volgende dosering per os per dag: Zuigelingen 100-150 mg/kg lichaamsgewicht Kinderen tot 12 jaar 50-100 mg/kg lichaamsgewicht Volwassen en kinderen boven de 12 jaar 20-40 mg/kg lichaamsgewicht In de praktijk betekent dit dat de gemiddelde dosering per os per dag ligt voor: Zuigelingen 1 gram Kinderen tot 12 jaar 2 gram Volwassen en kinderen boven de 12 jaar 2-4 gram (in twee a drie giften)
PEDIATRIC CLINICS AMSTERDAM - PAGE 11
Samenstelling: CARNITENE bevat L-carnitine en is verkrijgbaar als: CARNITENE tabletten, 330 mg, CARNITENE drank 1 gram/ 10 ml (100 mg/ml) CARNITENE injectievloeistof, 1 gram / 5 ml (200 mg/ml). Indicaties: Primaire (systemische) carnitine deficiënties, Eigenschappen: CARNITENE, L-carnitine (y-trimethylamino-B-hydroxybutyraat) is een lichaamseigen stof. L-carnitine wordt bij de mens hoofdzakelijk gevormd door endogene synthese uit lysine en methionine in de lever en de nier, maar kan ook verkregen worden uit de voeding. De L-isomeer, is biologisch actief en speelt een essentiële rol zowel in het lipide metabolisme als in het metabolisme van ketonlichamen en vertakte-keten aminozuren. L-carnitine is noodzakelijk voor het transport van lang-keten vetzuren over het binnenmembraan van de mitochondria naar de mitochondriale matrix, waar de B-oxidatie plaatsvindt met als resultaat productie van ATP. Bij een systemische carnitinedeficiëntie is er een tekort aan L-carnitine in het serum en in een of meerdere weefsels. De meest voorkomende symptomen van een systemische carnitine-deficiëntie zijn: 1. manifestatie begint in de eerste levensjaren, 2. acute episoden van encefalopathie (braken gevolgd door een progressief verlopende stupor, verwarring en coma) die geassocieerd wordt met leverfunctie stoornissen, zeer vaak geïnduceerd door een verminderde opname en/of fysieke inspanningen, 3. progressieve spierfunctie achteruitgang, 4. vetopstapeling in de spier- en andere weefsels (lever, nier enz.), 5. sterk verlaagde carnitinespiegels zowel in het bloed als in weefsel. Laboratorium onderzoek toont aan een hypoglykemie, een verhoging van CPK en leverenzymen in het serum, verhoogde ketose tijdens vasten, EMG (electromyogram) veranderingen. De rationale om patiënten met een carnitinedeficiëntie te behandelen met L-carnitine ligt in het normaliseren van de weefselspiegels en/of deze in overeenstemming te brengen met de behoefte van het organisme op dat moment en de spierfunctie te herstellen. Waarschuwingen voorzorgsmaatregelen: Daar L-carnitine slechts in geringe mate gemetaboliseerd wordt, en als L-carnitine door de nier wordt uitgescheiden, wordt bij patiënten met een verminderde nierfunctie (GFR < 10 ml/min) aangeraden de medicatie te doen plaatsvinden op geleide van plasmaspiegels. Toediening van een hoge orale doses Levocarnitine gedurende lange perioden wordt niet aanbevolen in patiënten met een chronische nierinsufficiëntie, die gedialyseerd worden. Er vindt dan een cumulatie plaats van belangrijke metabolieten zoals trimethylamine (TMA) en trimethylamine-N-oxide (TMAO) omdat deze niet in voldoende mate door de nier geëlimineerd kunnen worden. Dit verschijnsel treedt niet in dezelfde mate op na intraveneuze toediening. Een cumulatie van TMA is nadelig omdat hiermee de stikstofhoudende afval producten die door dialyse verwijderd worden, verhoogd wordt. Bovendien worden de verhoogde TMA spiegels geassocieerd met neurofysiolosche effecten. De onvolledige eliminatie van TMA kan resulteren in de ontwikkeling van een vislucht geur. Indien overwogen wordt om deze patiënten levocarnitine toe te dienen wordt aangeraden dit intraveneus te doen. Gebruik in de zwangerschap: Over het gebruik van deze stof in de zwangerschap bij de mens bestaan onvoldoende gegevens om de mogelijke schadelijkheid te beoordelen. Er zijn tot dusver geen aanwijzingen verkregen voor schadelijkheid bij dierproeven. Bijwerkingen: Een lichte vorm van diarree bij sommige patiënten is na hoge orale toediening gerapporteerd. Dosering: De dosering wordt bepaald door de mate van carnitine deficiëntie. Indien mogelijk moet op geleide van carnitine bloed-/weefselspiegels behandeld worden.
Indien er geen verbetering optreedt in de klinische en biochemische symptomen/spierzwakte, kan de dosering verhoogd worden tot 15 gram per dag, gedurende korte tijd. De CARNITENE injectievloeistof is bedoeld voor acute gevallen en wanneer toediening per os niet mogelijk is. De injectievloeistof dient langzaam (3 minuten) intraveneus toegediend te worden. Met de intraveneuze vorm kan met lagere doseringen (maximaal 30 mg/kg lichaamsgewicht per dag) worden volstaan, gezien de volledige beschikbaarheid van de stof na i.v. toediening ten opzichte van < 10% na orale toediening. Onderverdeeld naar leeftijd betekent dit per dag: Zuigelingen Kinderen tot 12 jaar Volwassen en kinderen boven de 12 jaar
maximaal 30 mg/kg lichaamsgewicht maximaal 20 mg/kg lichaamsgewicht maximaal 10 mg/kg lichaamsgewicht
Registratie: Ingeschreven in het register onder: RVG 11192 CARNITENE sigma tau injectievloeistof 1 gram RVG 11193 CARNITENE sigma tau drank 1 gram RVG 11194 CARNITENE sigma tau tabletten 330 mg Registratiehouder: Sigma Tau Ethifarma B.V., Postbus 10072, 9400 CB Assen. Voor inlichtingen: Sigma Tau Ethifarma B.V., Postbus 10072, 9400 CB Assen, telnr. 0592 333000.
