Journal http://jcn.sagepub.com/ of Child Neurology Homocystinuria With Transverse Sinus Thrombosis Sabrina Buoni, Massimo Molinelli, Aldo Mariottini, Caterina Rango, Sergio Medaglini, Sergio Pieri, Mirella Strambi and Alberto Fois J Child Neurol 2001 16: 688 DOI: 10.1177/088307380101600913 The online version of this article can be found at: http://jcn.sagepub.com/content/16/9/688 Published by: http://www.sagepublications.com Additional services and information for Journal of Child Neurology can be found at: Email Alerts: http://jcn.sagepub.com/cgi/alerts Subscriptions: http://jcn.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Citations: http://jcn.sagepub.com/content/16/9/688.refs.html >> Version of Record - Sep 1, 2001 What is This? Downloaded from jcn.sagepub.com at TEXAS SOUTHERN UNIVERSITY on November 16, 2014 688 4. Carpay HA, Arts WF, Kloet A, et al: Hemichorea reversible after operation in a boy with cavernous angioma in the head of caudate nucleus. J Neurol Neurosurg Psychiatry 1994;57:1547-1548. 5. Rigomonti D, Hsu FPK, Monsein LH: Cavernous malformations and related lesions, in Wilkins RH, Rengachary SS (eds): Neurosurgery, vol 2. New York, McGraw-Hill, 1996, 2503-2508. 6. Chaskis C, Brotchi J: The surgical management of cerebral cavernous angiomas. Neurol Res 1998;20:597-606. Fortuna A, Ferrante L, Mastronardi L, et al: Cerebral cavernous angioma in children. Childs Nerv Syst 1989;5:201-207. Akbostanci MC, Yigit A, Ulkatan S: Cavernous angioma presenting with hemidystonia. Neurol Neurosurg 1998;100:234-237. Perl J, Ross JS: Diagnostic imaging of cavernous malformations, in Awad IA, Barrow DL (eds): Cavernous Malformations. Park Ridap, IL, American Association of Neurological Surgeons, 1993, 37-44. Rapacki TF, Brantley MJ, Furlow TW, et al: Heterogeneity of cerebral cavernous hemangiomas diagnosed by MR imaging. J Comput Assist Tomogr 1990;14:18-25. Sze G, Krol G, Olsen WL, et al: Hemorrhagic neoplasm: MR mimics of occult vascular malformations. AJR Am J Roentgenol 1987;149: 7. 8. 9. 10. 11. 1223-1230. 12. Marder SR, Van Kammen DP: Dopamine receptor antagonists (typical antipsychotics), in Sadock BT, Sadock VA (eds): Comprehensive Textbook of Psychiatry. Philadelphia, Lippincott Williams & Wilkins, 2000, 2356-2377. Homocystinuria With Transverse Sinus Thrombosis ABSTRACT A case of cerebral venous thrombosis caused by undiagnosed homocystinuria is reported. The pitfalls regarding the diagnosis of a potentially medically treatable condition are discussed. Cerebral venous thrombosis in children has a variable type of onset and a multiplicity of causes. This type of pathology, although not frequent, is more common than previously thought. Among the different etiologies, undiagnosed homocystinuria is not routinely considered. We report a case of venous thrombosis of the left transverse cerebral sinus in a girl with drug-resistant partial epilepsy and homo- cystinuria. This diagnosis was considered and confirmed after the appearance of acute cerebral symptoms caused by venous thrombosis. (J Child Neurol 2001;16:688-690). The neurologic examination was normal. An EEG showed bilateral spike discharges over the central regions. Other examinations including magnetic resonance imaging (MRI), serum aminoacidogram, fundoscopy, cytogenetics, routine blood chemistry, and urinalysis were normal. Psychometric evaluation (March 1998) indicated a borderline intelligence, with an IQ of 78 according to the Wechsler Intelligence Scale for Children-Revised. Difficulties in visuomotor and spatial orientation performance were noted. The patient was placed on a therapy of magnesium valproate 550 mg/day and discharged. On October 3, 1999, the patient exhibited eyelid myoclonias and chewing automatism followed by a generalized tonic-clonic convulsion. The seizure lasted about 2 minutes and left her agitated, confused, and with the headache she had complained of prior to the seizure. She was admitted to another hospital. Fundoscopic examination was normal. A cerebral CT scan showed a slowing of blood flow within the left transverse sinus. An MRI taken on October 4, 1999, showed an extensive venous infarction on the left mid and posterior temporal region owing to thrombotic occlusion on the transverse omolateral sinus (Figure lA). Magnetic resonance angiography confirmed the absence of signal of the transverse left sinus and of Labb6’s veins (Figure 1B). The patient was admitted to the Neurosurgical Institute of the University of Siena on October 1999. She was confused and markedly agitated and could not answer simple questions. She could not walk and complained of headaches. Coagulation studies including fibrinogen, partial thromboplastin time, prothrombin time, protein S and C, factor V Leiden, and thrombocyte counts were normal. An EEG showed runs of slow waves in the left centro-occipital region and isolated spike and waves in the left central region. A serum aminoacidogram was again performed. Homocysteine was 388.50 )JLmoI/L and L-methionine was 70.72 [tmol/L. Folic acid and vitamin B12 were within normal limits. A urine test with nitroprusside was positive. A diagnosis of homocystinuria was reached, and the patient was given 300 mg of pyridoxine intramuscularly and thereafter by mouth. An anticoagulant treatment was also administered with continuous intravenous infusion of sodium heparin, followed by warfarin 8 mg/day. Serum aminoacidogram was again checked after 3 days of pyridoxine treatment. Levels of homocysteine and methionine were 62.90 f.Lmol/L and 43.49 ~,mol/L, respectively. The patient’s condition gradually improved. She regained the level of consciousness she had prior to the episode. She was able to walk, her speech became normal, and she was able to answer questions. An EEG showed runs of slow waves in the left centro-occipital regions that were less evident than in the previous EEG. She was discharged after 25 days with anticoagulant therapy (warfarin 8 mg/day), desamethasone (1 mg/day), pyridoxine 300 mg/day, diazepam 3.5 mg/day, ranitidine 150 mg twice daily, and carbamazepine 800 mg/day. A cyanide nitroprusside test on urine was negative. On November 9, 1999, an MRI showed a decrease in the size of the abnormal area in the left temporal region. On a magnetic resonance angiogram, occlusion of the left transverse sinus was still present. The EEG showed some slow waves in the left occipital region. A psychometric evaluation in February 2000 with the Wechsler Intelligence Scale for Children-Revised showed a Full-Scale IQ of 70, with a significant variance between Verbal IQ (81) and Perfomiance IQ (61), and the scores on the subtests of comprehension and visuomotor and spatial competence were significantly lower than those obtained in the previous examination in 1998. Case Report This 7-year-old girl was first evaluated when she was 6 years old at the Institute of Clinical Pediatrics of the University of Siena. She suffered a partial seizure with clonic jerks of the right arm accompanied by twitching of the right comer of the mouth, hypotonia, and loss of consciousness. Following this episode, which lasted about 1 hour, she was admitted to a local hospital. An electroencephalogram (EEG) showed paroxysmal activity in the left frontocentral region. A computed tomography (CT) cerebral scan was normal. She was placed on magnesium valproate 400 mg/day, but after 4 months, she suffered another brief partial seizure with clonus of the right arm, again followed by transient right arm paresis. She was then admitted to the Institute of Clinical Paediatrics for additional tests. In the mother’s serum, homocysteine was 76.66 f.Lmol/L and methionine was 30.37 f.Lmol/L. In the father’s serum, homocysteine was 27.27 [Lmol/L and methionine was 35.16 f.Lmol/L. ’ Discussion ’ ’ ’ This patient’s history was consistent with a diagnosis of epilepsy with complex partial seizures and Todd’s paralysis. The last seizure was characterized by a generalized convulsion followed by headache and an acute alteration of her mental state. This situation in chil- dren can be associated with viral encephalitis and, in particular, Downloaded from jcn.sagepub.com at TEXAS SOUTHERN UNIVERSITY on November 16, 2014 689 enhances the proteolytic activity of protein C. Denominated factor V Leiden is a mutant form of factor V with an amino-acid substitution at the protein C cleavage site and accounts for most cases of protein C resistance. The mutation of the gene for factor V is a single base-pair substitution.8--10 Prothrombin G 20210 gene mutation, heparin cofactor II defects, and primary thrombocythemia are also to be considered among the causes of thrombotic manifestations.ll Primary antiphospholipid syndrome is another recently described condition associated with superior sagittal sinus thrombosis.~2 Epstein-Barr virus infection has also been implicated in venous thrombosis in a patient with a heterozygous form of protein C deficiency. 13,14 Thrombocytopenia with a positive lupus anti- coagulant test associated with sagittal sinus thrombosis has been reported in a 22-month-old female.15 Neurobrucellosis, 16 sicklecell disease, autoimmune disease, and idiopathic hypereosinophilic syndrome must also be included in the differential diagnosis of deep cerebral vein thrombosis. 17,IS Among the possible etiologies in the above-reported literature, homocystinuria is not considered. However, hyperhomocystinemia is emerging as a strong risk factor for atherosclerotic vascular disease and for arterial and venous thromboembolism. Hyperhomocystinemia can be related to common genetic and acquired factors including folate and vitamin B12 deficiencies. Vitamin B12 supplements, in particular with folic acid, can reduce this effect. Homocystinuria is a genetic metabolic disorder owing to a defect of enzyme cystathionine p-synthase. Clinical manifestations include subluxation of ocular lenses, hypopigmentation, malar flush, and skeletal abnormalities. Mental retardation is common. Epilepsy is present in 20% of cases. Arterial and venous thromboses are frequent. Deep cerebral venous thrombosis is not ~re axia l iimage. red A, hyperi ntensity aarea mage. Extensive hyperintensity A,T2-weighted T~-weig hted axial localized in the left medial and posterior temporal lobe. B, Magnetic resonance angiogram. Coronal a section. Absence of circulation blood in the left transverse sinus. Figure 1.I . Fig herpes simplex infections, nonconvulsive status epilepticus,l and drug ingestion or hyperthermia.3 Cerebral ischemic infarcts of the thalamus of arterial origin can also lead to similar manifestations.44 Deep cerebral venous sinus thrombosis can also cause acute confusion .5 However, this condition is rare in children.6 MRI and magnetic resonance angiography can be very helpful in the diagnosis because they localize the thrombosis and the extent of the cerebral infarction. Sinus thromboses have multiple etiologies. Protein C, protein S, and antithrombin III deficiencies can be responsible for 5 to 10% of the cases of familial thromboses, and resistance to activated protein C can be the cause in another 50% of the cases. The mechanism of this abnormality has only recently been clarified. Protein C is a vitamin K-dependent proteinase locally activated by the thrombin thrombomodulin complex at the site of a vascular endothelial lesion. Factors V and VII are inactivated enzymatically by an activated protein C. Fibrin formation and clot stabilization are thus blocked. Protein S is the cofactor that reported. There are patients who are pyridoxine responsive and patients who are not.~9 The gene has been mapped in the subtelomeric area of chromosome 21q22.3 and cloned. In the patient we described, we also considered a diagnosis of homocystinuria when she was first admitted to the Institute of Clinical Paediatrics, but the first aminoacidogram report was normal. This was possibly owing to a mishandling of the blood. There were no clinical findings that could indicate homocystinuria such as skeletal abnormalities, ocular lens subluxation, malar flush, or peculiar gait. Epilepsy and borderline intelligence were the only clinical abnormalities. A nitroprusside test was not performed because freshly voided urine is necessary. Because headache, seizures, mental confusion, and somnolence indicated the possibility of an acute cerebral episode, MRI with gadolinium and magnetic resonance angiography demonstrated a thrombosis of the left transverse and sigmoid sinus plus an extensive venous infarction of the left mid and posterior temporal lobe (see Figure 1). The diagnosis of homocystinuria was then considered along with the other possible causes of hypercoagulability states and confirmed through the high values of plasma homocystine and methionine. Since the patient was responsive to pharmacologic doses of pyridoxine, a dietary treatment was not instituted. This case illustrates the necessity of considering the diagnosis of homocystinuria in any case with hypercoagulability syndrome and the usefulness of pyridoxine treatment if the diagnosis of homocystinuria is confirmed. Downloaded from jcn.sagepub.com at TEXAS SOUTHERN UNIVERSITY on November 16, 2014 690 Sabrina Buoni, MD 16. Zaidan R, Al Tahan AR: Cerebral venous thrombosis: A new manifestation of neurobrucellosis. Clin Infect Dis 1999;28:399-400. 17. Di Roio C, Jourdan C, Yilmaz H, Artru F: Cerebral deep vein thrombosis : Three cases. Rev Neurol (Paris) 1999;155:583-587. 18. Schulman H, Hertzog L, Zirkin H, Hertzanu Y: Cerebral sinovenous thrombosis in the idiopathic hypereosinophilic syndrome in childhood. Pediatr Radiol 1999;29:595-597. 19. Mudd SH, Skovby F, Levy HL, et al: The natural history of homocystinuria due to cystathionine β-synthase deficiency. Am J Hum Genet 1985;37:1-31. Massimo Molinelli, PhD Institute of Clinical Pediatrics Aldo Mariottini, MD Institute of Neurosurgery Caterina Rango, MD Institute of Preventive Pediatrics Sergio Medaglini, Psychologist Institute of Clinical Pediatrics Sergio Pieri, MD Institute of Neurosurgery Mirella Strambi, MD Institute of Preventive Pediatrics Optic Neuropathy in Primary Antiphospholipid Syndrome in Childhood Alberto Fois, MD Department of Pediatrics University of Siena Siena, Italy ABSTRACT Neurologic symptoms associated with antiphospholipid antibodReceived August 23, 2000. Received revised Jan 3, 2001. Accepted for publication Jan 4, 2001. Address correspondence to Dr Alberto Fois, Policlinico Le Scotte, Viale Bracci, 53100 Siena, Italy. Tel and fax: 39-577-586521; e-mail: ftnp@libero.it. References 1. Norman M, Lundberg B, Forsgren M, et al: Acute confusion. An unusual form of cerebral herpes simplex infection? Acta Pediatr Scand 1991;80:252-254. 2. Porter RJ: The absence epilepsies. Epilepsia 1993;34(Suppl3):S42-S48. 3. Amit R: Acute confusional state in childhood. Childs Nerv Syst 1988;4: 255-258. 4. Garg BP, DeMyer WE: Ischemic thalamic infarction in children: Clinical presentation, etiology and outcome. 1995;13:46-49. Pediatr Neurol 5. Kothare SV, Ebb DH, Rosemberger PB, et al: Acute confusion and mutism as a presentation of thalamic strokes secondary to deep cerebral venous thrombosis. J Child Neurol 1998;13:300-303. 6. Barron T, Gusnard DA, Zimmerman RA, et al: Cerebral venous thrombosis in neonates and children. 1992;8:112-116. Pediatr Neurol 7. Dahlback B: Inherited thrombophilia: Resistance to activated protein C as a pathogenic factor of venous thromboembolism. Blood 8. Martinelli L, Landi G, Merati G, et al: Factor V gene mutation is a risk factor for cerebral venous thrombosis. Thromb Haemost 1996;75: 393-394. 9. Cardo E, Campistol J, Kirkham F: The role of resistance to C active 1997;25:1589-1591. protein (R-APC) in a pediatric stroke. Rev NeuroL Weih M, Vetter B, Ziemer S, et al: Increased rate of factor V Leiden mutation in patients with cerebral venous thrombosis. 1988;245: J Neurol 1995;85:607-614. 10. 11. orders, or migraine. We present a 7-year-old girl with bilateral optic neuropathy, cerebral white-matter lesions, and antiphospholipid IgM that responded to prednisone and tended to relapse when it was stopped. Remission was obtained under maintenance corticosteroid therapy, and the antiphospholipid antibodies disappeared.This case suggests a role for antiphospholipid antibodies in the pathogenesis of optic neuropathy in childhood. (J Child Neurol 2001;16:690-693). Antiphospholipid antibodies are autoantibodies of the IgG or IgM type that affect in vitro coagulation tests.’ They include anticardiolipin antibodies, Venereal Disease Research Laboratory (VDRL) test, and lupus anticoagulant. Antiphospholipid antibodies can be detected in infectious, drug-induced, malignant or collagen vascular disorders, or in the absence of such underlying conditions as the primary antiphospholipid syndrome.’ Symptoms and signs associated with primary or secondary antiphospholipid antibodies have mostly been described in adults and include arterial or venous thrombotic events, thrombocytopenia, recurrent fetal loss, and a variety of neurologic symptoms. There are very few reports on primary antiphospholipid syndrome in children We present a child with primary antiphospholipid syndrome whose symptoms involved 149-152. the optic nerve and central nervous system. Frenkel EP, Bick RL: Protrombin G20210A gene mutation, heparin cofactor II defects, primary (essential) thrombocythemia, and thrombohemorrhagic manifestations. Semin Thromb Haemost 1999;25: 375-386. Case Report 12. Nagai S, Horie Y, Akai T, et al: Superior sagittal sinus thrombosis associated with primary antiphospholipid syndrome. Case report. Neurol Med Chir (Tokyo) 1998;38:34-39. 13. Knees U, Macdonald E, Stiegler H, et al: Pelvic vein thrombosis in protein C deficiency after infectious mononucleosis. Monatsschr Kinderheilkd 1993;141:928-931. 14. Visser MR, Tracy PB, Vercellotti GM: Enhanced thrombin generation and platelet binding on herpes simplex virus-infected endothelium. Proc Natl Acad Sci U S A 1988;85:8227-8230. 15. ies in children include thrombotic events, unilateral movement dis- Alper G, Berrak SG, Ekinci G, et al: Sagittal sinus thrombosis associated with thrombocytopenia: A report of two patients. Pediatr Neurol 1999;21:573-575. This 7-year-old girl started to complain of daily headache and abdominal pain in February 1998. Decreased vision in the right eye and total visual loss in the left eye were noticed 4 months later. Topical corticosteroids were prescribed by her local doctor, and vision improved in 2 months. She was symptom free until September 1998, when she experienced back pain, vomiting, decreased vision, and weight loss. Although she had no fever, she was treated for meningitis in another hospital for 2 weeks. The symptoms persisted, and she was referred to Hacettepe University Children’s Hospital in November 1998. Her past medical history included typhoid fever at the age of 1 year and measles at 2 years. Her parents were nonconsanguineous, and her nine siblings were healthy. There was no history of tuberculosis or brucellosis in the family. Two maternal uncles had died at 12 years of age from Downloaded from jcn.sagepub.com at TEXAS SOUTHERN UNIVERSITY on November 16, 2014