Nikos Gombakis

Central nervous system abnormalities in asymptomatic young patients with Sβ‐thalassemia

Twenty‐one children and young adults with sickle/β‐thalassemia without overt stroke were examined with magnetic resonance imaging and angiography (MRA), transcranial Doppler (TCD), visual (VEP) and median nerve somatosensory (SEP)–evoked potential recordings, and neuropsychological testing (Wechsler Intelligence Scale [WISC‐III]). Eight (38%) had silent infarction in the parietooccipital cortex, deep white matter, or basal ganglia, including two of three with previous seizures. Of 17 undergoing TCD, none had maximum middle cerebral artery (MCA) velocities greater than 126cm/sec, but 9 were abnormal, with low velocities and difficulty in tracking the MCA and/or asymmetry. Three patients had abnormal MRA, one of whom also had silent infarction. One patient had pathological VEP recordings, whereas all SEP recordings were normal. WISC‐III was performed in all 11 children, 4 with silent infarction: all but 1 had IQ scores greater than 85 (mean, 97.7; standard deviation, 14.2). We conclude that Greek children and young adults with Sβ‐thalassemia and no history of clinical stroke have TCD abnormalities and silent infarction similar to those reported in children and adolescents with sickle cell anemia, but cognitive function is not necessarily compromised. International collaboration is needed to establish the risk factors for central nervous system sequelae in patients with sickle cell disease, including Sβ‐thalassemia, leading to evidence‐based prevention. Ann Neurol 2004

Serial MRI and neurophysiological studies in late-infantile Krabbe disease

We report serial clinical, radiological, and neurophysiological findings of a patient with late-infantile Krabbe disease. At age 13 months, the patient was hospitalized for sudden stiffness and irritability and a diagnosis of spastic diplegia was made. At age 24 months, he was readmitted because of further psychomotor deterioration; neurologically, he manifested severe spastic tetraplegia with optic atrophy. MRI disclosed diffuse high intensity in the cerebral white matter on T2-weighted images. Nerve conduction velocity and evoked potential studies were markedly abnormal, as were the EEG and the EMG. Assay of galactocerebroside beta-galactosidase activity in leukocyte culture disclosed a marked deficiency of the enzyme, confirmatory of the diagnosis of late-infantile Krabbe disease. Serial MRI and neurophysiological studies performed every 6 months for 18 months demonstrated the progressive nature of the disorder, correlating with the clinical deterioration.

Neurophysiology and MRI in late-infantile metachromatic leukodystrophy

We present serial clinical, radiologic, and neurophysiologic findings of a patient with late-infantile metachromatic leukodystrophy who was first admitted at 30 months of age because of gait disturbance. The neurologic findings were consistent with mild spastic diplegia (occasionally with toe walking). Magnetic resonance imaging disclosed diffuse high intensity in the cerebral white matter on T2-weighted images. Nerve conduction velocity studies and evoked-potential studies were markedly abnormal. Assay of arylsulfatase A activity in leukocyte culture disclosed a marked deficiency of the enzyme, confirming the diagnosis of late-infantile metachromatic leukodystrophy. Serial neurophysiologic studies demonstrated a marked decrease of nerve conduction velocities, both motor and sensory, as well as prolongation or disappearance of brainstem auditory-, visual-, and somatosensory-evoked potential latencies. Magnetic resonance imaging studies revealed initially diffuse increased signal intensity of periventricular and subcortical white matter on T2-weighted images, progressing to cortical atrophy with involvement of the arcuate fibers and the cerebellar white matter, correlating with the clinical deterioration (severe spastic tetraplegia with optic atrophy and epilepsy).

Single dose immunoglobulin therapy for childhood Guillain-Barrésyndrome

To establish the efficacy of intravenous immunoglobulins (IVIG) in the treatment of acute Guillain-Barré syndrome (GBS), we treated nine consecutive pediatric cases (age 2.5-13.5 years) fulfilling the criteria for GBS with a single dose of IVIG (Sandoglobulin; 2 g/kg/BW). None of the patients experienced any IVIG related side-effects. The mean time required to improve by at least one grade on the functional GBS scale after IVIG treatment was 3.5 days, while the mean period to regain ambulation was 11.2 days. Full mobilization without evidence of relapse in the follow-up period (mean 14.5 months) was noted in all but one patient who relapsed after 5 months. We conclude that the early use of a single IVIG dose may prevent further progression of the disease, thus shortening the clinical course of childhood GBS. The most beneficial IVIG dose regimen remains to be determined by controlled trials.

Familial moyamoya disease in a Greek family.

Moyamoya disease (M-M) is characterized by progressive obstruction of the supraclinoid portion of internal carotid arteries and the proximal middle, anterior and posterior cerebral arteries, associated with the formation of a characteristic net of collateral vessels in the basal ganglia region. Clinical manifestations in childhood include transient ischaemic attacks, seizures and multiple infarcts. Approximately 7% of M-M cases are familial. We report two affected Greek siblings with typical clinical and neuroradiological findings of M-M. Linkage analysis of the whole family was consistent with linkage to the region 3p24-26, as previously reported in other familial Japanese M-M cases.

L-2-Hydroxyglutaric aciduria presenting as status epilepticus

L-2-Hydroxyglutaric aciduria (L-2-HGA) is a rare organic aciduria with a slowly progressive course regarding CNS involvement. We present a 13.5-year-old female patient who presented at the Emergency Department with a generalized status epilepticus, which promptly responded to intravenous phenytoin. CT and MRI demonstrated subcortical white matter alterations. The neurological examination revealed mild mental retardation, macrocephaly and ataxic gait with cerebellar signs. Repeated urinary organic acid analysis demonstrated increased excretion of 2-hydroxyglutaric acid which was of the L-configuration. The constellation of macrocephaly in a patient with mental retardation, cerebellar tract involvement and subcortical white matter signal alterations on MRI should alert the physician to the possibility of L-2-HGA. Although rare, epileptic seizures or even status epilepticus can be among the presenting symptoms in organic acidurias with a slow course, such as L-2-HGA.

Subclinical celiac disease in children: refractory iron deficiency as the sole presentation.

To the Editor: In response to the interesting case report by Mody et al, we would like to present our own experience on refractory iron deficiency as the sole manifestation of celiac disease (CD). CD is an autoimmune enteropathy developing in genetically predisposed individuals after mucosal contact with gluten, secondarily to unknown triggering factors. Although typical CD characterized by symptoms of malnutrition has been well known since first described in 1888, various other forms have more recently been reported, with an increasing prevalence probably attributed to a greater diagnostic awareness and a better use of screening methods. Subclinical, silent and latent are CD forms that do not include gastrointestinal symptoms and are considered to be present in the majority of CD patients, both children and adults. We report the experience of a pediatric gastroenterology outpatient clinic attended by 63 CD patients, in 9 of whom (14.28%) refractory iron deficiency was the sole presentation at the time of diagnosis. The patients, three boys and six girls, were initially referred to the pediatric hematology outpatient clinic or the pediatric department due to iron deficiency, with or without anemia, unresponsive to iron supplementation therapy or relapsing following treatment. Mean age of symptom onset was 4.7 ± 2.7 years, and the mean age of referral, and subsequent diagnosis, was 8.9 ± 4.2 years, with a mean diagnostic delay of approximately 4 years, ranging from 10 months to 10 years. The most commonly presenting symptoms were pallor and fatigue, while gastrointestinal symptoms were absent and growth curves were within normal limits in all cases. Hemoglobin concentration varied from 6.2 to 12.6 g/dL, mean corpuscular volume from 52 to 81.7 (μm), and ferritin from 2 to 6.5 ng/mL (Table 1). Testing for occult blood in the feces was negative, whereas antigliadin (AGA) and antiendomysium (EmA) antibody testing was positive in all patients. CD diagnosis was confirmed by endoscopic small bowel biopsy in accordance with the revised ESPGAN criteria. A gluten-free diet lad to laboratory normalization of serologic and hematologic markers, with concurrent clinical improvement. The personal and family history of all the patients was negative for CD or other autoimmune diseases, with the exception of patients 2 and 3, who were siblings; their mother’s brother suffered from CD and the mother herself had type I diabetes. Iron deficiency is one of the most common manifestations of CD, but its prevalence as the exclusive presentation in childhood CD has not been investigated. In iron-deficient adults screened for CD, the incidence of positive celiac antibodies has been reported to be 6.6% to 8%, and 5% with a positive intestinal biopsy. Given that iron deficiency is quite common during childhood and often anticipated in certain ages such as infancy and adolescence, it is possible that a larger number of cases are not thoroughly evaluated. In the majority of the nine patients described, refractory iron deficiency was not properly assessed for a long period of time, leading to a delay in CD recognition that reached a decade in the case of patient 5, even being present in patents 2 and 3, whose family history was positive for CD. Pediatricians must be aware that only a portion of CD cases are clinically overt, atypical forms are more common in children than previously considered, and CD may become apparent at any age, even years after gluten diet initiation. Early recognition of the disease, with direct gluten-free diet implementation, is extremely important to avoid secondary complications and development of associated malignancies in CD patients.

A patient with Lemierre syndrome

Lemierre syndrome, also known as postanginal sepsis, is a severe complication of an acute oropharyngeal infection that results in septic thrombophlebitis of the ipsilateral internal jugular vein with subsequent septicemia, often complicated by metastatic infections (Syed et al., Laryngoscope 117:1605–1610, 2007). We present the case of a previously healthy 12-year-old boy with Lemierre syndrome, caused by streptococci (Abiotrophia defectiva), complicating a subcutaneous neck abscess. The patient had metastatic sequelae, was treated with antibiotics (clindamycin and vancomycin) and low molecular weight heparin, and had an uneventful outcome.

Increased osteoclastic activity as shown by increased sRANK-L/OPG ratio in boys with hemophilia

Dear Editor, We read with interest the report by Katsarou et al. that originally assessed biochemical bone markers in patients with hemophilia and correlated these results to clinical and laboratory parameters [1]. As we have recently measured, bone markers in our hemophilic patients and our results differ significantly with those already released; we would like to report our experience. In 27 hemophilic boys with a mean decimal age of 11.63±4.66 years (range: 4-17 years) and 25 age-matched male controls (mean decimal age: 11.45±5.26 years), levels of soluble receptor activator of nuclear factor κB ligand (sRANK-L), osteoprotegerin (OPG) and osteocalcin (OC) were measured in serum. All samples were deep frozen after immediate centrifugation until the day of measurement. Enzyme-linked immunosorbent assays were used for the determination of bone markers: sRANK-L (total), Biovendor Laboratorni Medicina, Modrice, Czech Republic; OPG, Biomedica Medizinprodukte GmbH & Go, Vienna, Austria; OC, Bender MedSystems GmbH, Vienna, Austria. Our results demonstrate that, compared to controls, patients with hemophia have significant higher serum levels of sRANK-L (395.86±90.60 vs. 297.25±36.46 pmol/l, p=0.001) and of OC (5.31±2.26 vs. 3.09±0.61 ng/ml, p=0.001) and significantly decreased levels of OPG (0.78±0.13 vs. 1.19±0.22 pmol/l, p<0.001). These result to an even more striking difference of the ratio sRANK-L/OPG between patients and controls (527.27± 181.51 vs. 256.24±45.01, p<0.001, Fig. 1). Our results indicate an increased osteoclastic activity followed by a compensatory up-regulated osteoblastic function and further substantiate the common pathogenetic mechanism that both hemophilic and rheumatoid arthritis share [2, 3]. In the study by Katsarou et al. [1], serum sRAKL-L and OPG levels did not differ significantly between patients and controls, whereas OC levels were significantly decreased in hemophiliacs, in contrast to our results. In that study, an up-regulated osteoclastic activity in hemophiliacs was shown by the increased levels of Nterminal and C-terminal cross-linking telopeptide of collagen type I (NTX and CTX); the latter was also found in the recent study by Jansen et al. [4]. Further studies are warranted to elucidate the exact mechanism of the hemophilic arthropathy and translate this knowledge into potential therapeutic options.

Transfusion related acute lung injury syndrome (TRALI) in a patient with thalassaemia.

To the Editor: In reply to the very interesting article by Sanchez et al. [1] regarding transfusion related acute lung injury (TRALI syndrome), we would like to report a similar case of an adolescent girl with beta-thalassemia, whowas on a regular transfusion-chelation regimen since the age of 2 years. It is the first case of TRALI occurring during the 25-year course of our Pediatric Thalassemia Unit, where 5,500 of packed red blood cell units are transfused every year. The patient is a 13-year-old female who developed cough, respiratory distress, cyanosis and hypotension 1 hr after transfusion initiation, having received 125 ml of leukocyte depleted, ABO compatible, packed red cells. Chest auscultation revealed moist rales without presence of bronchospasm. The patient was managed for severe pulmonary oedema with oxygen, intravenous fluids, steroids, and adrenaline. Despite treatment, her condition rapidly deteriorated and shewas transferred to the intensive care unit within 20min of symptom initiation. There, she was immediately put on mechanical intubation, while aspiration of ample foamy sputum was required. Body temperature rose to 39.78C and chest X-ray revealed bilateral infiltrates. Although findings were consistent with cardiogenic pulmonary edema, ECG and heart ultrasound did not confirmpresence of cardiopathy. Heart ultrasound performed annually had also been normal. The patient was treated with diuretics, midazolam and inotropic drugs, as well as antibiotics, as diagnosis of transfusion related septic shock could not be ruled out. Fortyeight hours later, the patient clinically recovered. Chest Xray performed on the 4th day of hospitalization showed definite improvement. Investigation of the patient’s serum revealed anti-leukocyte and anti-platelet antibody presence, while the donor’s serum showed anti-leukocyte antibody presence in low titers. The blood donor was found to be a multiparous woman who was subsequently excluded from the donor pool. According to literature, diagnosis of TRALI syndrome is based on clinical findings, including respiratory distress, fever, hypotension, and hypoxia that develop during the first 6 hr of a blood product transfusion [1–4]. In the majority of cases, TRALI is a self-limiting condition with excellent prognosis, while mild cases can easily be misdiagnosed [5]. Given symptomatic treatment to patients with severe TRALI, improvement is expected to occur within 48–96 hr, whereas chest X-ray findings may take up to 4 days to show improvement. Diagnosis of TRALI requires high suspicion and exclusion ofmore common etiologies of past-transfusion respiratory failure such as cardiogenic pulmonary edema and volume overload [5,6]. Moreover, the presence of antileukocyte antibody, although not necessary for TRALI diagnosis, supports it [7]. Due to high prevalence of HLA sensitization, a donor’s multiparity is a known risk factor for the recipient developing TRALI, as in the case described [8]. In relation to TRALI incidence, Popovsky et al. [8] reported 5 cases of the syndrome occurring in a total of 3,130 patients. The low TRALI incidence in our patient group could be attributed to the use of leukocyte depleted red cells, while non-diagnosis of mild cases cannot be totally ruled out. In conclusion, doctors involvedwith blood product transfusions should have a high suspicion of the syndrome. All TRALI cases should be reported to blood banks in order to increase awareness of this potentially fatal complication.