A chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome. A specific entity analysed in 30 patients.

We have studied the clinical presentation and course of a chronic inflammatory disease occurring in childhood and observed in 30 patients. The first symptoms were generally present at birth, except in a few patients where they were first noticed in early infancy. All the patients had the association of three main symptoms: neurological, cutaneous and articular. The skin rash was the first symptom observed in all the patients and looked like a chronic non pruritic urticaria varying during the day. The articular manifestations involved knees, ankles and feet, elbows, wrists and hands unaffecting the other joints. They could be mild giving arthritis during flare-ups or severe with major radiological modifications affecting the epiphysis, metaphysis and growth cartilage. The neurological manifestations were characterized by a chronic meningitis and symptoms indicating meningeal irritation: headaches, seizures, spasticity of legs. Most patients had a cerebral atrophy and a low IQ. Sensory organ involvement occurred progressively during the follow-up: ocular inflammation with optic atrophy, deafness and hoarseness. Common morphological features characterized these patients with short stature, head enlargement, saddle back nose and short and thick extremities with clubbing of fingers. The course was that of a chronic inflammatory disease with numerous flare-ups associating fever, splenomegaly and adenomegaly. Except for a high level of eosinophils in blood, CSF and tissues, the biology was non specific and only exhibited features of inflammation. Except for two families, the disease was sporadic. A high frequency of prematurity with features resembling a foetal infection was observed but no proof of a possible causal virus has so far been found so that etiology remains unknown.

Improved neurologic function after long-term correction of vitamin E deficiency in children with chronic cholestasis.

We studied the effect of long-term correction of vitamin E deficiency on neurologic function in 14 children with chronic cholestasis. Vitamin E repletion was achieved in all, either by large oral doses (up to 120 IU per kilogram of body weight per day) or by intramuscular administration of dl-alpha-tocopherol (0.8 to 2.0 IU per kilogram per day). With early institution of therapy, neurologic function remained normal in two asymptomatic children below the age of three years after 15 and 18 months of therapy. Neurologic function became normal in three symptomatic children below age three after 18 to 32 months of therapy. Restitution of neurologic function was more limited in nine symptomatic children 5 to 17 1/2 years old after 18 to 48 months of therapy. We conclude that vitamin E repletion therapy should be initiated at an early age in children with chronic cholestasis complicated by vitamin E deficiency, to prevent irreversible neurologic injury.

Frequency and clinical progression of the vitamin E deficiency neurologic disorder in children with prolonged neonatal cholestasis.

To determine the frequency of biochemical vitamin E deficiency and of the clinical signs of the vitamin E deficiency neurologic syndrome in children with prolonged neonatal cholestatic disorders, we studied 46 children (aged 1 month to 17.0 years) with chronic forms of intrahepatic neonatal cholestasis and 47 children (aged 4 months to 8.0 years) with extrahepatic biliary atresia. Based on serum vitamin E concentrations and the ratios of serum vitamin E concentration to total serum lipid concentration, 64% of the intrahepatic and 77% of the extrahepatic cholestasis groups were vitamin E deficient. Prior to age 1 year, neurologic function was normal in all children. Between ages 1 and 3 years, neurologic abnormalities were present in approximately 50% of the vitamin E-deficient children; after age 3 years, neurologic abnormalities were present in all vitamin E-deficient children. Areflexia was the first abnormality to develop between ages 1 and 4 years; truncal and limb ataxia, peripheral neuropathy, and ophthalmoplegia developed between ages 3 and 6 years. Neurologic dysfunction progressed to a disabling combination of findings by ages 8 to 10 years in the majority of vitamin E-deficient children. Neurologic function was normal in the vitamin E-sufficient children. We conclude that vitamin E status should be evaluated in infants in whom cholestasis is diagnosed, and effective therapy should be initiated to prevent or treat vitamin E deficiency at an early age.

Schizencephaly: a clinical and CT study.

Schizencephaly is a primary developmental defect of the brain, presumably caused by failure of formation of the cerebral mantle in the regions of the cerebral fissures. Identification has usually been at autopsy, in association with severe neurologic abnormalities. We identified the characteristic features of schizencephaly on CTs in 11 patients. Age at detection ranged from an infant at 8 months to a 30-year-old adult. Clinical abnormalities varied from mild to severe, including developmental delays and retardation, microcephaly, focal or generalized motor abnormalities, and seizures. CT findings included cerebral clefts, infolding of cortical gray matter along the clefts, an abnormal ventricular system, and other associated cerebral anomalies.

Role of coagulopathy in newborn intracranial hemorrhage.

Fifty newborn infants of less than 33 weeks' gestation were followed prospectively from birth with serial coagulation and real-time ultrasound studies. A significant association of hypocoagulability in the first four hours of life with subsequent onset or progression of intraventricular or other clinical hemorrhages was documented. Abnormalities included lower values for fibrinogen, platelet count, antithrombin III, and factor VIII with higher values for fibrin monomer and longer Laidlaw whole blood clotting times. These abnormalities tended to correct spontaneously in surviving infants. An association between gestational complications and incidence of hypocoagulability and intracranial hemorrhage (ICH) was noted. Babies of preeclamptic mothers had fewer abnormalities and babies born to mothers with premature rupture of membranes and suspected amnionitis manifested more hypocoagulability and more severe intracranial hemorrhages.

Timing and antecedents of intracranial hemorrhage in the newborn.

Fifty newborn infants of less than 33 weeks' gestation were followed prospectively from birth to evaluate the temporal relationships of various clinical factors to the onset and progression of intracranial hemorrhage (ICH) in an inborn population given maximal support. ICH was diagnosed and followed with bedside ultrasound every eight hours. The incidence of intraventricular hemorrhage was 30% and of any ICH was 40% with onset from less than 2 hours to 8 days of age. Grades 2, 3, and 4 ICH correlated with Apgar scores of less than 5 at five minutes, vaginal delivery, longer labors, and intrapartum hemorrhage. There was a significant correlation between ICH and both blood pressure fluctuations of greater than 100% and rapid colloid infusions. Slow transfusions of packed red cells did not appear to precipitate episodes of ICH. In a setting of optimal care, ICH appears to be more related to prenatal stresses than to specific postnatal complications.

Ultrastructural and histochemical abnormalities of skeletal muscle in patients with chronic vitamin E deficiency.

We report muscle biopsy abnormalities in four patients with a chronic cholestatic syndrome, low serum vitamin E levels, absent reflexes, mild limb weakness, ataxia, and sensory loss in arms and legs. Skeletal muscle fibers contained multiple autofluorescent inclusions that show strong acid phosphatase and esterase reactivity. By electronmicroscopy, the inclusions lying between myofibrils were membrane-bound dense bodies having characteristics of both lysosomes and lipopigment material. The material was similar to that observed in vitamin E-deficient animals and probably formed in response to disordered intracellular lipid peroxidation.

Neonatal hyperviscosity. II. Effect of partial plasma exchange transfusion.

To determine the effect of partial plasma exchange transfusion, 20 newborn infants with neonatal hyperviscosity were randomly assigned to observation or treatment with partial plasma exchange transfusion within the first eight hours after birth. They were studied for organ involvement by roentgenogram, blood count, coagulation studies, and neurologic behavior and were followed up using the Brazelton Neonatal Behavior Assessment scale at 8, 24, and 72 hours and 2 weeks of age; in addition, ten control infants without hyperviscosity of similar birth weights and gestational ages were also studied. Exchange transfusion improved blood viscosity but both hyperviscous groups showed a higher proportion of abnormal results than did the control subjects. Infants receiving exchange transfusions subsequently improved during the period from 8 hours to 2 to 3 weeks of age, until they were indistinguishable from the control subjects. Neurologic improvement in hyperviscous infants who had not received exchange transfusions were significantly slower during this period. At 8 months of age, abnormal neurologic and developmental findings were impressive in both groups; no significant differences in neurologic abnormalities were noted at that time. Developmental delays, tremors, spastic diplegia, and monoparesis were found in four of six untreated infants and five of ten infants who had received exchange transfusions. A fine tremor was present in one control child.

Progressive neuromuscular disease in children with chronic cholestasis and vitamin E deficiency: diagnosis and treatment with alpha tocopherol.

We have studied four children (ages 6 to 17 years) with chronic cholestasis who developed a slowly progressive neuromuscular disease characterized by ataxia, dysmetria, areflexia, loss of vibratory sensation, and a variable ophthalmoplegia. Serum vitamin E concentration were low in all patients prior to treatment. Muscle histochemical studies in all four patients showed autofluorescent basophilic esterase and acid phosphatase-positive cytoplasmic inclusions and occasional necrotic fibers. These distinctive muscle changes are similar to those described in vitamin E-deficient animals. Intramuscular injections of alpha tocopherol were required in three patients to achieve normal serum vitamin E values. High-dose oral supplementation was effective in one patient. After normalization of serum vitamin E concentrations for six to 14 months, the neurologic disease has improved in all four patients.

Progressive neuromuscular disease in children with chronic cholestasis and vitamin E deficiency: clinical and muscle biopsy findings and treatment with alpha-tocopherol.

We have studied four children (ages 6 to 17 years) with chronic cholestasis who developed a slowly progressive neuromuscular disease characterized by ataxia, dysmetria, areflexia, loss of vibratory sensation, and a variable ophthalmoplegia. Serum vitamin E concentrations were low in all patients prior to treatment (0.17-2.0 mg/g cholesterol, normal greater than 3 mg/g). Muscle histochemical studies showed prominent yellow autofluorescence, basophilic cytoplasmic inclusions which stain with esterase and acid phosphatase, and occasional necrotic fibers. Ultrastructural findings consisted of increased number and size of membrane-bound dense bodies (lysosomes), membranous whorls, and autophagic vacuoles. Intramuscular injections of all-rac-alpha-tocopherol (0.55-1.42 mg/kg per 24 hours based on individualized pharmacokinetic data) were required in three patients to achieve normal serum vitamin E values. High-dose (32 mg/kg per 24 hours) oral supplementation was effective in one patient. After normalization of serum vitamin E concentrations for 12 to 20 months, the neurologic disease has improved in all four patients.

Neonatal intracranial hemorrhage and maternal use of aspirin.

A prospective study of 108 infants born at 34 weeks' gestation or earlier or weighing 1500 g or less was carried out to determine the incidence of intracranial hemorrhage and the multiple risk factors that may cause or aggravate this hemorrhage in premature infants. On day 2 post partum, mothers were questioned regarding maternal risk factors, including the use of either aspirin or acetaminophen during the last week of pregnancy. Between days 3 and 7 post partum, computed tomographic scanning was performed on the 108 infants. Of the total, 53 (49%) developed intracranial hemorrhage. The incidence of hemorrhage in the infants whose mothers had ingested aspirin was significantly greater (P less than .05) than that seen in infants whose mothers did not take either aspirin or acetaminophen (control group). The incidence of intracranial hemorrhage among infants whose mothers ingested acetaminophen was not significantly different from that of the control group. This study indicates that aspirin is associated with an increased incidence of intracranial hemorrhage in the authors' population. The use of aspirin in the last 3 months of pregnancy is highly questionable and probably inappropriate.

Glycerol kinase deficiency with neuromuscular, skeletal, and adrenal abnormalities.

Two brothers with a recently described inborn error of metabolism characterized by glyceroluria, hyperglycerolemia, and generalized glycerol kinase deficiency had moderate psychomotor retardation, spasticity, growth failure, a nonspecific myopathy, osteoporosis, and adrenal insufficiency. Glycerol kinase activity in leukocytes and cultured fibroblasts was less than 5% of control values. Hepatic and renal tissue obtained at autopsy in one patient had similarly low enzyme activity. Thus the deficiency of glycerol kinase in these patients appears to be generalized and heritable, though the relationship of the clinical phenotype to the enzymatic defect is not yet established.

Clinical studies of an interferon inducer, polyriboinosinic-polyribocytidylic acid [poly (I)-poly (C)], in children.

Fifteen children ranging in age from one and one-half to 14 years received intravenous polyriboinosinic-polyribocytidylic acid [poly (I)-poly (C)], an interferon inducer. The patients all had serious neurologic illness either directly or circumstatially related to viral infection. Peak titers of interferon in serum ranged from 8 to 500 units/ml in response to doses of poly (I)-poly (C) of 0.1-1.0 mg/kg. Serum interferon persisted for less than or equal to 24 hr after induction. Hyporesponsiveness to a second dose of poly (I)-poly (C) persisted for seven days after initial induction, after which time full response again occurred. The half-life of poly (I) poly (C) in plasma as measured in three patients was less than 30 min. poly (I-poly(C) appears to be safe when given intravenously, but the low titers of interferon induced may limit its clinical usefulness as an antiviral drug.

Guillain-Barré syndrome. Another cause of the "floppy infant".

We report a 4 1/2-month-old female infant with subacute onset of hypotonia. Symmetrical weakness, association with a viral illness, high CSF protein level, diminished nerve conduction velocities, and a prompt recovery were compatible with the diagnosis of Guillain-Barré syndrome. The possibility that this disorder may occur in young infants with weakness should be considered.