Ronald J. Kallen

The Screening and Diagnosis of Autistic Spectrum Disorders

The Child Neurology Society and American Academy of Neurology recently proposed to formulate Practice Parameters for the Diagnosis and Evaluation of Autism for their memberships. This endeavor was expanded to include representatives from nine professional organizations and four parent organizations, with liaisons from the National Institutes of Health. This document was written by this multidisciplinary Consensus Panel after systematic analysis of over 2,500 relevant scientific articles in the literature. The Panel concluded that appropriate diagnosis of autism requires a dual-level approach: (a) routine developmental surveillance, and (b) diagnosis and evaluation of autism. Specific detailed recommendations for each level have been established in this document, which are intended to improve the rate of early suspicion and diagnosis of, and therefore early intervention for, autism.

Practice parameter: Screening and diagnosis of autism Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Child Neurology Society

Article abstract Autism is a common disorder of childhood, affecting 1 in 500 children. Yet, it often remains unrecognized and undiagnosed until or after late preschool age because appropriate tools for routine developmental screening and screening specifically for autism have not been available. Early identification of children with autism and intensive, early intervention during the toddler and preschool years improves outcome for most young children with autism. This practice parameter reviews the available empirical evidence and gives specific recommendations for the identification of children with autism. This approach requires a dual process: 1) routine developmental surveillance and screening specifically for autism to be performed on all children to first identify those at risk for any type of atypical development, and to identify those specifically at risk for autism; and 2) to diagnose and evaluate autism, to differentiate autism from other developmental disorders.

Idiopathic membranous glomerulopathy preceding the emergence of systemic lupus erythematosus in two children

An idiopathic nephrotic syndrome associated with membranous glomerulopathy antedated the subsequent emergence of systemic lupus erythematosus in two patients (7-year-old and 14-year-old girls). At the onset of INS, there was neither clinical evidence of multisystem disease nor unequivocal serologic evidence of SLE. The only early possible indication of SLE was the presence of microtubular inclusions in glomerular endothelial cells on electron microscopy. In each instance (one year and three years after onset of INS), a second renal biopsy showed transformation of the membranous glomerular lesion to a more florid type with glomerular subendothelial dense deposits. One patient died of overwhelming pulmonary infection while she was receiving prednisone and cyclophosphamide; the other developed progressive renal failure despite steroid treatment. SLE should be considered in patients presenting with apparent idiopathic MG, in whom nephrotic syndrome persists. Intraendothelial cell microtubular inclusions may be an early clue to later emergence of SLE.

Population Genetics of Alport’s Syndrome

The diagnosis of Alport’s syndrome is generally not considered in the absence of a positive family history. Family studies indicate that transmission occurs by a rare autosomal dominant gene. The devi

A study of the plasma kinin-generating system in children with the minimal lesion, idiopathic nephrotic syndrome.

Extract: Although the precise etiologic incitant of the minimal lesion idiopathic nephrotic syndrome of childhood is not known, it is likely that a host mechanism mediates the permeability alterations of the glomerular capillary wall resulting in massive proteinuria. As a first step in examining the possibility that local kinin release may account for the proteinuria in this disorder, two parameters of the plasma kinin-generating system, plasma prekallikrein and kallikrein inhibitor, were assayed during 27 nephrotic episodes in 21 corticosteroid-responsive children. Plasma kallikrein was assayed by means of its esterase activity on a synthetic arginine ester substrate, N-α-tosyl-L-arginine methyl ester (TAMe), after activation of Hageman factor by kaolin. This activity, after subtraction of spontaneous arginine esterase activity (i.e., TAMe esterase activity measured in plasma not exposed to kaolin) is derived from prekallikrein. Plasma prekallikrein activity in 11 normal children was 99.6 ± 2.9 pnol TAMe hydrolyzed/ml plasma/hr (mean ± SEM). Kallikrein inhibitor was quantified in arbitrary units. Kallikrein inhibitor activity in 11 normal children was 0.94 ± 0.04 units. During the overt nephrotic syndrome, before initiation of intensive daily corticosteroid treatment, mean values were: prekallikrein, 58.5 ± 7.24 μmol/ml/hr; and kallikrein inhibitor, 0.35 ± 0.06 units. After corticosteroid-induced remission occurred, mean values were: plasma prekallikrein, 118.6 ± 3.2 μmol/ml/hr; and kallikrein inhibitor, 0.78 ± 0.03 μmol/ml/hr. Both parameters were again assayed in 14 of the 21 children after complete cessation of corticosteroid treatment. Plasma prekallikrein was normal, 99.6 ± 4.8 μmol/ml/hr; but kallikrein inhibitor was still somewhat depressed, 0.84 ± 0.03 units. A subset of 9 patients had marked depression of plasma prekallikrein to levels less than 20 μmol/ml/hr and essentially undetectable inhibitor activity. Serum α-2 macroglobulin was elevated in nephrotic patients: mean value during relapse, 862 ± 29 mg/100 ml; during corticosteroid-maintaining remission, 615 ± 29 mg/100 ml. After cessation of corticosteroids, mean serum level was 481 ± 20 mg/100 ml. The proportional reduction of plasma prekallikrein and kallikrein inhibitor suggested that an enzyme-inhibitor complex formed in vivo, perhaps at a local site of activation in proximity to the glomerular basement membrane. These data suggest that the plasma kinin-generating system may be the host effector mechanism subserving the increased glomerular capillary permeability in the minimal lesion nephrotic syndrome of childhood.Speculation: Local activation of the plasma kinin-generating system in close proximity to the glomerular capillary wall may mediate the proteinuria of the minimal lesion nephrotic syndrome. Inhibitors of the kinin-generating sequence may provide effective and rational treatment for children with frequent relapses of the nephrotic syndrome or those corticosteroid-resistant children destined to have a recurrence of the minimal lesion nephrotic syndrome in a renal allograft.

AN INVERSE RELATIONSHIP BETWEEN IMMUNOGLOBULIN G AND ALPHA-2 MACROGLOBULIN IN MINIMAL-LESION IDIOPATHIC NEPHROTIC SYNDROME

Patients with minimal-lesion nephrotic syndrome (MLNS) in relapse have hypogammaglobulinemia that is not solely explained by urinary losses, suggesting a defect in synthesis. Alpha-2 macroglobulin (alpha-2M) is elevated in MLNS (during relapse). Alpha-2M and IgG were measured by radial immunodiffusion in 18 patients with MLNS, during relapse and remission. During relapse mean (± 1 SD) alpha-2M was 896 ± 213 mg/dl; mean IgG was 218 ± 128 mg/dl. During remission mean alpha-2M was 422 ± 143 mg/dl; IgG was 493 ± 85 mg/dl. During relapse patients with the highest alpha 2-M had the lowest levels of serum IgG. 24 paired measurements were further analyzed and yielded an inverse log linear relationship. Although the mechanism for elevation of alpha-2M is unknown, we hypothesize that alpha-2M (which is known to have immunodepressant properties) specifically depresses IgG synthesis in MLNS, predisposing such patients to serious infection. Further studies of B-cell function in MLNS are in progress. The increase in alpha-2M may also account for altered T-lymphocyte function in MLNS.

INFORMATION MANAGEMENT FOR A COMMUNITY|[ndash]|BASED PEDIATRIC RESIDENCY PROGRAM

We designed a microcomputer-based information system (IS), using commercially-available relational data base management software, to track the succession of patient management encounters. The IS includes an algorithm for computing the average daily patient load (ADPL) of residents providing either primary care, or in a supervisory role on the general inpatient service. The IS yields a compilation of the patients managed by each resident (a patient “log”), a frequency distribution of diagnoses for the total program, and a computation of the ADPL on the inpatient service. To minimize the data-submission burden on the resident, much of the raw data was culled by secretarial level personnel from daily reports provided by the data processing department. We analyzed 1900 consecutive patient-encounters, both intra- and extramural, and derived the following distribution of the 10 most frequent diagnoses (decreasing frequency): prematurity; unspecified septicemia; non-infectious gastroenteritis; asthma; pneumonia (unspecified); status asthmaticus; convulsions; asthmatic bronchitis; toxic-effect, lead; and transient tachypnea of the newborn. The above distribution reflects the composite experience of a primary-care oriented program and a tertiary childrens hospital (where residents spend about one-third of their overall training experience). Separate ICDA codes assigned for asthma-related conditions were aggregated. This yielded a composite of 200 patient-encounters (10.5% of the sample). The asthma-related category was the most frequent diagnostic group encountered.

PULSE NITROGEN MUSTARD TREATMENT OF CHILDHOOD IDIOPATHIC NEPHROTIC SYNDROME (INS.)

As an alternative to long-term administration of oral cytotoxic agents, pulse intravenous nitrogen mustard (HN2) has been used in 5 patients with steroid-resistant INS (all had “early resistance”) and one patient with steroid responsive INS. The dose of HN2 was 0.1 mg/kg/day × 4 days. All patients had minimal-lesion histology. The patient with steroid-responsive INS had a frequently relapsing course (4.8 relapses/year) despite treatment with cyclophosphamide (2 courses) and chlorambucil. Since HN2, she has had no further relapses. The current status of 5 patients with steroid-resistant INS is: 3 have persistent mild proteinuria, normal excretory function and absence of overt nephrotic syndrome; 2 have persistent INS despite HN2 but subsequently remitted after cyclophosphamide and both have since had a steroid-responsive, relapsing course. No toxicity attributable to HN2 was noted. This preliminary experience suggests that HN2 may ameliorate INS in some patients with steroid-resistance. HN2 may also be a useful adjunct in the management of some patients with steroid-responsive, frequently-relapsing INS, in whom oral cytotoxic therapy may not be warranted. A controlled therapeutic trial to better assess the usefulness of HN2 is planned.

HYPERRENINEMIC ACUTE RENAL INSUFFICIENCY AND HYPERTENSION IN MINIMAL-LESION NEPHROTIC SYNDROME

A 16-year-old girl with recent onset of idiopathic nephrotic syndrome (INS) developed severe hypertension and sustained acute renal insufficiency (ARI) despite minimal lesion histology, treatment with albumin infusions, and absence of renal vein thrombosis. The nephrotic syndrome failed to respond to oral prednisone administration, “pulse” methylprednisoione, and cytotoxic agents. Peak BUN was 128 mg/dl; peak serum creatinine, 5.5 mg/dl. Plasma renin activity (PRA) was 49 ng/ml/hr. Plasma volume was 70% of normal. Elevated PRA was partially suppressed by albumin infusion. Azotemia persisted for 3 months. BUN declined to 18 mg/dl and serum creatinine to 1.8 mg/dl concurrent with tapering of prednisone dosage. We speculate that this oatient had incipient vasomotor nephropathy due to angiotensin-mediated renal vasoconstriction consequent to multiple factors: 1. corticosteroid-induced vascular sensitization to angiotensin (Am. J. Med. 58:216,1975): 2. hypovolemia; and 3. treatment with renin-raising drugs (hydralazine, furosemide). We suggest that patients with INS and ARI may benefit from treatment with an angiotensin-antagonist.

CONTROL OF AZOTEMIC HYPERPARATHYROIDISM BY PARATHYROID AUTOTRANSPLANTATION AND 1,25-DIHYDROXYCHOLE-CALCIFEROL |[lpar]|1,25-DHCC|[rpar]|

A 10-year-old male with congenital bilateral renal hypoplasia, chronic renal failure, and secondary hyperparathyroidism, developed bone pain and inability to walk. He was azotemlc (BUN, 117 mg/dl) and had characteristic blood biochemical alterations (serum calcium, 6.5 mg/dl, phosphorus, 8.4 mg/dl, and alkaline phosphatase, 1215 units). Immunoreactive serum parathyroid hormone (iPTH) was markedly elevated, 1900 μlEq/ml (normal range, undetectable to 40 μlEq/ml). Four months later a total parathyroidectomy was done with autotransplant of a 1/8 remnant of parathyroid tissue into a sternocleldomastoid muscle. The immediate postoperative period was attended by hypocalcemia requiring sustained intravenous infusion of calcium. The iPTH declined to 520μlEq/ml on the first postop day (preop level, 1500 μlEq/ml) and to 130 μlEq/ml on third postop day. Subsequently iPTH oscillated between 80 and 130 μEq/ml. Two months postoperatively, hemodialysis was begun. At this time iPTH was still elevated (110 μlEq/ml) and treatment with 1.25-DHCC. 0.5 mcg/day was begun. Muscle strength improved dramatically accompanied by ability to walk. Radiologically evident bone lesions regressed and iPTH further declined to less than 40 μlEq/ml and alkaline phosphatase returned to normal. We conclude that 1,25-DHCC adequately suppressed the parathyroid remnant, by promoting adequate intestinal absorption of calcium, preventing re-emergence of secondary hyperparathyroidism.