Robert S. Rust

Diet- and valproate-induced transient hyperammonemia: effect of l-carnitine

Hyperammonemia is an adverse effect of valproate (VPA) treatment. In particular, transient hyperammonemia has been reported to occur in VPA-treated patients after protein-rich meals. This phenomenon may occur secondary to a VPA-mediated carnitine insufficiency. We sought to confirm that protein ingestion would result in transient hyperammonemia and to determine whether supplementation with L-carnitine would prevent this effect. We studied the effect of consumption of a standardized protein-rich meal (45 g protein) before (phase I) and after (phase II) administration of L-carnitine 50 mg/kg/day for 7 days in 11 epileptic children (13.3 +/- 2.3 years of age) receiving VPA. Venous blood was obtained during fasting (baseline) and at 2 and 4 hours after the protein-rich meal for analysis of ammonia (NH3), and VPA concentrations. Mean VPA trough concentrations did not differ significantly at any time. After protein ingestion, 2-hour NH3 concentration increased by 86% (P < .05) from baseline in phase I as compared with a 38% increase in phase II. In both phases I and II, 4-hour NH3 concentrations decreased toward baseline values. We conclude that (1) modest protein ingestion can result in significant transient increases in NH3 in VPA-treated children, (2) significant increases may occur in patients with normal fasting NH3 concentrations, (3) these increases can be significantly attenuated by L-carnitine supplementation, and (4) these changes do not appear to be related to changes in VPA concentration.

Human Arboviral Encephalitis

Worldwide, arboviral illnesses constitute the most important international infectious threat to human neurological health and welfare. Before the availability of effective immunizations, approximately 50,000 cases of Japanese encephalitis occurred in the world each year, one-fifth of which cases proved lethal and a much larger number were left with severe neurological handicaps. With global climate change and perhaps other factors, the prevalences of some arboviral illnesses appear to be increasing. Arboviral illnesses, including Japanese encephalitis, tick-borne encephalitis, Yellow fever, and others, are emerging as possible global health care threats because of biological warfare. This chapter will review ecology, pathophysiology, diagnosis, management, and outcome of the forms of arboviral encephalitis that are of greatest importance in North America, together with some of the most important arboviral encephalitides prevalent in other parts of the world.

Late-onset nonketotic hyperglycinemia with a heterozygous novel point mutation of the GLDC gene.

BACKGROUND Atypical nonketotic hyperglycinemia is characterized by heterogeneous phenotypes that often include nonspecific behavioral problems, cognitive deficits, and developmental delays. PATIENT We describe a girl with late-onset nonketotic hyperglycinemia presenting at 5 years of age with hypotonia, chorea, ataxia, and alterations in consciousness in the setting of febrile illness. RESULTS Serum amino acid analysis was mildly elevated; however, urine amino acid analysis was instrumental in demonstrating marked hyperglycinuria. Mutation testing showed a heterozygous novel sequence change/point mutation in the glycine decarboxylase gene. CONCLUSIONS This patient illustrates the importance of obtaining urine amino acids in individuals whose clinical manifestations are suspicious for any form of nonketotic hyperglycinemia, because this testing may provide more prominent evidence of elevations in glycine. She also illustrates the potential for a heterozygous mutation to result in manifestations of an atypical form of nonketotic hyperglycinemia.

White Matter Changes in an Untreated, Newly Diagnosed Case of Classical Homocystinuria:

The authors report the case of a 4-year-old boy who developed progressive unilateral weakness and developmental delays prior to his diagnosis of classical homocystinuria. Magnetic resonance imaging (MRI) of the brain demonstrated diffuse white matter changes, raising the concern for a secondary diagnosis causing leukoencephalopathy, since classical homocystinuria is not typically associated with these changes. Other inborn errors of the transsulfuration pathway have been reported as causing these changes. Once begun on therapy for his homocystinuria, his neurologic deficits resolved and his delays rapidly improved. Repeat MRI performed one year after instating therapy showed resolution of his white matter abnormalities. This case illustrates the need to consider homocystinuria and other amino acidopathies in the differential diagnosis of childhood white matter diseases and lends weight to the hypothesis that hypermethioninemia may induce white matter changes.

Alpers-Huttenlocher Syndrome: Origins of Clinicopathologic Recognition

In this issue of Pediatric Neurology, Saneto and colleagues [1] summarize the remarkable story of the recognition and subsequent characterization of Alpers-Huttenlocher syndrome, taking us from the initial description of a single patient to the recognition of the clinical manifestations and the identification of the mitochondrial DNA replicase polymerase-g that causes it. Although it is traditionally categorized as a syndrome, its pathophysiology is distinct, and it is sufficiently understood that Alpers-Huttenlocher disease now seems to be a fully justified designation. Saneto and colleagues’ excellent review also provides us with an opportunity to recall the two remarkable physicians for whom the disease is named, Bernard Alpers and Peter Huttenlocher.

Training of child neurologists in the 21st century: overview.

In the wake of the First and Second World Wars and the Korean War, it had become abundantly clear that both the clinical and scientific basis of American medicine required improvement. The mobilization of citizen soldiers provided a disappointing awareness of the frequently unhealthy condition of recruits. The necessity of caring for wounded soldiers suggested that improvements in therapies were required, perhaps in no areas more importantly than those pertinent to neurologic and psychiatric diseases. The winning of these wars seemed in addition to have prompted great enthusiasm for improving the welfare of individuals of all ages and conditions. The American Board of Psychiatry and Neurology (ABPN) was established in 1934. Separate examinations for these parent specialties were first administered in 1948. By the 1950s, the combination of forces brought the question of subspecialized training in child neurology to the forefront. The subject arose in part because of an awakening of widespread interest in the establishment of a scientific basis for ensuring the welfare of children. The evolution of the idea was fostered because a number of remarkable individuals were perhaps fortuitously available and because these individuals possessed particular wisdom, forcefulness, and devotion to the needs of children. In the United States, Drs Sachs, Ford, Crothers, Buchanan, and Byers were particularly important demonstrators of the value of subspecialization in the care of children with neurologic problems. The rise of the National Institute of Neurologic Disorders and Stroke (NINDS) just after World War II coincided with a national mood that regarded considerable federal investment in the welfare of American citizens as a national priority of exceeding importance. Wealthy private citizens, such as Mary Lasker, as well as able and enlightened politicians, such as Senator Claude Pepper of Alabama, were among those who directed efforts to fund such priorities. The foundation of the American Academy of Neurology (AAN), an achievement for which AB Baker was particularly responsible, added youth and vigor to the personality of American neurology, along with such colleagues as Pearce Bailey, Houston Merritt, William Caviness, and Francis Forster. Raymond Adams shared the enthusiasm

Congenital myopathy with ringlike distribution of myonuclei and mitochondria and accumulation of nemaline rods. A variant of centronuclear myopathy

Histopathologic and ultrastructural findings in a muscle biopsy performed on an 11-year old boy with congenital hypotonia, weakness, respiratory insufficiency requiring chronic ventilatory support, and a probable X-linked inheritance are presented. The muscle biopsy disclosed a peculiar, ringlike arrangement of mitochondria and myonuclei in most muscle fibers. Accumulations of nemaline rods were present in approximately 10-15% of fibers. We believe that our patient represents a variant of myotubular/centronuclear myopathy. The histochemical findings suggest disturbance in developmental migration of nuclei and mitochondria probably due to impaired function of the cytoskeleton.

Headache competencies in child neurology.

This is a proposal for suggested physician competencies in the diagnosis and treatment of children and adolescent patients with headaches. Headaches are common in childhood and occur in up to 10% of school-aged children and over 20% of female adolescents. Therefore, the appropriate recognition, evaluation, and treatment should be a high priority of training and maintenance of certification programs.

What the Child Neurologist Should Know at the Conclusion of Training: History Taking, Examination, and Formulation (and a Few Other Generalizations)

Taking of neurological history, performance of neurological examination, and the employment of these sets of information to properly formulate a neurological question constitute the most fundamantal skills of the neurologist. Intelligent facility with these skills must be required of every child neurologist at the completion of training. They will subsequently be refined upon the basis of experience and wider knowledge of neurology and neuroscience which will improve upon the initial level of facility. There are other habits of mind and approach that must also be expected to have been awakened and refined by the time that formal training has been completed.

Alan Percy, MD—Hower Award, 2005

might have had, he perfected an enzymatic assay for sulfite oxidase activity. Perhaps his ability to dash between these various laboratories was foreshadowed by his success as a collegiate on the Harvard track team. Smitten with what would become a lifelong interest in scientific investigation of metabolic and genetic diseases, he was attracted to child neurology. He entered his studies at Johns Hopkins Hospital during a particularly golden era for that institution. He fell under the particular clinical and scientific influence of a faculty that included Dr Guy McKhann, Dr John Freeman, and Dr Richard Johnson. Dr Edwin Myer interested him in the neonate, and Percy benefitted from his interactions with his senior residents Dr Gary Goldstein, Dr William Logan, and Dr Ruthmary Deuel. During his neurology training, he completed, with astonishing speed and efficiency, landmark epidemiological studies of multiple sclerosis, optic neuritis, and central nervous system tumors. These studies were undertaken with Dr Leonard Kurland, who is often referred to as the “father of epidemiology.” Percy briefly joined the faculty at Johns Hopkins Hospital, participating in Kaback’s studies of ultrastructural abnormalities of GM1 gangliosidosis and in the development and validation of a prenatal test for this condition and tests for other neurolipidoses (notably Krabbe leukodystrophy) with Kaback, McKhann, and Dr Donald Farrell. With Dr William Lennarz at Hopkins, Percy, as a post-doc, reported studies on lipid biosynthesis in membrane preparations from immature erythrocytes and followed this interest in membrane structure and function with the demonstration of reduced erythrocyte deformability in boys with Duchenne muscular dystrophy. In 1972, Percy accepted a position at the University of California, Los Angeles (UCLA). In this early phase of his career, he demonstrated his enduring and passionate concern for human rights, dignity, and opportunity—his championship of the underdog. This commitment was among the motivations for his decision to move to Los Angeles, where he served as chair of the Committee for the Protection of Civil Rights and director of the Pediatric Clerkship at the Martin Luther King, Jr Hospital. He was also enticed by research opportunities within the Drew Postgraduate Medical School, of which he was to become the Director of Research and then Associate Research Dean. In his own laboratory, he completed and then published additional important studies of developmental changes and disease-related abnormalities of lipid biosynthesis and degradation. He developed an enduring collaboration with Charles Waechter, Born: May 12, 1938 in Watertown, New York Education: Harvard College, 1956-1960, AB; Stanford University, 1960-1965, MD. Training: Intern (Medicine/Pediatrics) and Resident (Pediatrics) at Stanford University Hospital, 1965-1969; Resident (Neurology/Child Neurology) at Johns Hopkins Hospital, 1969-1971