Kevin Farrell - Academia.edu (original) (raw)

Papers by Kevin Farrell

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 1986

ABSTRACT:The relationships between total and free serum valproate (VPA) concentrations and seizur... more ABSTRACT:The relationships between total and free serum valproate (VPA) concentrations and seizure control, serum liver enzyme activity and plasma ammonia concentration were studied in 61 epileptic children. Enzymeimmunoassay (EMIT)Rmethods gave higher values of total VPA concentration than gas-liquid chromatography (GLC) methods. In over 80% of children with complete seizure control the ranges of total VPA concentration were 140-420 umol/L with GLC methods and 210-560 umol/L with EMIT methods. The range of free VPA concentrations in 78% of children with complete seizure control was 8.8-26.4 umol/L. Increased liver enzyme activity was observed in 6 of the 61 children and raised plasma ammonia concentration in 11 of 50 children. Plasma ammonia concentration was related to total serum VPA but was not related to free serum VPA. Increased serum liver enzyme activity was related to VPA dose per kg but not to free or total serum VPA concentration. Thus free VPA concentrations do not appea...

Cochrane Database of Systematic Reviews, 2011

... seizures Ravindra Arya1, Sushil Kumar2, Benedict Michael3, Vidhu Anand4 1Division of Pediatri... more ... seizures Ravindra Arya1, Sushil Kumar2, Benedict Michael3, Vidhu Anand4 1Division of Pediatric Neurology, All India Institute of Medical Sciences, New Delhi, India. ... Mechanism of Action. In: Levy R, Mattson R, Meldrum B, et al. editor(s). Antiepileptic Drugs. 5th Edition. ...

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 1990

ABSTRACT:The incidence of fatal hepatic failure associated with valproic acid (VPA) therapy is hi... more ABSTRACT:The incidence of fatal hepatic failure associated with valproic acid (VPA) therapy is highest in children under the age of three years, particularly in those with developmental delay. The pathogenesis of VPA hepatotoxicity is unclear but may relate to the accumulation of a toxic metabolite of VPA which impairs fatty-acid oxidation. We describe two unrelated infants with developmental delay who developed hepatic failure while receiving VPA. Siblings of both children subsequently developed hepatic steatosis and intractable seizures without being exposed to VPA. This suggests that that the two children who developed liver failure when receiving VPA may have had a familial metabolic disorder. Familial metabolic disorders may account partly for the higher incidence of fatal hepatotoxicity described in infants receiving VPA.

Pediatrics in Review, 1999

After completing this article, readers should be able to: 1. Describe what most parents who want ... more After completing this article, readers should be able to: 1. Describe what most parents who want help for a child who has a headache are seeking. 2. List the most common cause of severe headache in children. 3. Describe what tests must be performed prior to lumbar puncture in any patient who has a headache. 4. Determine common causes of chronic daily headache. Chronic or recurrent headache is common in children, occurring in approximately 40% of children by 7 years of age and 75% of children by 15 years. Most parents who seek help for a child who has headaches are looking for reassurance that the headache is not due to a serious cause.

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 1993

ABSTRACT:Paralysis induced by neuromuscular blocking agents facilitates ventilation of seriously ... more ABSTRACT:Paralysis induced by neuromuscular blocking agents facilitates ventilation of seriously ill patients but may preclude clinical recognition of seizures. We describe the occurrence of severe cognitive impairment in a 14-year-old girl in whom status epilepticus was recognized only when pancuronium was withdrawn after 14 hours of paralysis. This patient emphasizes a potential danger of paralysis from drugs in patients with acute cerebral dysfunction.

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 1985

ABSTRACT:The demonstration of low arylsulfatase-A (ASA) activity in leucocytes or fibroblasts is ... more ABSTRACT:The demonstration of low arylsulfatase-A (ASA) activity in leucocytes or fibroblasts is used often to establish the diagnosis of metachromatic leucodystrophy (MLD). However, low ASA activity is observed also in pseudo-ASA deficiency which may be as common as MLD. We report two patients with pseudo ASA deficiency who had abnormal neurological findings consistent with atypical MLD. Because the measurement of ASA activity is neither a sensitive nor specific method with which to establish a diagnosis of MLD, this diagnosis should be confirmed by nerve biopsy, measurement of urinary sulfatide or a cerebroside sulfate loading test, using cultured fibroblasts.

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 1996

This multi-authored text by Waxman, Kocsis and Stys is a very nice compendium of current informat... more This multi-authored text by Waxman, Kocsis and Stys is a very nice compendium of current information about axonal histological structure, physiology and pathophysiology. There is an "all star" cast of authors. Particularly enjoyable chapters were those by Mark Bisby on Regeneration in the Peripheral Nervous System, Abnormal Excitability in Injured Axons by Marshall Devor and Axonal Degeneration and Disorders of the Axonal Cytoskeleton by John Griffin and group. The chapter on voltage-gated ion channels and axons by Steven Waxman is clear, concise, well illustrated and up-to-date. The chapter on pathology of the myelin sheath by Sam Ludwin is very nicely illustrated with EM photographs. All of the chapters have superb reference lists allowing the readers to pursue further information on specific items. This would not be a book to specifically address clinical aspects of axonal disease per se. Although pathophysiology is beautifully discussed in the various chapters and there are chapters on clinical electrophysiology in human peripheral nerve disease, these are really short summary chapters of previous work by these authors and would be only of limited use. For example, the chapters by Burger and Schaumberg on peripheral neuropathy is not at all a substitute for a more in depth clinical text. Ian McDonald's chapter on MS is also fairly limited in the information presented and wouldn't really be helpful for those seeking specific clinical information. On the other hand the basic science chapters are much more comprehensive and rounded.

CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne, Jan 22, 2003

Zinc is a common supplement and is widely available as a standard component of many over-the-coun... more Zinc is a common supplement and is widely available as a standard component of many over-the-counter products. A number of reports have identified an association between excessive zinc intake and severe cytopenia. We report a case of zinc-induced copper deficiency in a young adult to illustrate this under-recognized cause of anemia and neutropenia.

Advances in Experimental Medicine and Biology, 2002

PEDIATRICS, 1998

Rationale. Human herpesvirus 6 (HHV-6) has been demonstrated to be the causative agent in roseola... more Rationale. Human herpesvirus 6 (HHV-6) has been demonstrated to be the causative agent in roseola infantum. It has been suggested that HHV-6 may have neurotropic properties and be involved in the pathogenesis of febrile seizures in infants. We describe a case-control study to examine the hypothesis that acute HHV-6 infection occurs more commonly in children with febrile seizures than in controls. Methods. Patients presenting with a first or second febrile seizure between 6 months and 2 years of age were entered in the study. Control patients did not have a seizure but had similar inclusion and exclusion criteria. Specimens were obtained for HHV-6 viral serology and polymerase chain reaction in the acute stage and approximately 2 weeks later. A diagnosis of HHV-6 infection was based on HHV-6-specific IgM and IgG serology and HHV-6 polymerase chain reaction of peripheral blood mononuclear cells and saliva. Results. Eighty-six patients (45 with febrile seizures; 41 controls) were enrolled. The HHV-6 infection status could be determined in only 68 patients (35 with febrile seizures; 33 controls). Acute HHV-6 infection was identified in 15 of 35 febrile seizure patients and in 15 of 33 controls. Evidence of past HHV-6 infection was demonstrated in 13 febrile seizure patients and in 8 controls. Conclusions. The incidence of primary HHV-6 infection is similar in patients with febrile seizures and agematched controls. HHV-6 does not seem to be a major factor in the pathogenesis of first and second febrile seizures. Pediatrics 1998;101(2). URL: http://www. pediatrics.org/cgi/content/full/101/2/e3; human herpesvirus 6, febrile seizures, case-control.

Journal of Neurology, Neurosurgery & Psychiatry, 1995

Letters to the Editor ferred to an organic psychiatric unit for further investigation. The dyspha... more Letters to the Editor ferred to an organic psychiatric unit for further investigation. The dysphasia resolved, but he became increasingly perseverative in his speech and actions, confabulating frequently, and his behaviour was socially disinhibited. He began to express grandiose ideas. Neuropsychological assessment showed pronounced frontal lobe impairment. At this point, syphilis serology showed venereal disease research laboratory test (VDRL) positive (1:32), TPHA positive (1:256), and fluorescent treponemal antibody (FTA) positive + + + +. Further investigation of CSF showed VDRL positive

Journal of Mass Spectrometry, 2000

We report a GC/NICI-MS assay and a LC/ESI-MS/MS assay for the analysis of N-acetylcysteine (NAC) ... more We report a GC/NICI-MS assay and a LC/ESI-MS/MS assay for the analysis of N-acetylcysteine (NAC) conjugates of (E)-2,4-diene VPA (NAC I and NAC II) identified in humans. The assay also includes the analysis of the NAC conjugate of 4,5-epoxy VPA (NAC III), an identified metabolite in rats treated with 4-ene VPA for its use in metabolic studies in animals. The highly sensitive GC/MS assay was designed to monitor selectively the diagnostic and most abundant [M − 181] − fragment anion of the di-PFB derivatives of NAC I, NAC II, and NAC IV, the internal standard (IS) and the PFB derivative of NAC III. The higher selectivity of LC/MS/MS methodology was the basis for an assay which could identify and quantitate the underivatized conjugates simultaneously using MRM of the diagnostic ions m/z 130 and 123 arising from the CID of their protonated molecular ions [MH] Y. The GC/MS assay employed liquid-liquid extraction whereas the LC/MS/MS assay used a solid-phase extraction procedure. Linearity ranges of the calibration curves were 0.10-5.0 µg ml −1 by GC/MS and 0.10-1.0 µg ml −1 by LC/MS/MS for NAC I, NAC II and NAC III (r 2 = 0.999 or better). Both assays were validated for NAC I and NAC II and provided good inter-and intra-assay precision and accuracy for NAC I and NAC II. The LOQ by LC/MS/MS was 0.1 µg ml −1 , representing 1 ng of NAC I and NAC II. The same LOQ (0.1 µg ml −1) was observed by GC/MS and was equivalent to 100 pg of each metabolite. NAC III was detected at concentrations as low as 0.01 µg ml −1 by both methods. The total urinary excretion of the NAC conjugates in four patients on VPA therapy was determined to be 0.004-0.088% of a VPA dose by GC/MS and 0.004-0.109% of a VPA dose by LC/MS/MS.

Drug Metabolism and Disposition, 2003

In this study, spectroscopic and chromatographic evidence is presented for the identification and... more In this study, spectroscopic and chromatographic evidence is presented for the identification and characterization of the metabolites, valproyl glutamate (2-propylpentanoyl glutamate, VPA-GLU) and valproyl glutamine (2-propylpentanoyl glutamine, VPA-GLN) in the urine, serum, and cerebrospinal fluid (CSF) of patients on valproic acid (VPA) therapy. Moreover, the identification of valproyl glycine (2-propylpentanoyl glycine, VPA-GLY) in the serum and urine of patients on VPA, albeit in trace concentrations, is also reported here. The three amino acid conjugates excreted in urine accounted for about 1% of the VPA dose in four patients who were on VPA therapy chronically and had reached steady state. VPA-GLU was quantitatively the most prominent metabolite (0.66-13.1 g/mg creatinine) compared with VPA-GLN (0.78-9.93 g/mg creatinine) and VPA-GLY (trace-1.0 g/mg creatinine) in overnight urine samples of all patients studied (n ‫؍‬ 29). The relatively low serum concentrations of the three amino acid conjugates of VPA in six patients suggest that the metabolites are readily excreted once formed. In contrast, whereas VPA GLY was absent in the CSF of one patient on VPA, the concentrations of VPA-GLU and VPA-GLN in this CSF sample were 9 and 5 times, respectively, their corresponding serum concentrations.

Developmental Medicine & Child Neurology, 2008

Any information contained in this pdf file is automatically generated from digital material submi... more Any information contained in this pdf file is automatically generated from digital material submitted to EPOS by third parties in the form of scientific presentations. References to any names, marks, products, or services of third parties or hypertext links to thirdparty sites or information are provided solely as a convenience to you and do not in any way constitute or imply ECR's endorsement, sponsorship or recommendation of the third party, information, product or service. ECR is not responsible for the content of these pages and does not make any representations regarding the content or accuracy of material in this file. As per copyright regulations, any unauthorised use of the material or parts thereof as well as commercial reproduction or multiple distribution by any traditional or electronically based reproduction/publication method ist strictly prohibited. You agree to defend, indemnify, and hold ECR harmless from and against any and all claims, damages, costs, and expenses, including attorneys' fees, arising from or related to your use of these pages. Please note: Links to movies, ppt slideshows and any other multimedia files are not available in the pdf version of presentations. www.myESR.org

British Journal of Clinical Pharmacology, 1989

Pharmacokinetic parameters for valproic acid (VPA) were determined before and following 2 weeks o... more Pharmacokinetic parameters for valproic acid (VPA) were determined before and following 2 weeks of carbamazepine (CBZ) administration in five healthy male volunteers. Mean VPA dosage was 16.4 mg kg-1 day-1. CBZ dosage was started at 100 mg twice daily and increased after 1 week to a total daily dose of 300 mg. 2 After CBZ administration, mean VPA plasma clearance increased from 0.90 ± 0.18 s.d. to 1.26 ± 0.241 h-1 (P < 0.05) as did clearance of free VPA (20.8 ± 7.6 to 37.0 ± 13.6 1 h-1). Mean VPA elimination rate constant increased from 0.051 ± 0.011 to 0.067 + 0.011 h-1 (P < 0.05) after CBZ administration. 3 Mean area under the serum concentration vs time curve decreased from 675.0 ± 130.5 to 475.7 ± 75.7 mg 1-1 h (P < 0.05) after CBZ administration. Mean serum VPA half-life decreased from 14.0 ± 2.4 to 10.6 ± 1.4 h (P < 0.05). Mean serum VPA trough concentrations decreased from 44.0 ± 16.7 to 27.0 ± 10.4 ,ug ml-' (P < 0.05). 4 A significant change was not observed in the mean VPA volume of distribution after CBZ coadministration suggesting that enzyme induction rather than a competition for plasma protein binding sites was involved in this interaction. 5 Despite the increased clearance of VPA, the urinary recovery of VPA or conjugate did not increase after CBZ administration.

Brain, 2007

The relationship between severe myoclonic epilepsy of infancy (SMEI or Dravet syndrome) and the r... more The relationship between severe myoclonic epilepsy of infancy (SMEI or Dravet syndrome) and the related syndrome SMEI-borderland (SMEB) with mutations in the sodium channel alpha 1 subunit gene SCN1A is well established. To explore the phenotypic variability associated with SCN1A mutations, 188 patients with a range of epileptic encephalopathies were examined for SCN1A sequence variations by denaturing high performance liquid chromatography and sequencing. All patients had seizure onset within the first 2 years of life. A higher proportion of mutations were identified in patients with SMEI (52/66; 79%) compared to patients with SMEB (25/36; 69%). By studying a broader spectrum of infantile epileptic encephalopathies, we identified mutations in other syndromes including cryptogenic generalized epilepsy (24%) and cryptogenic focal epilepsy (22%). Within the latter group, a distinctive subgroup designated as severe infantile multifocal epilepsy had SCN1A mutations in three of five cases.This phenotype is characterized by early onset multifocal seizures and later cognitive decline. Knowledge of an expanded spectrum of epileptic encephalopathies associated with SCN1A mutations allows earlier diagnostic confirmation for children with these devastating disorders.

Archives of Disease in Childhood, 1990

Twenty five children in remission, who were asymptomatic and who had last been treated at least t... more Twenty five children in remission, who were asymptomatic and who had last been treated at least two years before for acute lymphoblastic leukaemia, were examined neurologically and neuropsychologically. Their treatment included early cranial irradiation (24 Gy or 18 Gy), intrathecal methotrexate, and systemic chemotherapy. One half of the children demonstrated a decline in head circumference centile, which occurred in all patients treated with 24 Gy and in those patients treated with 18 Gy under the age of 3 years. In those children whose head growth was reduced, performance was significantly impaired in neuropsychological tests designed to assess concentration and short term memory. These children also developed clinically important learning difficulties in the classroom. Minor neurological dysfunction was present in almost half of the entire group. These data suggest that the treatment employed to prevent central nervous system leukaemia (primarily cranial irradiation) has a deleterious effect on head and brain growth and intellectual function.

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 2005

ABSTRACT:The epileptic encephalopathies comprise a group of devastating seizure syndromes which b... more ABSTRACT:The epileptic encephalopathies comprise a group of devastating seizure syndromes which begin in infancy and early childhood and usually result in intractable epilepsy. While some syndromes are relatively easily diagnosed early in their course, others take time to evolve, hampering an early, confident diagnosis. Epileptic encephalopathies are associated with slowing of cognitive function and evolution of severe behavioral disorders, which are often more distressing to families than the epilepsy. While an underlying etiology may explain some of this co-morbidity, many children have no identifiable etiology found for their seizures. In these “idiopathic” cases, recurrent subtle seizures, frequent epileptiform discharge and non-convulsive status epilepticus probably all play a role in deterioration of cognitive function and evolution of behavior disorders. This paper will review the most common epileptic encephalopathy syndromes, discuss the cognitive and behavioral co-morbidit...