Michael Podell

Antiepileptic drug therapy

Successful treatment of seizure disorders in small animals requires proper patient assessment, understanding the principles of antiepileptic drug (AED) therapy, designing a strategy for pharmacotherapy, and plans for emergency treatment. Several levels of assessment are needed in managing an epileptic patient to include the diagnosis, effectiveness of therapy, and health-related quality of life assessments. Three levels of diagnosis are important in determining the appropriate AED therapy: 1) confirmation that an epileptic seizure has occurred, and if so, the seizure type(s) manifested; 2) diagnosis of the seizure etiology; and 3) determination of an epileptic syndrome. Monotherapy is the initial goal of treating any cat or dog with epilepsy to reduce possible drug-drug interactions and adverse effects. Unfortunately, many of the AEDs useful in people cannot be prescribed to small animals either due to inappropriate pharmacokinetics (too rapid of an elimination), and potential hepatotoxicity. Thus, the most commonly used AEDs in veterinary medicine are from the same mechanistic category, that of enhancing inhibition of the brain. Antiepileptic drugs can be classified into three broad mechanistic categories: 1) enhancement of inhibitory processes via facilitated action of gamma amino-butyric acid (GABA); 2) reduction of excitatory transmission; and 3) modulation of membrane cation conductance. Pharmacotherapy strategies should be designed based on the decision when to start treatment, choice of the appropriate AED, and proper AED monitoring and adjustment. Information is presented for the current AEDs of choice, phenobarbital and bromide. Additional guidelines are provided for administration of newer AEDs, felbamate and gabapentin. All owners should be aware that emergency therapy may be necessary if recurrent or severe seizures occur in their pet. A rapid, reliable protocol is presented for the emergency management of seizuring cats and dogs in the hospital and at home. Home treatment with per rectal administration of diazepam in the dog has proven to be an effective means of reducing seizure frequency and owner anxiety. Treating each animal as an individual, applying the philosophy that seizure prevention is better than intervention, and consulting specialists to help formulate or revise treatment plans will lead to improved success in treating seizure disorders in the cat and dog.

Methamphetamine enhances cell-associated feline immunodeficiency virus replication in astrocytes

Human immunodeficiency virus (HIV) infection among substance abusers is on the rise worldwide. Psychostimulants, and in particular methamphetamine (METH), have detrimental effects on the immune system as well as causing a progressive neurodegeneration, similar to HIV infection. Many Lentivirinae, including feline immunodeficiency virus (FIV), penetrate into the central nervous system early in the course of infection with astrocytes serving as a reservoir of chronic brain infection. We demonstrate that the FIV-Maryland isolate infects feline primary and cell line (G355-5)-cultured astrocytes only under cell-associated conditions. Infected astrocytes yielded a new astrocytotropic isolate, capable of cell-free infection (termed FIV-MD-A). This isolate contained four amino acid substitutions in the envelope polyprotein resulting in a change in net charge as compared to FIV-MD. Infection for both isolates was dependent upon a functional astrocyte CXCR4 receptor. Methamphetamine increased significantly FIV replication in feline astrocytes for cell-associated infection only, with no effect on peripheral blood mononuclear cells or astrocytes infected with FIV-MD-A. This viral replication was related to proviral copy number, suggesting the effect of METH is at the viral entry or integration into host genome levels, but not at the translational level. Thus, lentiviral infection of the brain in the presence of the psychostimulant METH may result in enhanced astrocyte viral replication, producing a more rapid and increased brain viral load.

International veterinary epilepsy task force consensus report on epilepsy definition, classification and terminology in companion animals

Dogs with epilepsy are among the commonest neurological patients in veterinary practice and therefore have historically attracted much attention with regard to definitions, clinical approach and management. A number of classification proposals for canine epilepsy have been published during the years reflecting always in parts the current proposals coming from the human epilepsy organisation the International League Against Epilepsy (ILAE). It has however not been possible to gain agreed consensus, “a common language”, for the classification and terminology used between veterinary and human neurologists and neuroscientists, practitioners, neuropharmacologists and neuropathologists. This has led to an unfortunate situation where different veterinary publications and textbook chapters on epilepsy merely reflect individual author preferences with respect to terminology, which can be confusing to the readers and influence the definition and diagnosis of epilepsy in first line practice and research studies.In this document the International Veterinary Epilepsy Task Force (IVETF) discusses current understanding of canine epilepsy and presents our 2015 proposal for terminology and classification of epilepsy and epileptic seizures. We propose a classification system which reflects new thoughts from the human ILAE but also roots in former well accepted terminology. We think that this classification system can be used by all stakeholders.

Benefits of Calcitriol Therapy and Serum Phosphorus Control in Dogs and Cats with Chronic Renal Failure: Both Are Essential to Prevent or Suppress Toxic Hyperparathyroidism

Daily oral calcitriol at low doses is safe and effective in the control of renal secondary hyperparathyroidism in dogs and cats. Low doses of calcitriol are most effective when started early in uremia before the advanced stages of renal secondary hyperparathyroidism. At early stages calcitriol both diminishes PTH synthesis in the parathyroid cells present and prevents the hyperplasia that, if unchecked, results in the most extensive an difficult-to-control hyperparathyroidism. The salutary effects on the dogs or cats sense of well being, appetite, activity, strength, and lifespan as reported by the veterinarians of our survey are attributed primarily to keeping PTH levels below a toxic threshold. Additionally, some of the benefits achieved by calcitriol are likely a direct consequence of calcitriol interacting with the vitamin D receptor in a wide variety of tissues throughout the body. Phosphorus restriction through a combination of diet and intestinal phosphate binders is important to allow calcitriol therapy to successfully lower PTH levels, but it likely has no direct effects that are independent of interactions involving calcitriol. Phosphorus restriction is also important to minimize chances for adverse tissue mineralization. Calcitriol therapy can be considered for treatment of chronic renal failure after serum phosphorus has been decreased to less than 6.0 mg/dL in patients in whom it was initially elevated. Calcitriol supplementation to dogs and cats with chronic renal failure makes good endocrinologic sense. Calcitriol deficits cause increased PTH and, as these two hormones are designed to maintain calcium and phosphorus homeostasis, the PTH increase is initially adaptive. One of the important effects of PTH is to stimulate additional calcitriol formation as a powerful means to raise blood calcium through increased calcium absorption from the diet. With too great an increase in PTH, however, its effects become harmful to many tissues due to the widespread distribution of the PTH receptor in many cell types that are likely normally responsive only to the paracrine PTH-related peptide that shares the PTH receptor. Exogenous supplemental calcitriol administration allows concentrations of calcitriol in the bloodstream to remain normal without the toxic consequences of excessive PTH secretion that would otherwise be provoked. Studies involving young dogs with subtotal nephrectomy may not parallel those on older dogs and cats with spontaneous chronic renal failure. In particular, higher doses are needed to effect PTH change in these young dogs than we have found necessary for older dogs and cats. Because survey participants agreed most strongly with the idea that their calcitriol-treated dogs and cats were living longer than comparably uremic animals they had treated previously, further studies to evaluate the ability of calcitriol to retard the progression of renal lesions and loss of excretory renal function seem warranted. Additional studies to document the beneficial effects of calcitriol on the many organs adversely affected by excess PTH during uremia are also needed because findings thoroughly documented and proven in humans and rats may not always extrapolate to dogs and cats.

Progressive encephalopathy associated with CD4/CD8 inversion in adult FIV-infected cats.

Experimental intravenous challenge of five adult cats with the feline immunodeficiency virus Maryland isolate (FIV-MD) was investigated for its ability to induce neurologic abnormalities associated with the onset of immunodeficiency. Five 8-month-old cats were inoculated with 1000 median tissue culture infective dose of FIV-MD isolate, with five age-matched cats serving as uninfected controls. All FIV-MD-infected cats tested positive for serum antiviral antibodies and plasma viral DNA as detected by polymerase chain reaction at 2, 4, 10, and 16 months postinfection (PI). At 10 and 16 months PI, there was a significant reduction in the CD4/CD8 lymphocyte ratio, with all cats having a CD4/CD8 ratio of 1 or less. Total protein electrophoretic analysis of cerebrospinal fluid demonstrated a significantly increased albumin quotient at 4 and 16 months PI, representing a disrupted blood-brain barrier (BBB). At 16 months PI, all cats demonstrated a preferential increase in frontal cortical slow-wave activity compared with control cats. Serial evaluation of brainstem auditory evoked potential recordings revealed a prolongation of the interpeak latencies times over the study time. At least one abnormality was found over time in visual and somatosensory evoked potential testing in three and four infected cats, respectively. Comparing lymphocyte subtype ratios with neurologic testing revealed that every FIV-MD-infected cat exhibited an abnormality in at least one neurologic functional test with a concurrent CD4/CD8 count ratio of 1 or less. Overall, this study demonstrated that FIV-MD infection in adult cats results in a delayed-onset, progressive encephalopathy that parallels the decline in the CD4/CD8 lymphocyte ratio. Compared with prior information from pediatric FIV-MD-infected cats, these results indicate that age of infection influences the onset and severity of disease and may be associated with CD4 cell depletion in FIV-MD-infected cats, as seen in HIV-1-infected humans.

Proton magnetic resonance imaging and spectroscopy identify metabolic changes in the striatum in the MPTP feline model of parkinsonism.

We administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to adult, male cats to model Parkinsons disease (PD), and utilized proton magnetic resonance imaging (MRI) and spectroscopy (MRS) at a field strength of 1.5 T to identify metabolic degenerative changes in the striatum in vivo. Neurologic status and somatosensory-evoked potentials in vivo, as well as postmortem striatal histopathological and immunohistochemical parameters, were examined. Nine cats were equally divided into three groups and treated daily for 10 days as follows: saline, MPTP, and pargyline (a monoamine oxidase inhibitor) plus MPTP. The MPTP-treated cats displayed bradykinesia, head tremor, and reduced oculovestibular reflex activity. MRI showed a diffuse increase of the T2-weighted signal in the striatum of two MPTP-treated cats. Analysis of the MRS spectra indicated significantly lower N-acetylaspartate/creatine (CR) and glutamine-glutamate complex/CR ratios than the control baseline. Two MPTP-treated cats had low choline-containing compounds/CR ratio, whereas a lactate peak was present in all MPTP-treated cats. In the striatum of the MPTP-treated cats, there was a significant decline of tyrosine hydroxylase immunoreactivity and histological evidence for a diffuse cytotoxic reaction. Pretreatment with pargyline attenuated the MPTP-induced clinical signs, MRI and MRS changes, and the histopathological and immunoreactivity alterations. We conclude that proton MRI/MRS is a sensitive, noninvasive measure of neural toxicity and biochemical alteration of the striatum in a feline model of PD.

The feline model of neuroAIDS: understanding the progression towards AIDS dementia.

Feline immunodeficiency virus (FIV) is a neurotropic lentivirus that produces a protracted state of immunodeficiency and encephalopathy in the cat. Recent evidence has shown several similarities to the natural progression of human immunodeficiency virus infection (HIV-1) associated degenerative effects on the central and peripheral nervous systems. Similar to HIV-1, FIV-induced encephalopathy neurovirulence is strain dependent, results in progressive immunodeficiency and increasing early peripheral but not brain viral load, preferentially affects the developing nervous system, produces quantifiable behavioural and neurophysiological impairment that is not directly linked to neuronal infectivity, and induces neuronal injury and loss both in vivo and in vitro. This paper highlights the cumulative scientific body of evidence supporting the use of the feline model of neuroAIDS.

Inherited polyneuropathy in Leonberger dogs: a mixed or intermediate form of Charcot-Marie-Tooth disease?

A spontaneous distal, symmetrical polyneuropathy in related Leonberger dogs with onset between 1 to 9 years of age was characterized clinically, electrophysiologically, histologically, and morphometrically. Exercise intolerance and weakness was associated with a high‐steppage pelvic‐limb gait, a loss or change in the pitch of the bark, and dyspnea. Neurological examination revealed marked atrophy of the distal limb muscles, depressed spinal and cranial nerve reflexes, and weak or absent movement of the laryngeal and pharyngeal muscles. Electrophysiological evaluation was consistent with denervation and was characterized by loss or marked attenuation of compound muscle action potentials and slowed motor nerve conduction velocity. Muscle biopsy specimens showed neurogenic atrophy. Chronic nerve fiber loss associated with decreased myelinated fiber density and a shift of the axonal size–frequency distribution toward smaller fibers was the predominant finding in peripheral nerve specimens. Pedigree analysis of a large multigenerational family, including nine sibships with at least one affected individual, suggested X‐linked inheritance. Mutational and linkage analysis of this family may aid in identification of the chromosomal loci and gene responsible for this inherited axonal neuropathy. Further characterization of this inherited axonal neuropathy may establish the Leonberger dog as a spontaneous animal model of inherited axonal neuropathy and possibly lead to the discovery of a new gene or genes associated with axonal variants. Muscle Nerve 27: 471–477, 2003

Frontal lobe neuronal injury correlates to altered function in FIV-infected cats.

Six cats infected intravenously at 8 weeks of age with feline immunodeficiency virus Maryland isolate (FIV-MD), were evaluated at 8 and 14 months of age (6 months and 12 months postinfection, respectively) with high spatial resolution proton magnetic resonance spectroscopy (MRS) of the frontal cortex. Two separate control cat groups were evaluated at 8 months and 16 months of age. Single voxel two-dimensional high-resolution proton magnetic resonance imaging was performed using the PRESS sequence by selecting a 0.125 ml volume of interest in the medial frontal cortex. A significant reduction in both N-acetylaspartate (NAA) and NAA: choline ratio was found in the FIV 14-month-old group compared with FIV 8-month-old cats, and to the respective age-matched control 16-month-old cats. A negative correlation between NAA and CD4 lymphocyte count was seen in the FIV-14 group only. This group of FIV cats also exhibited a higher proportion of quantitative electroencephalographic relative slow wave activity (RSWA) that correlated to lower NAA content in the frontal cortical voxel. Although peripheral blood proviral load increased over time of infection, no correlation was found between proviral blood or lymph node load and NAA values, CD4 lymphocyte counts, or frontal cortical RSWA. Thus, this study demonstrated that neurologic functional disruption of the frontal cortex correlated strongly with neuronal injury and/or loss in FIV-MD-infected cats independent of peripheral proviral load. The ability to define in vivo neurodegeneration further in this animal model helps in understanding the neuropathogenesis of lentivirus infection, and possibly, a means to follow progression and reversibility during the initial stages of brain infection as therapeutic agents are identified.

Effects of feline immunodeficiency virus on cognition and behavioral function in cats.

Experimental intravenous challenge of 8-week old cats with the Maryland isolate of feline immunodeficiency virus, Maryland isolate (FIV-MD) was investigated for its effects on cognitive and behavioral function at 12 months postinfection. Six cats infected with FIV-MD were compared with age-matched controls on several behavioral measures. These measures included an open field observation, locomotion tests, traversing planks of various widths for food reinforcement, and a spatial learning task. No group differences were observed on any measure of locomotion. Differences were present with exploratory and stationary activity in the open field observation, with infected cats exhibiting higher levels of exploratory activity and in less stationary activity compared with that of control cats. In the plank-walking experiment, infected cats were less able to successfully cross progressively narrower planks compared with control animals. A holeboard paradigm was constructed to test spatial learning and memory, in which cats were required to locate food reinforcement based on position in the holeboard array. As a group, FIV-infected cats committed more reference (exploring an unbaited cup) and working memory (returning to a previously visited baited cup) errors than control cats. The main difference demonstrated was a higher activity level and associated distractibility in FIV-infected cats that appears to be related to their overall deficient performance when learning new tasks. These results indicate that behavioral function is altered and cognition is quantitatively impaired in FIV-infected cats.