Sparky's shaking again: Seizures in young dogs (Proceedings)

Seizure disorders in young animals pose different considerations as to etiology and therapeutic decisions compared to adult dogs. Congenital, developmental, metabolic, toxic, infectious and inflammatory causes should be considered more likely in younger dogs and puppies. Seizures are the manifestation of abnormal synchronous electrical activity in the brain and are the most common neurological disorder in dogs. Seizures may be categorized as generalized, when whole body involvement is present or partial, when a portion of the body is affected. Consciousness is unimpaired during simple partial seizures and is altered during complex partial seizures. A pre ictal period prior to the seizure and a post ictal period lasting minutes to hours after the seizure are common with generalized seizures. Pre and post ictal signs may include anxiety, attention seeking, panting and pacing. The recognition of seizures can sometimes be difficult as vestibular episodes, dyskinesias and syncopal episodes can appear seizure like. A thorough history should be gathered including potential for toxin exposure, familial history, previous events, activity during onset, time of onset, duration of the event, elimination during the event, and interictal behavioral or gait changes. In puppies information regarding birth, litter mates, suckling and weight gain is also important. CBC, serum chemistry and urinalysis should be done on all dogs presenting for seizures. Hypoglycemia should be ruled out in all puppies. Bile acid testing is important in all puppies and small breed dogs.

Portosystemic shunts (PSS) often cause episodic encephalopathic signs such as mentation changes, ataxia, blindness and seizures. Other signs include vomiting, anorexia, PU/PD, decreased weight, hematuria and stranguria. Pre and post prandial bile acids are often over 100 and 200 µmol/L. Ammonium biurate or uric acid crystalluria is common.1 Confirmation of PSS may be done via abdominal ultrasound or nuclear scintigraphy. Therapy includes a low protein diet, antibiotics, lactulose and surgical ligation/constriction. Anticonvulsant therapy is indicated if seizures are present or perioperatively as post operative generalized seizures are associated with a poor prognosis.1 The mechanism of hepatic encephalopathy has been unclear. Possible causes include hyperammonemia, altered tryptophan synthesis and metabolism, false neurotransmitter synthesis, alterations in amino acid neurotransmitters and increased cerebral concentrations of an endogenous benzodiapine.2

A metabolic defect causing L-2 Hydroxyglutaric aciduria has recently been recognized in Staffordshire Bull Terriers3 and the West Highland White Terrier.4 Clinical signs include seizures, ataxia, stiff gait, decreased mentation and head tremors. Signs occur from 4 months to 7 years of age, but are often identified less than 1 year of age. Organic acid analysis of urine, CSF and plasma are abnormal in affected dogs. MR imaging identified bilaterally symmetric, diffuse hyperintensity on T2 imaging in the gray matter throughout the brain. No known effective treatment is known at this time, other than symptomatic anticonvulsant therapy. Dietary therapy may be of benefit. Cobalamin therapy may be beneficial in methylmalonic aciduria in people.3 A 6 month old Cavalier King Charles Spaniel was reported to have seizures secondary to a hexanoylglycine aciduria. L-Carnitine therapy is recommended in people with medium- chain acyl CoA dehydrogenase deficiency and thus may be of benefit for hexanoylglycine aciduria.5

Hydrocephalus is an increase in CSF volume and should be considered in toy and brachiocephalic breeds. A domed shaped head or persistent fontanelle may be present. Most commonly, stenosis of the mesencephalic aquaduct is present. CSF accumulates rostral to the obstruction and cerebral cortical atrophy occurs. Ventricular dilatation can lead to tearing of ependymal cells and periventricular diverticula. Hydrocephalus may also result secondary to neoplasia or infection obstructing CSF flow. Clinical abnormalities may not be present. Loss of cortical neurons can lead to cerebral signs and seizures. Vestibular and cerebellar signs can be seen. Diagnosis is made via cranial MRI or CT scan. Ultrasound through a persistent fontanelle may also be used in diagnosis. CSF analysis is important to rule out concurrent inflammatory or infectious disorders. Recurrent seizures should be treated with anticonvulsant therapy. If seizures are refractory to anticonvulsant therapy, or if addition neurological abnormities are present medical or surgical therapy may be considered. Glucocorticoids decrease CSF production and may be beneficial if periventricular edema is present. Prednisone starting at 0.5 mg/kg PO BID may be given with tapering to the lowest effective dose. Omeprazole also decreases CSF production and may be of benefit. Acetazolamide, a carbonic anhydrase inhibitor may be of benefit. Surgical placement of a ventriculoperitoneal shunt is considered for dogs with progressive signs not responsive to medical therapy. Success with shunting is variable. Potential complications include infection, occlusion, and shunt migration. The need for surgical revision is not uncommon.6

Lissencephaly results in a smooth cerebral cortical surface as gyri and sulci fail to develop. The cerebral cortex is becomes thicker than normal. Fusion of the corpus collosum and internal capsule cause the corona radiata (white matter tracts) to be absent. Seizures are common and may be seen at 1 year of age. Behavioral changes, circling, and visual deficits may also be seen. Lissencephaly has been seen in the Lhasa Apso, Wire Haired Fox Terrier and Irish Setter. Diagnosis is made via MRI. Symptomatic anticonvulsant therapy is recommended.6

Necrotizing meningoencephalitis is an inflammatory disease causing necrotic cystic lesions within the gray and white matter of the cerebrum. In Pugs, Chihuahuas and Maltese terriers the necrotic condition is often adjacent to the cerebral gray-white matter junction. In the Yorkshire terrier necrotizing encephalitis causes cystic white matter lesions in the cerebrum and typically has inflammatory lesions in the brainstem and cerebellum. Due to the breed specific variance in lesion location it is uncertain if these diseases are in fact variants of the same disease or different diseases.7 Male and female, young to middle age dogs are typically affected, however dogs as old as 10 years of age have been reported. Seizures are common. Mentation changes, circling and placing deficits may also be seen. Vestibular signs may predominate when the brainstem is affected. CSF typically indicates a mononuclear pleocytosis with elevated protein. MR imaging helps confirm the location and presence of cavitative lesions. MR imaging may also differentiate the disease from granulomatous meningoencephalomyelitis (GME). Recommended treatment is prednisone at 1 mg/kg PO BID. The prognosis for necrotizing encephalitis is poor. Mean survival time with corticosteroid treatment was 97 days in one study.8 Dogs with necrotizing encephalitis may be less responsive to therapy than those treated for suspected GME.

GME accounts for 5% to 25 % of all CNS disorders in dogs. Young to middle aged small breed dogs are most commonly affected. However, any age or breed may develop GME. Histologically, GME is characterized by perivascular cuffs of primarily mononuclear cells within white matter. The accumulation of inflammatory cells is typically microscopic, however areas can coalesce to form a focal granulomatous mass. Histologically, the brainstem is commonly involved. Multifocal disease is common, and all regions of the CNS; Cerebrum, cerebellum, brainstem and spinal cord (cervical) may be affected. Ocular GME has also been reported. Clinical signs vary based upon the region of the CNS involved. Onset may be acute or chronic.9 CBC, serum chemistry and urinalysis are unremarkable. CSF is the single most useful test in inflammatory brain disease.10 CSF typically yields a mononuclear pleocytosis with elevated protein, however a mixed pleocytosis with an increased percentage of neutrophils is not uncommon. MR imaging may identify contrast enhancing lesions as well evidence of brain edema. In rapidly deteriorating dogs, or in dysphagic dogs, dexamethasone sodium phosphate 0.25 mg/kg IV or SQ SID to BID is given. Prednisone at 1 mg/kg PO BID is later given. In severe or refractory cases cytosine arabanoside may be given at 50 mg/m2 BID for two consecutive days and then repeated if necessary q 3 weeks. Alternatively, procarbazine at 25 mg/m2 PO SID11 or cyclosporine 3 to 15 mg/kg PO BID12 may be given. Routine monitoring of the CBC should be done when either of these drugs is given. Clinical signs and serial CSF evaluation are used to assess therapeutic success. Prednisone is tapered over a several month period. Many dogs require long-term prednisone therapy. Adjunctive therapy such as cytosine arabanoside, cyclosporine or procarbazine may lessen the dependence on corticosteroids and lead to a more favorable prognosis. The prognosis for GME has been considered guarded. Recent studies have shown a better prognosis. One study reported a median survival time of 14.0 months with procarbazine and prednisone treatment compared to 0.62 months for dogs not receiving treatment.13 Another study showed a median survival time of 930 days with use of cyclosporine or in combination with corticosteroids or ketoconazole.12

Benign familial juvenile epilepsy has been reported in Lagotto Romagnolo Dogs and is thought to be recessively inherited. Seizures are noted between 5 to 9 weeks of age. Seizures typically respond to anticonvulsant therapy. Discontinuation of anticonvulsants is often possible after several months. Seizure recurrence may occur in adulthood.14

Idiopathic epilepsy is classified as recurrent seizures without an apparent cause. Interictal neurological examination is normal. Results of bloodwork, MRI and CSF are all normal. Seizures typically are first noted between the ages of 1 and 5. Generalized tonic clonic seizures are typically seen, although focal seizures are also possible. Idiopathic epilepsy is sometimes used to imply familial epilepsy as it is inherited in Beagles, Golden Retrievers, Irish Wolfhounds, English Springer Spaniels, Labrador Retrievers, Vizslas, Bernese Mountain Dogs, Boxers, Belgian Tervurens, British Alsatians, Keeshonds and Standard Poodles. Autosomal recessive inheritance is most common.15

Bromide hyperpolarizes the neuron through its replacement of chloride ions.16 Bromide has a half life of 21-24 days and is excreted by the kidneys. The lack of hepatic metabolism makes potassium bromide, 40 mg/kg/day in food, a good choice for young dogs. The therapeutic range is 1.0 to 3.0 mg/ml. If dogs are in status epilepticus or have cluster seizures, the long half life of bromide can make it more difficult to use effectively. In these situations, a drug with a shorter 1/2 life may be a better choice. Adverse effects include sedation, ataxia, PU/PD, polyphagia and may have an association with pancreatitis. Increased dietary salt intake increases renal excretion.16

Phenobarbital increases the seizure threshold and decreases the spread to surrounding neurons. It enhances the inhibitory postsynaptic effects of GABA, inhibits glutamate activity and increases calcium flux across neuronal membranes. Peak levels are achieved 4-6 hours post oral administration and its 1/2 life is 1 1/2 to 3 days. Phenobarbital metabolism increases with chronic therapy. Adverse effects include sedation, ataxia, polyphagia, PU/PD and increased liver enzymes. The potential for liver failure increases at higher plasma levels 35-40 µg/ml (therapeutic range 15-40 µg/ml). Routine liver monitoring is recommended.16 Phenobarbital's shorter 1/2 life allows for quicker manipulation of plasma levels, making it a good choice for dogs with frequent seizures. Levetiracetam, zonisamide and pregabalin are newer anticonvulsants with shorter 1/2 lives than Phenobarbital and appear efficacious. These drugs are typically third choice drugs due to expense. However, the efficacy and limited adverse effects of levetiracetam, 10-20 mg/kg PO TID, make it a promising choice.

References

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Abramson CJ, Platt SR, Jakobs C, et al. L-2 Hyroxyglutaric aciduria in staffordshire bull terriers. J Vet Intern Med 2003;17: 551-556.

Garosi LS, Penderis J, McConnell JF, et al. L-2 Hyroxyglutaric aciduria in a west highland white terrier. Vet Rec 2005;156:145-147.

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Higgins RJ, Dickinson PJ, Kube SA et al. Necrotizing meningoencephalitis in 5 Chihuahua dogs. Vet Pathol 2008 May;45(3):336-46.

Levine JM, Fosgate GT, Porter B, et al. Epidemiology of necrotizing meningoencephalitis in pug dogs. J Vet Intern Med 2008:22:961-968.

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Cuddon PA, Coates JR, Murray M. New treatments for granulomatous meningoencephalomyelitis. In proceedings 20th ACVIM. Dallas:2002, p 319-321.

Adamo PF, Rylander H, Adams WM. Ciclosporin use in multi-drug therapy for meningoencephalomyelitis of unknown aetiology in dogs. J Small Anim Pract. 2007;48(9):486-96.

Coates JR, Barone G, Dewey CW et al. Procarbazine as Adjunctive treatment of dogs with presumptive antemortem diagnosis of granulomatous meningoencephalomyelitis: 21 cases (1998-2004). J Vet Int Med 2007;21:100-106.

Jokinen TS, Metsahonkala L, Bergamasco L, et al. Benign familial juvenile epilepsy in lagotto romagnolo dogs. J Vet Intern Med;21: 464-471.

Licht BG, Lin S, Luo Y, et al. Clinical characteristics and mode of inheritance of familial focal seizures in standard poodles. J Am Vet Med Assoc 2007;231(10):1520-1528

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