Diagnosis and long-term management of post-traumatic seizures in a white-crowned pionus (Pionus senilis)

Claudia Kabakchiev 1Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.

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Delphine Laniesse 1Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.

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Fiona James 1Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.

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Alex zur Linden 1Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.

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Emily Brouwer 2Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.

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Hugues Beaufrère 1Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.

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Abstract

CASE DESCRIPTION

A 13-year-old female white-crowned pionus (Pionus senilis) was examined because of seizures 22 months after it was treated for a traumatic brain injury (TBI) characterized by vision loss, hemiparesis, nystagmus, circling, and head tilt.

CLINICAL FINDINGS

Bloodwork performed during the initial seizure workup revealed hypercalcemia and hypercholesterolemia, which were attributed to vitellogenesis given the bird's previous egg-laying history and recent onset of reproductive behavior. Magnetic resonance imaging of the brain revealed diffuse right pallium atrophy with multifocal hydrocephalus ex vacuo, which were believed to be the result of the previous TBI. Findings were most consistent with post-traumatic seizures (PTS).

TREATMENT AND OUTCOME

Levetiracetam (100 mg/kg [45 mg/lb], PO, q 12 h) was initiated for PTS management. A 4.7-mg deslorelin implant was injected SC to suppress reproductive behavior. The bird was reexamined for presumed status epilepticus 5 times over 22 months. Seizure episodes coincided with onset of reproductive behavior. The levetiracetam dosage was increased (150 mg/kg [68 mg/lb], PO, q 8 h), and zonisamide (20 mg/kg [9.1 mg/lb], PO, q 12 h) was added to the treatment regimen. Additional deslorelin implants were administered every 2 to 6 months to suppress reproductive behavior. The owner was trained to administer midazolam intranasally or IM as needed at home. The treatment regimen helped control but did not eliminate seizure activity. The bird was euthanized 22 months after PTS diagnosis for reasons unrelated to the TBI or PTS.

CLINICAL RELEVANCE

Long-term management of PTS in a pionus was achieved with levetiracetam and zonisamide administration.

Abstract

CASE DESCRIPTION

A 13-year-old female white-crowned pionus (Pionus senilis) was examined because of seizures 22 months after it was treated for a traumatic brain injury (TBI) characterized by vision loss, hemiparesis, nystagmus, circling, and head tilt.

CLINICAL FINDINGS

Bloodwork performed during the initial seizure workup revealed hypercalcemia and hypercholesterolemia, which were attributed to vitellogenesis given the bird's previous egg-laying history and recent onset of reproductive behavior. Magnetic resonance imaging of the brain revealed diffuse right pallium atrophy with multifocal hydrocephalus ex vacuo, which were believed to be the result of the previous TBI. Findings were most consistent with post-traumatic seizures (PTS).

TREATMENT AND OUTCOME

Levetiracetam (100 mg/kg [45 mg/lb], PO, q 12 h) was initiated for PTS management. A 4.7-mg deslorelin implant was injected SC to suppress reproductive behavior. The bird was reexamined for presumed status epilepticus 5 times over 22 months. Seizure episodes coincided with onset of reproductive behavior. The levetiracetam dosage was increased (150 mg/kg [68 mg/lb], PO, q 8 h), and zonisamide (20 mg/kg [9.1 mg/lb], PO, q 12 h) was added to the treatment regimen. Additional deslorelin implants were administered every 2 to 6 months to suppress reproductive behavior. The owner was trained to administer midazolam intranasally or IM as needed at home. The treatment regimen helped control but did not eliminate seizure activity. The bird was euthanized 22 months after PTS diagnosis for reasons unrelated to the TBI or PTS.

CLINICAL RELEVANCE

Long-term management of PTS in a pionus was achieved with levetiracetam and zonisamide administration.

An 11-year-old confirmed female white-crowned pionus (Pionus senilis) was referred to the Ontario Veterinary College Health Sciences Centre for evaluation following a traumatic injury. The owner had stepped on the bird 5 days previous to the referral examination. Blood was observed coming from the left ear immediately after the injury. The owner also reported that the bird had a head tilt and was observed circling after the injury and was concerned that the bird had lost some vision. Treatments initiated by the referring veterinarian included administration of a corticosteroid, amoxicillin-clavulanic acid, famotidine, furosemide, eye lubricant, and SC fluids (dosages unknown) and gavage feeding. The owner reported gradual improvement in the bird's clinical condition in the 5 days since the injury.

During the initial examination at the referral hospital, the bird appeared tentative in the examination room and did not respond appropriately to visual cues, which supported the owner's belief that the bird was blind. The pupillary light reflex was absent, although the fundus appeared clinically normal, in both eyes. Results of a neurologic examination revealed right-sided hemiparesis, nystagmus with fast phase to the left, weak palpebral reflex of the right eye, circling to the right, and a head tilt to the right. Those findings were suggestive of multifocal brain lesions, with localization to the rostral medulla, midbrain, and left pallium or right medulla (given the right-sided paresis). Diagnostic imaging was not performed at that time owing to the risks associated with sedating or anesthetizing the bird. Results of a plasma biochemical analysis including bile acids concentration revealed markedly increased aspartate aminotransferase (1,182 U/L; reference interval, 120 to 346 U/L) and creatine kinase (1,326 U/L; reference interval, 106 to 365 U/L) activities,1 which were consistent with muscle damage. Results of a CBC revealed moderate anemia1 (Hct, 0.31 L/L; reference interval, 0.47 to 0.55 L/L) with a regenerative response2 (12 to 18 polychromatophils/100 RBCs; reference interval, 0.6 to 8 polychromatophils/100 RBCs).

The pionus still required gavage feeding, and it was hospitalized until it began to eat on its own. While hospitalized, the bird received meloxicama (1 mg/kg [0.45 mg/lb], PO, q 12 h), butorphanolb (2 mg/kg [0.9 mg/lb], IM), and tramadolc (10 mg/kg [4.5 mg/lb], PO, q 12 h) as needed for analgesia. Sucralfated (25 mg/kg [11.4 mg/lb], PO, q 8 h) was given as a gastroprotectant while the bird was not eating well. Enrofloxacine (15 mg/kg [6.8 mg/lb], PO, q 12 h) and itraconazolef (10 mg/kg, PO, q 24 h) were administered to prevent secondary infections, especially given the recent history of corticosteroid administration. Because the palpebral reflex of the right eye was impaired, topical administration of 0.3% tobramycin ophthalmic ointmentg and an eye lubricant in the right eye 4 times daily was initiated. Other treatments included SC fluid administration and gavage feeding. The bird's coordination, head tilt, nystagmus, and muscle strength gradually improved, and it was discharged from the hospital after 5 days. A recheck examination performed 1 month later revealed continued clinical improvement, with resolution of the paresis, head tilt, and circling. The bird was lost to follow-up after that time owing to relocation by the owner.

Twenty-two months after the traumatic injury, the pionus was examined because of an acute onset of focal seizures with clonic spasms of the left leg. It had a marked head tilt to the right and nystagmus with fast phase to the right. The right eye had a delayed pupillary light reflex. The owner reported that the blindness had not improved. The pionus was able to perch only on the right foot, which had increased tone and was clenched; the left leg was paretic. The neurologic signs could not be localized to just 1 hemisphere of the brain; therefore, multifocal lesions were again suspected. In addition to the neurologic signs, the bird was bradycardic (heart rate, 124 to 172 beats/min; reference intervals,3 230 to 240 beats/min [at rest] and > 240 beats/min [restrained]) and overweight (body weight, 237 g), with a body condition score of 4/5 on the basis of palpation of the pectoral musculature and subcutaneous fat. Plasma biochemical analysis including bile acids concentration revealed moderate hypercalcemia1 (total calcium concentration, 4.04 mmol/L; reference interval, 2.05 to 2.5 mmol/L) and hypercholesterolemia4 (cholesterol concentration, 16.73 mmol/L; reference interval, 2.59 to 6.48 mmol/L [for most parrots]), which were assumed to be associated with vitellogenesis because the pionus routinely laid eggs annually around that time of year and had been displaying reproductive behaviors with the owner.

The pionus received diazepamh (1 mg/kg, IV), and administration of meloxicam (1 mg/kg, PO, q 12 h) and levetiracetami (100 mg/kg [45 mg/lb], PO, q 12 h) was initiated. Magnetic resonance imaging was recommended to further elucidate the cause of the seizures.

The pionus was premedicated with butorphanol (0.5 mg/kg [0.23 mg/lb], IM) and midazolamh (1 mg/kg, IM). Anesthesia was induced with 2.5% isofluranej in oxygen, which was administered via a face mask. Following orotracheal intubation, anesthesia was maintained with 1.75% to 3.5% isoflurane administered with oxygen at a flow rate of 1.5 L/min. While anesthetized, the bird was mechanically ventilated with the respiratory frequency adjusted between 5 and 30 breaths/min to maintain end-tidal CO2 concentration between 35 and 45 mm Hg. A catheter was aseptically placed in an ulnar vein, and IV administration of an isotonic electrolyte solutionk with 2.5% dextrose (10 mL/kg/h) was initiated. The pionus was instrumented with a Doppler ultrasonographic probe to monitor heart rate and capnography to monitor end-tidal partial pressure of CO2 while it was anesthetized.

A 1.5-T MRI scannerl was used to obtain MRI sequences of the brain before and after administration of the contrast medium gadobenate dimegluminem (1 mmol/kg [0.45 mmol/lb], IV). Sequences acquired included T2-weighted FSE in the transverse (TR, 4,067 milliseconds; TE, 102 milliseconds; slice thickness, 2 mm; and NEX, 4), sagittal (TR, 3,950 milliseconds; TE, 85 milliseconds; slice thickness, 2 mm; and NEX, 4), and dorsal (TR, 5,200 milliseconds; TE, 86.8 milliseconds; slice thickness, 2 mm; and NEX, 4) planes; T2-weighted FSE with FLAIR in the transverse plane (TR, 8,002 milliseconds; TE, 125 milliseconds; slice thickness, 2 mm; NEX, 2; FOV, 12 × 12 cm; and matrix size, 160 × 160); T2* gradient recall echo in the transverse plane (TR, 550 milliseconds; TE, 15 milliseconds; slice thickness, 2 mm; NEX, 4; FOV, 12 × 12 cm; and matrix size, 192 × 160); T1-weighted FSE in the transverse (TR, 567 milliseconds; TE, 13.2 milliseconds; slice thickness, 2 mm; and NEX, 4), sagittal (TR, 617 milliseconds; TE, 14.4 milliseconds; slice thickness, 2 mm; and NEX, 4), and dorsal (TR, 717 milliseconds; TE, 14.7 milliseconds; slice thickness, 2 mm; and NEX, 4) planes; and diffusion-weighted imaging in the transverse plane (TR, 6,100 milliseconds; TE, 122.3 milliseconds; slice thickness, 2 mm; NEX, 4; FOV, 6 × 6 cm; and matrix size, 64 × 64). For all sequences, the FOV was 12 × 10.2 cm and matrix size was 224 × 192 unless otherwise noted. Following completion of MRI sequencing, isoflurane administration was discontinued, and the bird was administered flumazenilh (0.025 mg/kg [0.011 mg/lb], IM). Recovery from anesthesia was uncomplicated.

Evaluation of the MRI sequences revealed mild diffuse atrophy of the right pallium. Multiple regions of the right pallium were focally decreased in size, and the focal defects were filled with fluid, which had a signal intensity similar to that of CSF (Figure 1) The largest focal defect was at the caudoventral aspect of the right nidopallium and had an adjacent thin, linear T1 and T2 hypointense structure centrally, most consistent with a small chronic skull fracture. A smaller lesion was present at the rostral and ventromedial periphery of the right nidopallium. A linear lesion was present at the medial and dorsal aspects of the right pallium that extended along the length of the pallium. Those lesions were consistent with focal brain atrophy and hydrocephalus ex vacuo. Rostral to the largest defect in the right pallium were poorly circumscribed areas in the nidopallium that were hyperintense on T2 images but were not suppressed on the FLAIR sequence. Those findings were most consistent with vasogenic edema or gliosis. Within the midbrain, there were 2 tubular fluid-filled structures that were dilated rostroventrally; the structure on the right side was larger than that on the left side. Those structures were consistent with mesencephalic tectal ventricles,5 and because they were present bilaterally, they likely represented a portion of an abnormally dilated ventricular system. Additionally, there was a mild focal indentation of the caudoventral aspect of the cerebellum by the occiput. No portion of the brain had abnormal contrast enhancement.

Figure 1—
Figure 1—

T2-weighted FSE (first and second [left-most] columns), T-2 weighted FLAIR (third column), and T1-weighted FSE (fourth [right-most] column) MRI sequences obtained in the dorsal (first column) and transverse (second, third, and fourth columns) planes at the level of the midportion of the pallium (row A), ventral portion of the pallium (row B), and midbrain (row C) of a 13-year-old female white-crowned pionus (Pionus senilis) that was examined because of seizures 22 months after it was treated for a TBI. Images reveal evidence of right pallial atrophy (arrowheads), a small skull fracture (open arrow; row A), vasogenic edema or gliosis (dashed circles; row C), and multifocal sites of hydrocephalus ex vacuo (white arrows). The mesencephalic tectal ventricles (open arrows; row C) were dilated bilaterally, the right ventricle was dilated more than the left ventricle. Findings were most consistent with a diagnosis of PTS. The right side is to the left in all images.

Citation: Journal of the American Veterinary Medical Association 256, 10; 10.2460/javma.256.10.1145

On the basis of the MRI findings, the primary differential diagnosis for the changes in the right pallium was atrophy secondary to trauma with multifocal sites of hydrocephalus ex vacuo. Hydrocephalus ex vacuo develops subsequent to cerebral hemorrhage and infarction that cause focal destruction of brain tissue, which is then replaced with CSF.6–8 Given the bird's history, post-traumatic pallial atrophy and hydrocephalus ex vacuo were considered the cause of the seizures, particularly with the small skull fracture that extended into the largest hydrocephalus ex vacuo site.

Levetiracetam (100 mg/kg, PO, q 12 h) administration was initiated for long-term seizure management. Because the bird was exhibiting reproductive behavior (eg, regurgitation and nesting behavior) and was hypercalcemic and hypercholesterolemic on the plasma biochemical analysis, it was administered a 4.7-mg deslorelin implant,n SC, prior to its discharge from the hospital.

The pionus was reexamined 5 times over the next 22 months. Each time, the bird was presumed to be in focal status epilepticus, with seizures characterized by clenching of the right foot, tonic-clonic movements of the left foot, nystagmus with fast-phase to the right, twitching of the right wing, and a head tilt to the right. The seizures often lasted for a couple of hours until the pionus was given diazepam (0.5 to 1.0 mg/kg, IV or IM) or midazolam (0.5 to 1.0 mg/kg, IM). Bradycardia, which was identified when the seizures first manifested, was not consistently present during the examinations for seizure activity. Plasma biochemical analyses performed at examinations for seizure activity consistently revealed hypercholesterolemia (cholesterol concentration, 8.1 to 22.5 mmol/L) and elevated creatine kinase activity (648 to 9,654 U/L); occasionally, there were also elevations in aspartate aminotransferase activity and total calcium concentration. Results of CBCs frequently revealed changes in the leukogram consistent with inflammation (ie, toxic changes of heterophils and presence of band cells). Seizure activity usually occurred 10 to 12 hours after levetiracetam administration, which suggested that more frequent administration of the drug was warranted. The levetiracetam dosage was increased to 150 mg/kg (68 mg/lb), PO, every 8 hours. Seizures also regularly coincided with the onset of reproductive behavior such as vocalization, vent rubbing, affectionate behavior toward the owner, and nesting. The bird was administered one 4.7-mg deslorelin implant, SC, at each follow-up examination for seizure activity. The owner reported that the deslorelin implant appeared to suppress reproductive behavior and limit seizure frequency. Because the veterinary literature lacks information regarding the duration of efficacy for deslorelin implants in Pionus spp, the frequency of implant administration was dictated by the occurrence of reproductive behavior. The dosing interval was 6 months between the first 2 deslorelin implants, and then every 2 to 4 months thereafter, such that the bird received 8 implants over 2 years.

After the fourth examination for seizure activity, which was 12 months after the MRI evaluation and initiation of levetiracetam administration, zonisamidei (20 mg/kg [9.1 mg/lb], PO, q 12 h) was added to the treatment regimen to aid with ongoing seizure control. The owner was also trained to administer midazolam intranasally or IM at home, which helped manage, but did not eliminate, future seizure episodes.

The pionus had 2 additional seizure episodes after zonisamide administration was initiated (at 14 months and 21 months after initial diagnosis), which coincided with the onset of reproductive behavior. Examination of the bird during one of those episodes revealed a localized area of feather loss around the neck, which progressed over the subsequent 4 months. The bird also developed severe dermatitis that extended over the back and around the eyes and was characterized by hyperkeratosis, the presence of a yellow crust on the skin, and feather loss. Additionally, it had become polyphagic, polydipsic, polyuric, and weak. The owners reported that they applied a topical antimicrobial-corticosteroid ointmento on the affected skin; the ointment had been prescribed for another pet with dermatitis. At that time, the pionus had lost a substantial amount of weight, frequently fell off its perch, and had developed a cardiac arrhythmia. Histologic and microbiologic evaluations of skin biopsy specimens revealed ulcerative intracorneal vesiculopustular bacterial pyoderma and growth of Staphylococcus hominis. Administration of amoxicillin-clavulanic acidp (120 mg/kg [54.5 mg/lb], PO, q 12 h) was initiated along with itraconazole (5 mg/kg [2.3 mg/lb], PO, q 24 h) owing to concerns about a secondary fungal infection. Further diagnostic imaging was declined by the owner at that time. Approximately 1 week later, the bird's clinical condition deteriorated, and it was euthanized.

Necropsy revealed unilateral fungal pyelonephritis and fungal air sacculitis (aspergillosis), which were presumed to be the cause of the clinical deterioration. The bird also had mild multifocal pulmonary mycobacteriosis. Gross examination of the brain revealed unilateral pallial atrophy on the right side (Figure 2) Histologic evaluation of the brain revealed a reduced number of neuronal cell bodies and perineuronal glial cell clusters in the right cerebral hemisphere. The neuropil was decreased relative to the cells, such that the right cerebral hemisphere appeared more hypercellular than the left cerebral hemisphere (Figure 3) No inflammatory cells were observed in the brain tissue. The atrophy of the right cerebral hemisphere of the brain and lack of inflammatory cells was most consistent with chronic infarction. A skull fracture was not identified during necropsy, but that was 2 years after the MRI examination was performed, which was sufficient time for the fracture to heal and become inevident.

Figure 2—
Figure 2—

Photograph of a transverse section of the brain of the pionus of Figure 1. Notice that the right (R) cerebral hemisphere is smaller than the left (L) cerebral hemisphere owing to pallial atrophy. Gross findings for the brain were consistent with the MRI findings described in Figure 1.

Citation: Journal of the American Veterinary Medical Association 256, 10; 10.2460/javma.256.10.1145

Figure 3—
Figure 3—

Photomicrographs of sections of the left (histologically normal; A) and right (atrophied; B) cerebral hemispheres of the pionus of Figure 1. Notice that the right cerebral hemisphere has less neuropil and more cells than the left cerebral hemisphere. H&E stain; bar = 20 μm.

Citation: Journal of the American Veterinary Medical Association 256, 10; 10.2460/javma.256.10.1145

Discussion

The present clinical report described the diagnosis and long-term management of PTS in a white-crowned pionus. In birds, as in mammals, seizures can be caused by many factors, including infectious diseases, toxicoses (eg, heavy metals), acute trauma, metabolic disorders,9,10 vascular disease (eg, atherosclerosis or lipid emboli),11,12 hydrocephalus,13,14 and neoplasia (eg, pituitary adenomas, choroid plexus tumors, and glioblastomas).15 Idiopathic epilepsy has been reported in peach-faced lovebirds (Agapornis roseicollis),16 red-lored Amazon parrots (Amazona autumnalis),17 double yellow-headed Amazon parrots (Amazona oratrix), and greater Indian hill mynahs (Gracula religiosa intermedia).18 Those conditions seemed to be unlikely causes for the seizures in the pionus of this report given the history of trauma; neurologic examination, hematologic, and plasma biochemical findings; and MRI evidence of multifocal brain lesions. To our knowledge, the present report was the first to describe PTS in an avian patient.

Post-traumatic seizures are a well-documented phenomenon in companion mammals and humans. In contrast to seizures that occur acutely after a traumatic incident, PTS or post-traumatic epilepsy are defined as seizures or seizure episodes that occur at least 1 week after an initial TBI. Approximately half of PTS-affected patients develop seizures within 1 year after the TBI, and 80% to 90% of such patients develop seizures within the first 2 years after the TBI.19,20 However, PTS can develop years or even decades after a TBI.21 For the pionus of the present report, the first seizure episode occurred almost 2 years after the initial TBI. In human patients, the prevalence of PTS ranges from 4% to 53%, depending on the extent of the injury, the population that was studied, and the length of follow-up.22 In human medicine, the risk of PTS is positively associated with the severity of the TBI and presence of brain contusions and skull fractures.22–25 In 2 retrospective case-series reports, 5 of 74 (6.8%)26 and 13 of 198 (6.6%) dogs27 with head trauma developed seizures after being discharged from a veterinary hospital; however, many of those dogs were not assessed for all possible causes of seizures, so PTS or post-traumatic epilepsy could not be definitely diagnosed. In one of those reports,27 the apparent prevalence rate of PTS was 14.3% (4/28) for dogs with confirmed skull fractures. Conversely, 0 of 52 cats with a history of mild to moderate head trauma developed PTS.28 We believe that PTS in birds are likely underdiagnosed owing to concurrent abnormalities or the limited diagnostic testing pursued by owners.

The pathogenesis of PTS differs from that of acute seizures because it is influenced by events that occur following brain trauma. It is currently believed that PTS occur as a result of oxidative cellular damage caused by the presence of iron in brain tissue following extravasation and lysis of RBCs.19 Results of experimental studies indicate that injection of iron into the brain tissue of cats29 and rats30 causes production of reactive oxygen species and epileptic seizures. Additionally, neuronal cell death, inflammation, and edema in the period immediately after a TBI lead to reorganization of synapses and neural networks and increase the risk for future seizures.31 Neuronal cellular damage also promotes the release of excitatory neurotransmitters (eg, aspartate and glutamate) and decreases the release of inhibitory neurotransmitters (eg, γ aminobutyric acid).19 Although the pathogenic mechanism responsible for PTS has not been fully elucidated for human patients and has not been investigated in detail for companion mammals, it is clear that mechanism differs from that for acute trauma-induced seizures and involves ongoing chronic changes in the brain. Further investigation into the nature and possible prevention of those intracranial changes and long-term treatment options is necessary.

It is important to rule out other possible causes of seizures before a diagnosis of PTS is made. A CBC and serum biochemical profile are necessary to assess patients for systemic inflammation, metabolic abnormalities, electrolyte derangements, and renal or hepatic insufficiency. The patient's history and clinical signs may also indicate specific testing for infectious agents or heavy metal, organophosphate, or carbamate toxicoses. Given the focal seizures observed in the bird of the present report and its lack of exposure to toxic agents, testing for toxicoses was not performed. For patients with a history of TBI, MRI of the brain is recommended. Compared with CT, MRI provides better contrast and visualization of the CNS.6,8 The type and severity of CNS lesions observed on MRI sequences may help predict the onset of PTS.19,25,32–34 For the bird of the present report, MRI sequencing revealed evidence of atrophic pallial lesions and hydrocephalus ex vacuo that were most likely secondary to trauma. Those lesions correlated well with the postmortem findings of cerebral atrophy and loss of neuronal cells. The MRI findings for the bird of this report also led to a definitive diagnosis of a skull fracture, which likely contributed to the pallial atrophy. If the bird had undergone MRI of the brain prior to the onset of seizures, the results would likely have indicated that the patient was at risk for developing PTS and discussion of plans for medical management of the patient could have been had with the owner. Magnetic resonance imaging is underutilized in avian practice because of its limited availability, concerns regarding the anesthesia required for MRI sequencing, small patient size that contributes to a reduced signal-to-noise ratio, and high cost. Nevertheless, MRI is the best diagnostic modality for the identification of brain lesions associated with PTS.

Management of PTS differs from that for seizures that occur immediately after a TBI (acute seizures). Treatment of acute seizures following a TBI in birds is similar to that for mammals and generally includes immediate seizure control (ie, administration of anticonvulsants such as diazepam), oxygen and fluid therapy, analgesics, and mannitol to minimize intracranial pressure.10 In human medicine, although research is ongoing, there is currently no consensus regarding the management of acute TBI for the prevention of PTS. In human patients, the risk of PTS does not appear to decrease following prophylactic treatment with anticonvulsants such as phenytoin, phenobarbital, valproate, and carbamazepine.31,35 Further research into the use of other prophylactic anticonvulsants (eg, levetiracetam), antioxidants, and additional management strategies (eg, hypothermia) is ongoing in both human and veterinary medicine. Levetiracetam appears to have promising neuroprotective effects in rodents with experimentally induced head trauma, which suggests that it may be beneficial for prophylactic management of PTS.36–38 In human patients with acute seizures associated with TBI, the current recommended treatment is administration of phenytoin or another anticonvulsant such as levetiracetam for 7 days.19,39 For human patients with PTS, remission rates of up to 40% have been reported following the use of novel anticonvulsant therapies,22 but up to a third of human patients with PTS become refractory to antiepileptic drugs and require other treatments such as surgical resection of brain lesions and nerve stimulation.40,41 For veterinary patients with PTS, management is currently limited to the administration of anticonvulsants, which is generally not initiated until after the first unprovoked seizure episode.

Review of anticonvulsant administration for the management of seizures in birds was beyond the scope of the present report and is available elsewhere.10,42,43 The pharmacokinetics of phenobarbital in African grey parrots (Psittacus erithacus erithacus)44 and of levetiracetam and gabapentin in Hispaniolan Amazon parrots (Amazona ventralis)45,46 have been described. However, there is little in the peer-reviewed literature regarding successful long-term management of seizures in avian species. An African grey parrot with seizures believed to be secondary to ischemic stroke was managed with levetiracetam (up to 100 mg/kg, PO, q 8 h), zonisamide (20 mg/kg, PO, q 8 h), clonazepam (0.5 mg/kg, PO, q 12 h), and gabapentin (20 mg/kg, PO, q 12 h) for 20 months.11 Monitoring of levetiracetam and zonisamide concentrations for the bird of that report11 indicated that both drugs achieved plasma concentrations that were considered therapeutic in human medicine. The pionus of the present report was administered a higher dose of levetiracetam (up to 150 mg/kg, PO, q 8 h) in an attempt to improve seizure control in the absence of pharmacokinetic data for that species. In another case report,47 therapeutic plasma concentrations of potassium bromide were achieved in an umbrella cockatoo (Cacatua alba) following daily administration of a dose of 80 mg/kg (36.4 mg/lb), PO. Response to anticonvulsant treatment varies among species. Despite a lack of information regarding therapeutic plasma concentrations of anticonvulsants in avian species, drug concentration monitoring is recommended for individual birds undergoing treatment. Unfortunately, drug concentration monitoring was not performed for the pionus of the present report owing to the lack of available tests locally and the high cost of pursuing such tests.

It is important to note that the clinical deterioration of the bird of the present report was the result of what appeared to be opportunistic infections rather than PTS. The inciting cause of the bacterial pyoderma was unclear; however, topical administration of a corticosteroid ointment to manage the signs of pyoderma may have allowed other infections to develop including the mycobacteriosis and fungal pyelonephritis and air sacculitis. In birds, corticosteroid use is associated with immunosuppression.48,49

For the pionus of the present report, we found it interesting that suppression of reproductive hormones by periodic SC administration of deslorelin (a gonadotropin-releasing hormone agonist) implants appeared to be beneficial for seizure management. Results of studies50–52 involving mammals indicate that sex hormones, such as estradiol and progesterone, have proconvulsant or anticonvulsant effects depending on the experimental design and outcome under investigation. However, the effects of sex hormones on various tissues and physiologic processes are complex and not fully understood.50 There is currently no information regarding how endocrine and metabolic processes associated with reproduction affect the neural activity in the brain of birds. For the bird of this report, seizures consistently occurred after the onset of reproductive behavior and were frequently concurrent with high plasma concentrations of calcium and cholesterol. In birds, a hyperlipidemic syndrome associated with high estrogen concentrations has been reported as a possible trigger for seizures as a result of blood hyperviscosity, emboli, and hypoxia.42 It is also possible that the perceived reproductive behaviors for the bird of the present report were actually part of a preictal phase of PTS or a consequence of focal limbic seizures. The nature of the association between reproductive behavior and seizures in birds cannot be determined from a single clinical report. Further research into the interaction between reproductive hormones and seizure activity is necessary.

Deslorelin implants were used to manage the neurostimulatory and cardiovascular effects associated with the presumed elevated sex hormone concentrations in the pionus of the present report. However, we cannot rule out the possibility that the seizures might have been equally well-controlled without the hormonal treatment. In humans and other mammals, there is a bidirectional interaction between reproductive hormones and seizure activity,52 and seizure activity can alter reproductive hormone concentrations. If the same process occurs in avian species, the seizure activity could have caused changes in reproductive hormones and behaviors that were falsely attributed to the inhibitory effects of deslorelin. This is a subject that requires further research.

The present report was the first to describe diagnosis and long-term management of PTS in an avian patient. The use of MRI was an important component of the diagnostic process and was invaluable for the identification of traumatic brain lesions. Post-traumatic seizures may be underdiagnosed in birds owing to the high cost or anesthetic risks associated with advanced diagnostic imaging. It is important to note that PTS may not manifest until months to years after the initial TBI, and PTS should be included in the differential diagnoses list for any patient with seizures and a history of a TBI. Also, owners of birds examined for acute head trauma should be informed of the risk for future seizure activity. The efficacy of anticonvulsant treatment varies among species. However, novel anticonvulsants used in mammals can be safely and successfully administered to avian patients. Monitoring of drug concentrations is recommended for individual patients to facilitate anticonvulsant dosage adjustments on the basis of clinical response.

ABBREVIATIONS

FOV

Field of view

FSE

Fast-spin echo

NEX

Number of excitations

PTS

Post-traumatic seizures

TBI

Traumatic brain injury

TE

Echo time

TR

Repetition time

Footnotes

a.

Metacam, Boehringer Ingelheim, Burlington, ON, Canada.

b.

Torbugesic, Zoetis Canada Inc, Kirkland, QC, Canada.

c.

Compounded by Ontario Veterinary College Pharmacy, University of Guelph, Guelph, ON, Canada.

d.

Sulcrate suspension, Aptalis Pharma Canada Inc, Mont-St-Hilaire, QC, Canada.

e.

Baytril, Bayer Inc, Mississauga, ON, Canada.

f.

Sporanox, Janssen Inc, Toronto, ON, Canada.

g.

Tobrex, Novartis Pharmaceuticals Canada Inc, Dorval, QC, Canada.

h.

Sandoz Canada Inc, Boucherville, QC, Canada.

i.

Compounded by Chiron Compounding Pharmacy, Guelph, ON, Canada.

j.

IsoFlo, Zoetis Canada Inc, Kirkland, QC, Canada.

k.

Baxter Healthcare, Deerfield, Ill.

l.

Signa Excite II, General Electric Healthcare, Milwaukee, Wis.

m.

MultiHance, Bracco Imaging Canada, Montreal, QC, Canada.

m.

Suprelorin, Virbac, Milperra, NSW, Australia.

o.

Taro Pharmaceutical Industries Ltd, Brampton, ON, Canada.

p.

Clavamox, Zoetis Canada Inc, Kirkland, QC, Canada.

References

  • 1. Speer BL. Appendices 2 and 3: normal clinical pathologic data and normal biological data. In: Speer BL, ed. Current therapy in avian medicine and surgery. St Louis: Elsevier, 2016;825879.

    • Search Google Scholar
    • Export Citation
  • 2. Johns JL, Shooshtari MP, Christopher MM. Development of a technique for quantification of reticulocytes and assessment of erythrocyte regenerative capacity in birds. Am J Vet Res 2008;69:10671072.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3. West NH, Langille BL, Jones DR. Cardiovascular system. In: King AS, McLelland J, eds. Form and function in birds. London: Academic Press, 1981;235339.

    • Search Google Scholar
    • Export Citation
  • 4. Campbell TW. Clinical chemistry of birds. In: Thrall MA, Weiser G, Allison R, et al, eds. Veterinary hematology and clinical chemistry. Hoboken, NJ: Wiley-Blackwell, 2012;582598.

    • Search Google Scholar
    • Export Citation
  • 5. Mestres P, Rascher K. The ventricular system of the pigeon brain: a scanning electron microscope study. J Anat 1994;184:3558.

  • 6. Go KG, Hew JM, Kamman RL, et al. Cystic lesions of the brain. A classification based on pathogenesis, with consideration of histological and radiological features. Eur J Radiol 1993;17:6984.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. Kazemi H, Hashemi-Fesharaki S, Razaghi S, et al. Intractable epilepsy and craniocerebral trauma: analysis of 163 patients with blunt and penetrating head injuries sustained in war. Injury 2012;43:21322135.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. Harris TC, de Rooij R, Kuhl E. The shrinking brain: cerebral atrophy following traumatic brain injury. Ann Biomed Eng 2019;47:19411959.

  • 9. Bennett RA. Neurology. In: Ritchie BW, Harrison GJ, Harrison LR, eds. Avian medicine: principles and application. Lake Worth, Fla: Wingers Publishing, 1994;723747.

    • Search Google Scholar
    • Export Citation
  • 10. Bowles H, Lichtenberger M, Lennox A. Emergency and critical care of pet birds. Vet Clin North Am Exot Anim Pract 2007;10:345394.

  • 11. Beaufrère H, Nevarez J, Gaschen L, et al. Diagnosis of presumed acute ischemic stroke and associated seizure management in a Congo African grey parrot. J Am Vet Med Assoc 2011;239:122128.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12. de Matos R, Morrisey JK. Emergency and critical care of small psittacines and passerines. Semin Avian Exot Pet 2005;14:90105.

  • 13. Wack RF, Lindstrom JG, Graham DL. Internal hydrocephalus in an African Grey parrot. J Assoc Avian Vet 1989;3:9496.

  • 14. Thurber MI, Mans C, Fazio C, et al. Antemortem diagnosis of hydrocephalus in two Congo African grey parrots (Psittacus erithacus erithacus) by means of computed tomography. J Am Vet Med Assoc 2015;246:770776.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15. Latimer KS. Oncology. In: Ritchie BW, Harrison GJ, Harrison LR, eds. Avian medicine: principles and application. Lake Worth, Fla: Wingers Publishing, 1994;640672.

    • Search Google Scholar
    • Export Citation
  • 16. Rosskopf WJ Jr. Common conditions and syndromes of canaries, finches, lories and lorikeets, lovebirds, and macaws. Semin Avian Exot Pet 2003;12:131143.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17. Rosskopf WJ, Woerpel RW. Epilepsy in red lored Amazons, in Proceedings. Assoc Avian Vet 1985;141145.

  • 18. Quesenberry KE, Hillyer EV. Supportive care and emergency therapy. In: Ritchie BW, Harrison GJ, Harrison LR, eds. Avian medicine: principles and application. Lake Worth, Fla: Wingers Publishing, 1994;382416.

    • Search Google Scholar
    • Export Citation
  • 19. Agrawal A, Timothy J, Pandit L, et al. Post-traumatic epilepsy: an overview. Clin Neurol Neurosurg 2006;108:433439.

  • 20. Verellen RM, Cavazos JE. Post-traumatic epilepsy: an overview. Therapy 2010;7:527531.

  • 21. Annegers JF, Hauser WA, Coan SP, et al. A population-based study of seizures after traumatic brain injuries. N Engl J Med 1998;338:2024.

  • 22. Frey LC. Epidemiology of posttraumatic epilepsy: a critical review. Epilepsia 2003;44:1117.

  • 23. Asikainen I, Kaste M, Sarna S. Early and late posttraumatic seizures in traumatic brain injury rehabilitation patients: brain injury factors causing late seizures and influence of seizures on long-term outcome. Epilepsia 1999;40:584589.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24. Englander J, Bushnik T, Duong TT, et al. Analyzing risk factors for late posttraumatic seizures: a prospective, multicenter investigation. Arch Phys Med Rehabil 2003;84:365373.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25. Tubi MA, Lutkenhoff E, Blanco MB, et al. Early seizures and temporal lobe trauma predict post-traumatic epilepsy: a longitudinal study. Neurobiol Dis 2019;123:115121.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26. Friedenberg SG, Butler AL, Wei L, et al. Seizures following head trauma in dogs: 259 cases (1999–2009). J Am Vet Med Assoc 2012;241:14791483.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27. Steinmetz S, Tipold A, Löscher W. Epilepsy after head injury in dogs: a natural model of posttraumatic epilepsy. Epilepsia 2013;54:580588.

  • 28. Grohmann KS, Schmidt MJ, Moritz A, et al. Prevalence of seizures in cats after head trauma. J Am Vet Med Assoc 2012;241:14671470.

  • 29. Willmore LJ, Sypert GW, Munson JB. Recurrent seizures induced by cortical iron injection: a model of posttraumatic epilepsy. Ann Neurol 1978;4:329336.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30. Kabuto H, Yokoi I, Habu H, et al. Reduction in nitric oxide synthase activity with development of an epileptogenic focus induced by ferric chloride in the rat brain. Epilepsy Res 1996;25:6568.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31. Algattas H, Huang JH. Traumatic brain injury pathophysiology and treatments: early, intermediate, and late phases post-injury. Int J Mol Sci 2013;15:309341.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32. Olszewska DA, Costello DJ. Assessment of the usefulness of magnetic resonance brain imaging in patients presenting with acute seizures. Ir J Med Sci 2014;183:621624.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33. Messori A, Polonara G, Carle F, et al. Predicting posttraumatic epilepsy with MRI: prospective longitudinal morphologic study in adults. Epilepsia 2005;46:14721481.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34. Kumar R, Gupta RK, Husain M, et al. Magnetization transfer MR imaging in patients with posttraumatic epilepsy. AJNR Am J Neuroradiol 2003;24:218224.

    • Search Google Scholar
    • Export Citation
  • 35. Schierhout G, Roberts I. Prophylactic antiepileptic agents after head injury: a systematic review. J Neurol Neurosurg Psychiatry 1998;64:108112.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36. Wang H, Gao J, Lassiter TF, et al. Levetiracetam is neuroprotective in murine models of closed head injury and subarachnoid hemorrhage. Neurocrit Care 2006;5:7178.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37. Zou H, Brayer SW, Hurwitz M, et al. Neuroprotective, neuroplastic, and neurobehavioral effects of daily treatment with levetiracetam in experimental traumatic brain injury. Neurorehabil Neural Repair 2013;27:878888.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38. Shetty AK. Prospects of levetiracetam as a neuroprotective drug against status epilepticus, traumatic brain injury, and stroke. Front Neurol 2013;4:172.

    • Search Google Scholar
    • Export Citation
  • 39. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons, et al. Guidelines for the management of severe traumatic brain injury. XIII. Antiseizure prophylaxis (Erratum published in J Neurotrauma 2008;25:276–278). J Neurotrauma 2007;24:S83S86.

    • Search Google Scholar
    • Export Citation
  • 40. Hung C, Chen JW. Treatment of post-traumatic epilepsy. Curr Treat Options Neurol 2012;14:293306.

  • 41. Larkin M, Meyer RM, Szuflita NS, et al. Post-traumatic, drug-resistant epilepsy and review of seizure control outcomes from blinded, randomized controlled trials of brain stimulation treatments for drug-resistant epilepsy. Cureus 2016;8:e744.

    • Search Google Scholar
    • Export Citation
  • 42. Delk K. Clinical management of seizures in avian patients. J Exot Pet Med 2012;21:132139.

  • 43. Orosz SE, Antinoff N. Clinical avian neurology and neuroanatomy. In: Speer BL, ed. Current therapy in avian medicine and surgery. St Louis: Elsevier, 2016;363377.

    • Search Google Scholar
    • Export Citation
  • 44. Powers LV, Papich MG. Pharmacokinetics of orally administered phenobarbital in African grey parrots (Psittacus erithacus erithacus). J Vet Pharmacol Ther 2011;34:615617.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45. Schnellbacher R, Beaufrère H, Vet DM, et al. Pharmacokinetics of levetiracetam in healthy Hispaniolan Amazon parrots (Amazona ventralis) after oral administration of a single dose. J Avian Med Surg 2014;28:193200.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 46. Baine K, Jones MP, Cox S, et al. Pharmacokinetics of compounded intravenous and oral gabapentin in Hispaniolan Amazon parrots (Amazona ventralis). J Avian Med Surg 2015;29:165173.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 47. Bowles HL. Management with potassium bromide of seizures of undetermined origin in an umbrella cockatoo. Exotic DVM 2003;5:78.

  • 48. Hess L. Corticosteroid synthesis and metabolism in birds. Semin Avian Exot Pet 2002;11:6570.

  • 49. Gao S, Sanchez C, Deviche PJ. Corticosterone rapidly suppresses innate immune activity in the house sparrow (Passer domesticus). J Exp Biol 2017;220:322327.

    • Search Google Scholar
    • Export Citation
  • 50. Scharfman HE, MacLusky NJ. The influence of gonadal hormones on neuronal excitability, seizures, and epilepsy in the female. Epilepsia 2006;47:14231440.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 51. Van Meervenne SA, Volk HA, Matiasek K, et al. The influence of sex hormones on seizures in dogs and humans. Vet J 2014;201:1520.

  • 52. Taubøll E, Sveberg L, Svalheim S. Interactions between hormones and epilepsy. Seizure 2015;28:311.

  • Figure 1—

    T2-weighted FSE (first and second [left-most] columns), T-2 weighted FLAIR (third column), and T1-weighted FSE (fourth [right-most] column) MRI sequences obtained in the dorsal (first column) and transverse (second, third, and fourth columns) planes at the level of the midportion of the pallium (row A), ventral portion of the pallium (row B), and midbrain (row C) of a 13-year-old female white-crowned pionus (Pionus senilis) that was examined because of seizures 22 months after it was treated for a TBI. Images reveal evidence of right pallial atrophy (arrowheads), a small skull fracture (open arrow; row A), vasogenic edema or gliosis (dashed circles; row C), and multifocal sites of hydrocephalus ex vacuo (white arrows). The mesencephalic tectal ventricles (open arrows; row C) were dilated bilaterally, the right ventricle was dilated more than the left ventricle. Findings were most consistent with a diagnosis of PTS. The right side is to the left in all images.

  • Figure 2—

    Photograph of a transverse section of the brain of the pionus of Figure 1. Notice that the right (R) cerebral hemisphere is smaller than the left (L) cerebral hemisphere owing to pallial atrophy. Gross findings for the brain were consistent with the MRI findings described in Figure 1.

  • Figure 3—

    Photomicrographs of sections of the left (histologically normal; A) and right (atrophied; B) cerebral hemispheres of the pionus of Figure 1. Notice that the right cerebral hemisphere has less neuropil and more cells than the left cerebral hemisphere. H&E stain; bar = 20 μm.

  • 1. Speer BL. Appendices 2 and 3: normal clinical pathologic data and normal biological data. In: Speer BL, ed. Current therapy in avian medicine and surgery. St Louis: Elsevier, 2016;825879.

    • Search Google Scholar
    • Export Citation
  • 2. Johns JL, Shooshtari MP, Christopher MM. Development of a technique for quantification of reticulocytes and assessment of erythrocyte regenerative capacity in birds. Am J Vet Res 2008;69:10671072.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3. West NH, Langille BL, Jones DR. Cardiovascular system. In: King AS, McLelland J, eds. Form and function in birds. London: Academic Press, 1981;235339.

    • Search Google Scholar
    • Export Citation
  • 4. Campbell TW. Clinical chemistry of birds. In: Thrall MA, Weiser G, Allison R, et al, eds. Veterinary hematology and clinical chemistry. Hoboken, NJ: Wiley-Blackwell, 2012;582598.

    • Search Google Scholar
    • Export Citation
  • 5. Mestres P, Rascher K. The ventricular system of the pigeon brain: a scanning electron microscope study. J Anat 1994;184:3558.

  • 6. Go KG, Hew JM, Kamman RL, et al. Cystic lesions of the brain. A classification based on pathogenesis, with consideration of histological and radiological features. Eur J Radiol 1993;17:6984.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. Kazemi H, Hashemi-Fesharaki S, Razaghi S, et al. Intractable epilepsy and craniocerebral trauma: analysis of 163 patients with blunt and penetrating head injuries sustained in war. Injury 2012;43:21322135.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. Harris TC, de Rooij R, Kuhl E. The shrinking brain: cerebral atrophy following traumatic brain injury. Ann Biomed Eng 2019;47:19411959.

  • 9. Bennett RA. Neurology. In: Ritchie BW, Harrison GJ, Harrison LR, eds. Avian medicine: principles and application. Lake Worth, Fla: Wingers Publishing, 1994;723747.

    • Search Google Scholar
    • Export Citation
  • 10. Bowles H, Lichtenberger M, Lennox A. Emergency and critical care of pet birds. Vet Clin North Am Exot Anim Pract 2007;10:345394.

  • 11. Beaufrère H, Nevarez J, Gaschen L, et al. Diagnosis of presumed acute ischemic stroke and associated seizure management in a Congo African grey parrot. J Am Vet Med Assoc 2011;239:122128.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12. de Matos R, Morrisey JK. Emergency and critical care of small psittacines and passerines. Semin Avian Exot Pet 2005;14:90105.

  • 13. Wack RF, Lindstrom JG, Graham DL. Internal hydrocephalus in an African Grey parrot. J Assoc Avian Vet 1989;3:9496.

  • 14. Thurber MI, Mans C, Fazio C, et al. Antemortem diagnosis of hydrocephalus in two Congo African grey parrots (Psittacus erithacus erithacus) by means of computed tomography. J Am Vet Med Assoc 2015;246:770776.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15. Latimer KS. Oncology. In: Ritchie BW, Harrison GJ, Harrison LR, eds. Avian medicine: principles and application. Lake Worth, Fla: Wingers Publishing, 1994;640672.

    • Search Google Scholar
    • Export Citation
  • 16. Rosskopf WJ Jr. Common conditions and syndromes of canaries, finches, lories and lorikeets, lovebirds, and macaws. Semin Avian Exot Pet 2003;12:131143.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17. Rosskopf WJ, Woerpel RW. Epilepsy in red lored Amazons, in Proceedings. Assoc Avian Vet 1985;141145.

  • 18. Quesenberry KE, Hillyer EV. Supportive care and emergency therapy. In: Ritchie BW, Harrison GJ, Harrison LR, eds. Avian medicine: principles and application. Lake Worth, Fla: Wingers Publishing, 1994;382416.

    • Search Google Scholar
    • Export Citation
  • 19. Agrawal A, Timothy J, Pandit L, et al. Post-traumatic epilepsy: an overview. Clin Neurol Neurosurg 2006;108:433439.

  • 20. Verellen RM, Cavazos JE. Post-traumatic epilepsy: an overview. Therapy 2010;7:527531.

  • 21. Annegers JF, Hauser WA, Coan SP, et al. A population-based study of seizures after traumatic brain injuries. N Engl J Med 1998;338:2024.

  • 22. Frey LC. Epidemiology of posttraumatic epilepsy: a critical review. Epilepsia 2003;44:1117.

  • 23. Asikainen I, Kaste M, Sarna S. Early and late posttraumatic seizures in traumatic brain injury rehabilitation patients: brain injury factors causing late seizures and influence of seizures on long-term outcome. Epilepsia 1999;40:584589.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24. Englander J, Bushnik T, Duong TT, et al. Analyzing risk factors for late posttraumatic seizures: a prospective, multicenter investigation. Arch Phys Med Rehabil 2003;84:365373.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25. Tubi MA, Lutkenhoff E, Blanco MB, et al. Early seizures and temporal lobe trauma predict post-traumatic epilepsy: a longitudinal study. Neurobiol Dis 2019;123:115121.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26. Friedenberg SG, Butler AL, Wei L, et al. Seizures following head trauma in dogs: 259 cases (1999–2009). J Am Vet Med Assoc 2012;241:14791483.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27. Steinmetz S, Tipold A, Löscher W. Epilepsy after head injury in dogs: a natural model of posttraumatic epilepsy. Epilepsia 2013;54:580588.

  • 28. Grohmann KS, Schmidt MJ, Moritz A, et al. Prevalence of seizures in cats after head trauma. J Am Vet Med Assoc 2012;241:14671470.

  • 29. Willmore LJ, Sypert GW, Munson JB. Recurrent seizures induced by cortical iron injection: a model of posttraumatic epilepsy. Ann Neurol 1978;4:329336.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30. Kabuto H, Yokoi I, Habu H, et al. Reduction in nitric oxide synthase activity with development of an epileptogenic focus induced by ferric chloride in the rat brain. Epilepsy Res 1996;25:6568.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31. Algattas H, Huang JH. Traumatic brain injury pathophysiology and treatments: early, intermediate, and late phases post-injury. Int J Mol Sci 2013;15:309341.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32. Olszewska DA, Costello DJ. Assessment of the usefulness of magnetic resonance brain imaging in patients presenting with acute seizures. Ir J Med Sci 2014;183:621624.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33. Messori A, Polonara G, Carle F, et al. Predicting posttraumatic epilepsy with MRI: prospective longitudinal morphologic study in adults. Epilepsia 2005;46:14721481.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34. Kumar R, Gupta RK, Husain M, et al. Magnetization transfer MR imaging in patients with posttraumatic epilepsy. AJNR Am J Neuroradiol 2003;24:218224.

    • Search Google Scholar
    • Export Citation
  • 35. Schierhout G, Roberts I. Prophylactic antiepileptic agents after head injury: a systematic review. J Neurol Neurosurg Psychiatry 1998;64:108112.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36. Wang H, Gao J, Lassiter TF, et al. Levetiracetam is neuroprotective in murine models of closed head injury and subarachnoid hemorrhage. Neurocrit Care 2006;5:7178.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37. Zou H, Brayer SW, Hurwitz M, et al. Neuroprotective, neuroplastic, and neurobehavioral effects of daily treatment with levetiracetam in experimental traumatic brain injury. Neurorehabil Neural Repair 2013;27:878888.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38. Shetty AK. Prospects of levetiracetam as a neuroprotective drug against status epilepticus, traumatic brain injury, and stroke. Front Neurol 2013;4:172.

    • Search Google Scholar
    • Export Citation
  • 39. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons, et al. Guidelines for the management of severe traumatic brain injury. XIII. Antiseizure prophylaxis (Erratum published in J Neurotrauma 2008;25:276–278). J Neurotrauma 2007;24:S83S86.

    • Search Google Scholar
    • Export Citation
  • 40. Hung C, Chen JW. Treatment of post-traumatic epilepsy. Curr Treat Options Neurol 2012;14:293306.

  • 41. Larkin M, Meyer RM, Szuflita NS, et al. Post-traumatic, drug-resistant epilepsy and review of seizure control outcomes from blinded, randomized controlled trials of brain stimulation treatments for drug-resistant epilepsy. Cureus 2016;8:e744.

    • Search Google Scholar
    • Export Citation
  • 42. Delk K. Clinical management of seizures in avian patients. J Exot Pet Med 2012;21:132139.

  • 43. Orosz SE, Antinoff N. Clinical avian neurology and neuroanatomy. In: Speer BL, ed. Current therapy in avian medicine and surgery. St Louis: Elsevier, 2016;363377.

    • Search Google Scholar
    • Export Citation
  • 44. Powers LV, Papich MG. Pharmacokinetics of orally administered phenobarbital in African grey parrots (Psittacus erithacus erithacus). J Vet Pharmacol Ther 2011;34:615617.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45. Schnellbacher R, Beaufrère H, Vet DM, et al. Pharmacokinetics of levetiracetam in healthy Hispaniolan Amazon parrots (Amazona ventralis) after oral administration of a single dose. J Avian Med Surg 2014;28:193200.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 46. Baine K, Jones MP, Cox S, et al. Pharmacokinetics of compounded intravenous and oral gabapentin in Hispaniolan Amazon parrots (Amazona ventralis). J Avian Med Surg 2015;29:165173.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 47. Bowles HL. Management with potassium bromide of seizures of undetermined origin in an umbrella cockatoo. Exotic DVM 2003;5:78.

  • 48. Hess L. Corticosteroid synthesis and metabolism in birds. Semin Avian Exot Pet 2002;11:6570.

  • 49. Gao S, Sanchez C, Deviche PJ. Corticosterone rapidly suppresses innate immune activity in the house sparrow (Passer domesticus). J Exp Biol 2017;220:322327.

    • Search Google Scholar
    • Export Citation
  • 50. Scharfman HE, MacLusky NJ. The influence of gonadal hormones on neuronal excitability, seizures, and epilepsy in the female. Epilepsia 2006;47:14231440.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 51. Van Meervenne SA, Volk HA, Matiasek K, et al. The influence of sex hormones on seizures in dogs and humans. Vet J 2014;201:1520.

  • 52. Taubøll E, Sveberg L, Svalheim S. Interactions between hormones and epilepsy. Seizure 2015;28:311.

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