Feline hippocampal and piriform lobe necrosis as a consequence of severe cluster seizures in two cats in Finland
© Fors et al. 2015
Received: 12 November 2014
Accepted: 23 June 2015
Published: 28 July 2015
Feline hippocampal and piriform lobe necrosis (FHN) has been reported from several countries worldwide and is considered an important aetiology for feline epileptic seizures. The aetiology of FHN remains unclear, however it is suspected that FHN might occur secondary to intense epileptic activity as described in humans and dogs although this has not yet been documented in cats. The purpose of our report is to describe the first cases of FHN in Finland diagnosed by magnetic resonance imaging (MRI) and histopathology. The two cases we describe had a well documented history of pre-existing seizures with normal brain MRI at the onset of cluster seizures but MRI done when the cats exhibited clinical deterioration secondary to severe seizure activity, revealed lesions in the hippocampus and piriform lobes typical of FHN. Our report confirms that feline hippocampus and piriform lobe necrosis does occur in the Finnish cat population and should therefore be considered as a differential diagnosis in cats with seizures. In addition, the presentation, clinical findings, results of MRI and/or histopathology shows that cats may develop FHN secondary to severe seizure activity.
KeywordsEpilepsy Cat Hippocampal necrosis Seizure
Feline hippocampal necrosis (FHN), also known as necrosis of the hippocampus and piriform lobe, is recognized in several countries worldwide, with reports from Switzerland, Italy, Austria, United Kingdom, USA and Australia among others, and is considered an important aetiology for seizures [1–7], especially in feline complex partial seizures with orofacial automatism associated with hippocampal necrosis (FEPSO-HN) . Interictal behavioural changes are regularly seen in addition to the seizures [1–4, 8]. A presumptive diagnosis of feline hippocampal necrosis can be made with magnetic resonance imaging (MRI) in vivo [3, 4, 8, 9] and is characterized by bilateral lesions in the hippocampus and occasionally in the piriform lobe, and the final diagnosis is confirmed by histopathology; with lesions consisting of acute neuronal degeneration and evolving to complete necrosis mainly in the pyramidal layer and occasionally the dentate gyrus of the hippocampus [1–3].
Feline hippocampal necrosis appears to have a diverse aetiology, with a presumable environmental or toxic aetiology suspected in early reports [1–3]. Later reports have described FHN as a consequence of auto-immune inflammation (limbic encephalitis) , together with neoplasia, a so called dual-pathology  and vascular aetiology has been suggested [11, 12]. Recently, FHN as a consequence of seizures has been hypothesized [5, 8].
The first purpose of this retrospective case study is to demonstrate that FHN occurs in Finland. The second purpose is to report that cats with hippocampal lesions typical for FHN at necropsy and/or MRI can have a longer history of seizures with normal MRI at the onset of cluster seizures, indicating that FHN may develop secondary to severe seizure activity in cats.
Summary of selected material, methods and results not mentioned in the text for two cats with FHN
Haematology and serum biochemistry profile normal, CSF normal
Haematology and serum biochemistry profile normal, EEGd-no epileptic activity
EEGd (2nd exam): duration 39 min 55 s; continuous short paroxysms and spikes at the C3 electrode
2nd exam: medetomidineª 75 µg/kg
1st exam: phenobarbitalb 10 + 4 + 4 mg/kg IV, diazepamc 0.5 mg/kg IV, medetomidinea 40 µg/kg intramuscular
IM, phenobarbitalb 10 mg/kg IV
2nd exam: medetomidinea 30 µg/kg IM, diazepamc 0.5 mg/kg IV and phenobarbitalb 6 mg/kg IV
At home treatment
Diazepam 0.6 mg/kg twice daily (BID) orally (PO) was started the day prior to referral
Phenobarbitalb 3 mg/kg BID PO prior to referral
Phenobarbitalb 1.9 mg/kg BID PO, increased to 3.8 mg/kg BID after 2 months
Summary of methods: anaesthesia, MRI sequences, imaging parameters and contrast media for two cats with FHN
Anaesthesia for MRI
Medetomidinea 75 µg/kg IM, propofolb IV isofluranec, O2
Medetomidinea 30 µg/kg IM, propofolb IV isofluranec, O2
MRI equipment and positioning
0.2 T Vet-MR, Esaote S.p.A, Genoa, Italy) with the cat placed in sternal recumbency in a human knee coil
0.2 T Vet-MR, Esaote S.p.A, Genoa, Italy) with the cat placed in sternal recumbency in a human knee coil
MRI sequences and imaging parameters and contrast media 1st examination
Pre-and post-contrast T1W trans (TR 460 ms, TE 18 ms, acquisition matrix 256 × 192, FOV 150 × 150 mm, slice thickness 4.5 mm, interslice gap 0.4 mm)
Pre-and post-contrast T1W trans (TR 750 ms, TE 26 ms, matrix 256 × 192, FOV 140 × 140 mm, slice thickness 3.5 mm, interslice gap 0.3 mm)
T2W trans and sag (TR 2,600 ms, TE 90 ms, acquisition matrix 192 × 192, FOV 130 × 130 mm, slice thickness 4.5 mm, interslice gap 0.4 mm)
T2W trans and sag (TR 3,000 ms, TE 90 ms, acquisition matrix 256 × 192, FOV 170 × 170 mm, slice thickness 3.5 mm, interslice gap 0.3 mm)
Gadopentetd 0.1 mmol/kg IV
Gadopentetd 0.1 mmol/kg IV
MRI sequences and imaging parameters and contrast media 2nd examination
Pre-contrast T1W trans (TR 750 ms, TE 26 ms, acquisition matrix 256 × 192, FOV 170 × 170 mm, slice thickness 4.0 mm, interslice gap 0.4 mm)
Pre- and post-contrast T1W trans (TR 800 ms, TE 26 ms, acquisition matrix 256 × 192, FOV 170 × 170 mm, slice thickness 4.0 mm, interslice gap 0.4 mm)
Post-contrast T1W trans (TR 750 ms, TE 26 ms, acquisition matrix 256 × 192, FOV 170 × 170 mm, slice thickness 4.0 mm, interslice gap 0.4 mm) dors (TR 600 ms, TE 26 ms, acquisition matrix 256 × 192, FOV 180 × 180 mm, slice thickness 4.0 mm, interslice gap 0.4 mm)
T2W trans and sag (TR 3,000 ms, TE 80 ms, acquisition matrix 256 × 192, FOV 180 × 180 mm, slice thickness 4.0 mm, interslice gap 0.4 mm)
T2W trans (TR 3,000 ms, TE 80 ms, acquisition matrix 192 × 192, FOV 180 × 180 mm, slice thickness 4.0 mm, interslice gap 0.4 mm) and sag (TR 3,000 ms, TE 90 ms, acquisition matrix 192 × 192, FOV 170 × 170 mm, slice thickness 4.0 mm, interslice gap 0.4 mm)
FLAIR trans and dors (TR 5,100 ms, TE 80 ms, acquisition matrix 288 × 192, FOV 220 × 220 mm, slice thickness 4.0 mm, interslice gap 0.4 mm)
FLAIR dors (TR 2,000 ms, TE 80 ms, acquisition matrix 256 × 192, FOV 200 × 200 mm, slice thickness 4.0 mm, interslice gap 0.4 mm)
Gadopentetd 0.1 mmol/kg IV
Gadopentetd 0.1 mmol/kg IV
A 2 years and 2-month-old male neutered (MN) domestic shorthaired cat (DSH) was referred because of generalized tonic–clonic epileptic seizures which started 10 days prior to referral. The cat had experienced four seizures within 24 h, the last seizure had occurred within hours at the time of presentation and treatment with diazepam was given the day prior to referral. There was no previous medical history of seizures.
Magnetic resonance imaging findings consisted of moderate bilateral symmetric T2 hyperintensity and T1-hypointensity of the hippocampus and piriform lobe, no mass effect was evident. Marked bilateral hyperintensity of the hippocampus was recognized in FLAIR and mild contrast enhancement bilaterally in the hippocampus in T1W post-contrast, in accordance with a presumed ante-mortem diagnosis of FHN (Figure 4e–h) [3, 4, 8, 9]. The cat was euthanized. Necropsy was declined by the owner and not performed in this case.
The two cats described here constitute the first reported cases of FHN from Finland. This verifies that FHN also occurs in Finland and should be considered as a differential diagnosis in cats with epilepsy. The clinical presentation with acute onset of severe cluster seizure (CS) activity, abnormal menace responses, abnormal behaviour and abnormal mentation, together with the results of follow-up MRI of the brain as well as the neuropathological findings reported here are identical to what has been reported earlier in cats with necrosis of the hippocampus and piriform lobe [1–3, 8, 9]. However, both of the cats reported here had a well-documented history of pre-existing sporadic seizures, of 32 months and 7 months duration respectively, before onset of severe CS activity. In case 1 the MRI done at the initial examination at seizure onset was normal, but when the cat returned with severe cluster seizures after 32 months the MRI was consistent with hippocampal and piriform lobe pathology, and the diagnosis of FHN was confirmed by histopathology. In case 2 no MRI was performed at the referring clinic at the first onset of sporadic seizures, but at the first consultation in AISTI 7 months later the initial MRI was interpreted as normal. The second MRI 4 days later after onset of severe seizure activity indicated hippocampal pathology, possibly FHN. This suggests that in both cats hippocampal pathology might have been secondary to severe seizures, although it cannot be excluded that FHN was already present at the first MRI, and may have progressed over time during the course of seizure disease, and lesions were too subtle for detecting initially. As the MRI findings are not exclusive for FHN: oedema, perfusion change, vasodilatation and blood–brain barrier alteration could not be ruled out as possible lesions leading to the described MRI changes, especially in absence of histopathology. In case 2 no post-mortem examination was allowed and the presumed FHN could not be confirmed by histology.
FHN has for a long time been accepted as a cause of seizures in cats, with a presumable environmental or toxic aetiology [1–3]. Later reports have described FHN together with neoplasia, a so called dual-pathology  or as a consequence of auto-immune inflammation (limbic encephalitis) . Recently, FHN as a consequence of seizures has been hypothesized [5, 8]. To the authors’ knowledge, these are the first reports of cats with FHN having a normal MRI at onset of sporadic seizures and abnormal MRI at follow-up after experiencing severe cluster seizures indicating these seizures, as a possible cause for the development of subsequent FHN.
A proposed pathological mechanism preceding hippocampal necrosis is endogenous or exogenous excitotoxicity, a pathological process where neurons are damaged and/or killed by glutamate, the main excitatory neurotransmitter in the brain [13–15], or related substances. The consequence of excitotoxicity-mediated neuronal injury is selective hippocampal neuronal loss of primarily CA1 and CA3 pyramidal cells. None of the cats described in this report had any evidence of exposure to toxins. They lived primarily indoors, and other cats in the same household, exposed to the same environmental factors, remained healthy throughout the observation period. This suggests that environmental toxins are a less likely cause of FHN in the animals described here. In addition excessive glutamate concentrations and secondary endogenous excitotoxicity-mediated neuronal injury can be seen as a consequence to incidences such as head trauma, ischemia/hypoxia and hypoglycaemia [13–15]. No evidence of any traumatic, ischemic/hypoxic event or hypoglycaemia was present in the two cats making those factors unlikely to be the cause of FHN.
Dual pathology is a situation where FHN is accompanied by an additional extra-hippocampal brain lesion acting as an epileptic focus causing hippocampal sclerosis, or co-existing with the hippocampal lesion. There is one case report in the literature of a cat with FHN and an oligodendroglioma in the piriform lobe . Dual pathology cannot be entirely ruled out in the cats described here but it is unlikely that a second lesion would go undetected by MRI and/or necropsy in both cases.
Suspected autoimmune limbic encephalitis (LE) associated with voltage-gated potassium channel complex antibodies resulting in hippocampal pathology in 14 cats with FEPSO-HN was recently described [9, 16]. Necropsy was available in one cat and lesions consisted of hippocampal necrosis . The triggering factor for the immune-mediated process is under investigation. A positive response to immunosuppressive doses of prednisolone and antiepileptic therapy was noted in the majority of cases with full remission of signs. In case 1, LE cannot be completely excluded due to mild lymphoplasmacytic and histiocytic cuffing around blood vessels, a feature that has been described in previous reports of FHN [1–3]. No additional testing for auto-antibodies was available at the time of the case. Whether LE could be present or not in case 2 is not possible to discuss in the absence of post-mortem examination.
Necrosis of the hippocampus is described in humans [17–19] and in dogs [20–25] as a sequela to status epilepticus and/or cluster seizures, with both typical MRI changes and histopathology resembling the changes reported for cats with confirmed FHN [3, 4, 8, 9]. A well-known dilemma in humans is whether brain lesions in the postictal period are the cause or the consequence of the seizures. In humans it is also known that seizures or status epilepticus also can induce reversible, completely or incompletely, abnormalities in the brain [26–28]. These matters has not been analysed in cats but it must be taken into consideration that the same situation may be true. Cases 1 and 2, although having normal first MRI at onset of cluster seizures, showed those typical hippocampal changes on MRI later in the course of the disease after worsening of CS, indicating that lesion may be seizure-induced but it cannot be excluded that both cats may have developed FHN for unrelated reasons. Also, histological findings in case 1 were consistent with what has been described earlier in FHN and in seizure-induced lesions reported in humans and dogs [17–25, 29].
There is only limited data available on EEG in cats with naturally occurring seizures. Brauer et al.  did find generalized spikes as an EEG abnormality at maximum voltage in one of three cats with a presumptive diagnosis of hippocampal necrosis. Pakozdy  described synchronous discharges in a cat with seizures due to limbic encephalitis. The changes started in the occipital region and spread to the ipsilateral frontal and contralateral occipital region, presumably representing a subclinical partial epileptic seizure. Interestingly a convincing association between ictal semiology and limbic localization could not be confirmed by EEG in case number 1. Epileptic activity in this cat was recognized in the C3 region; placed caudo-dorsally and centrally over brain, representing the left occipital lobe, as the placement of electrodes was done resembling the 10–20 international system for humans, and not over the temporal-parietal region. This indicates that seizures might have been originating from an extra-hippocampal region, and could strengthen the hypothesis that the hippocampal changes are consequence and not cause of the seizures, although the representation of the superficial EEG may differ from the epileptic activity of deeper situated structures depending on the propagation of the seizure.
Feline hippocampal necrosis appears to have a heterogeneous aetiology and may be the consequence as well as the cause of seizures in some individuals. Our findings that cats with FHN can have a longer history of seizures preceding acute cluster seizures or status epilepticus and subsequently develop FHN, could lead to the conclusion that intense seizure activity can lead to FHN in some cats. A possible explanation why FHN as a consequence of seizures has not been reported earlier may be that cats in general are less susceptible to seizure-induced neuronal injury than other species . However, ischemic injury compatible with the changes found in cats with FHN are found in experimental global cerebral ischemia . Another potential reason why previously reported cases of FHN have no history of seizures preceding development of hippocampal necrosis may be that the first (often focal) seizures have not been witnessed by the owner, as many cats are living partly outdoors and/or without constant supervision. The accuracy of history can be low in such cases and cats may therefore falsely been classified as healthy prior to/until the diagnosis of FHN. A third reason might be the lack of initial and/or follow up MRI in the majority of feline patients.
Our findings that cats with FHN can have a longer history of seizures preceding acute CSs or SE and subsequent development of FHN suggest that intense seizure activity can lead to FHN in some cats. Cats with changes typical for FHN at necropsy and/or MRI may have a longer history with preceding epileptic seizures before onset of severe cluster seizures or status epilepticus. The presentation, results of MRI and histopathology suggest that cats may develop FHN secondary to severe seizure activity. Feline hippocampal necrosis occurs in Finland and should be considered a differential diagnosis in epileptic cats.
Written informed consent was obtained from the owners of the cats for publication of this case report and any accompanying images. A copy of the written consents is available for review by the Editor-in-Chief of this journal on request.
SF and SVM drafted the manuscript and SF, JJ, MR and SC were all involved in the clinical procedures concerning the cases. All authors read and approved the final manuscript.
Karin Hultin Jäderlund (PhD, DECVN) is kindly acknowledged for valuable comments on the manuscript. Prof. Dr. Kaspar Matiasek is kindly acknowledged for assisting with neuropathology and photomicrographs in case 1.
Compliance with ethical guidelines
Competing interests The authors declare that they have no competing interests.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Fatzer R, Gandini G, Jaggy A, Doherr M, Vandevelde M (2000) Necrosis of hippocampus and piriform lobe in 38 domestic cats with seizures: a retrospective study on clinical and pathologic findings. J Vet Intern Med 14:100–104PubMedView ArticleGoogle Scholar
- Brini E, Gandini G, Crescio I, Fatzer R, Casalone C (2004) Necrosis of hippocampus and piriform lobe: clinical and neuropathological findings in two Italian cats. J Feline Med Surg 6:377–381PubMedView ArticleGoogle Scholar
- Schmied O, Scharf G, Hilbe M, Michal U, Tomsa K, Steffen F (2008) Magnetic resonance imaging of feline hippocampal necrosis. Vet Radiol Ultrasound 49:343–349PubMedView ArticleGoogle Scholar
- Pakozdy A, Leschnik M, Sarchahi AA, Tichy AG, Thalhammer JG (2010) Clinical comparison of primary versus secondary epilepsy in 125 cats. J Feline Med Surg 12:910–916PubMedView ArticleGoogle Scholar
- Marioni-Henry K, Monteiro R, Behr S (2012) Complex partial orofacial seizures in English cats. Vet Rec 170:471PubMedView ArticleGoogle Scholar
- Gelberg HB (2013) Sudden behavior change in a cat. Vet Pathol 50:1156–1157PubMedView ArticleGoogle Scholar
- Adagra C, Piripi SA (2014) Hippocampal necrosis in a cat from Australia. Case Rep Vet Med. doi:https://doi.org/10.1155/2014/306789 Google Scholar
- Pakozdy A, Gruber A, Kneissl S, Leschnik M, Halasz P, Thalhammer JG (2011) Complex partial cluster seizures in cats with orofacial involvement? J Feline Med Surg 13:687–693PubMedView ArticleGoogle Scholar
- Pakozdy A, Halasz P, Klang A, Bauer J, Leschnik M, Tichy A et al (2013) Suspected limbic encephalitis and seizure in cats associated with voltage-gated potassium channel (VGKC) complex antibody. J Vet Intern Med 27:212–214PubMedView ArticleGoogle Scholar
- Vanhaesebrouck AE, Posch B, Baker S, Plessas IN, Palmer AC, Constantino-Casas F (2012) Temporal lobe epilepsy in a cat with a piriform lobe oligodendroglioma and hippocampal necrosis. J Feline Med Surg 14:932–937PubMedView ArticleGoogle Scholar
- Altay UM, Skerrit GC, Hilbe M, Ehrensperger F, Steffen F (2011) Feline cerebrovascular disease: clinical and histopathologic findings in 16 cats. J Am Anim Hosp Assoc 47:89–97PubMedView ArticleGoogle Scholar
- Jurk IR, Thibodeau MS, Whitney K, Gilger BC, Davidson MG (2001) Acute vision loss after general anesthesia in a cat. Vet Ophthalmol 4:155–158PubMedView ArticleGoogle Scholar
- Meldrum BS (2000) Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J Nutr 130:1007S–1015SPubMedGoogle Scholar
- Mark LP, Prost RW, Ulmer JL, Smith MM, Daniels DL, Strottmann JM et al (2001) Pictorial review of glutamate excitotoxicity: fundamental concepts for neuroimaging. AJNR Am J Neuroradiol 22:1813–1824PubMedGoogle Scholar
- Silvagni PA, Lowenstine LJ, Spraker T, Lipscomb TP, Gulland FMD (2005) Pathology of domoic acid toxicity in california sea lions (Zalophus Californianus). Vet Pathol 42:184–191PubMedView ArticleGoogle Scholar
- Pakozdy A, Halasz P, Klang A (2014) Epilepsy in cats: theory and practice. J Vet Intern Med 28:255–263PubMedView ArticleGoogle Scholar
- Wasterlain CG, Fujikawa DG, Penix L, Sankar R (1993) Pathophysiological mechanisms of brain damage from status epilepticus. Epilepsia 34(Suppl 1):S37–S53PubMedView ArticleGoogle Scholar
- DeGiorgio CM, Tomiyasu U, Gott PS, Treiman DM (1992) Hippocampal pyramidal cell loss in human status epilepticus. Epilepsia 33:23–27PubMedView ArticleGoogle Scholar
- Fujikawa DG, Itabashi HH, Wu A, Shinmei SS (2000) Status epilepticus-induced neuronal loss in humans without systemic complications or epilepsy. Epilepsia 41:981–991PubMedView ArticleGoogle Scholar
- Andersson B, Olsson SE (1959) Epilepsy in a dog with extensive bilateral damage to the hippocampus. Acta Vet Scand 1:98–104Google Scholar
- Montgomery DL, Lee AC (1983) Brain damage in the epileptic beagle dog. Vet Pathol 20:160–169PubMedGoogle Scholar
- Yamasaki H, Furuoka H, Takechi M, Itakura C (1991) Neuronal loss and gliosis in limbic system in an epileptic dog. Vet Pathol 28:540–542PubMedView ArticleGoogle Scholar
- Mellema LM, Koblik PD, Kortz GD, LeCouteur RA, Chechowitz MA, Dickinson PJ (1999) Reversible magnetic resonance imaging abnormalities in dogs following seizures. Vet Radiol Ultrasound 40:588–595PubMedView ArticleGoogle Scholar
- Hasegawa D, Fujita M, Nakamura S, Takahashi K, Orima H (2002) Electrocorticographic and histological findings in a shetland sheepdog with intractable epilepsy. J Vet Med Sci 64:277–279PubMedView ArticleGoogle Scholar
- Hasegawa D, Nakamura S, Fujita M, Takahashi K, Orima H (2005) A dog showing Klüver–Bucy syndome-like behavior and bilateral limbic necrosis after status epilepticus. Vet Neurol Neurosurg J 7:1–14Google Scholar
- Cianfoni A, Caulo M, Cerase A, Della Marca G, Falcone C, Di Lella GM et al (2013) Seizure-induced brain lesions: a wide spectrum of variably reversible MRI abnormalities. Eur J Radiol 82:1964–1972PubMedView ArticleGoogle Scholar
- McNamara JO (1994) Cellular and molecular basis of epilepsy. J Neurosci 14:3413–3425PubMedGoogle Scholar
- Jefferys JGR (1999) Hippocampal sclerosis and temporal lobe epilepsy: cause or consequence? Brain 122:1007–1008PubMedView ArticleGoogle Scholar
- Briellman RS, Wellard RM, Jackson GD (2005) Seizure-associated abnormalities in epilepsy: evidence from MR imaging. Epilepsia 46:760–766View ArticleGoogle Scholar
- Brauer C, Kästner SB, Kulka AM, Tipold A (2012) Activation procedures in the electroencephalograms of healthy and epileptic cats under propofol anaesthesia. Vet Rec 170:360PubMedView ArticleGoogle Scholar
- Pakozdy A, Glantschnigg U, Leschnik M, Hechinger H, Moloney T, Lang B et al (2014) EEG-confirmed epileptic activity in a cat with VGKCcomplex/LGI1 antibody-associated limbic encephalitis. Epileptic Disord 16:116–1120PubMedGoogle Scholar
- Poncelet L (2011) Epileptic brain damage in dogs and cats: myth or reality? Vet Rec 169:359–360PubMedView ArticleGoogle Scholar
- Schmidt-Kastner R, Ophoff BG, Hossmann KA (1990) Pattern of neuronal vulnerability in the cat hippocampus after one hour of global cerebral ischemia. Acta Neuropathol 79:444–455PubMedView ArticleGoogle Scholar