A Novel Idiopathic Superficial Neocortical Degeneration and Atrophy in

Young Adult Dogs

S. D. Cahalan1, R. Cappello2, A. de Lahunta3, and B. A. Summers1

Veterinary Pathology 2015, Vol. 52(2) 344-350 The Author(s) 2014 Reprints and
permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0300985814531498
vet.sagepub.com

Abstract

A diffuse, chronic, superficial neocortical degeneration that resulted in atrophy was detected in
five 1 to 2-year-old-dogs. Presenting neurologic signs included ataxia, dysphagia, blindness, and
mentation changes. Magnetic resonance imaging on brains from 2 dogs demonstrated severe
bilateral cerebrocortical atrophy and enlarged lateral and third ventricles. Grossly, multifocal,
bilaterally symmetrical, extensive areas of neocortical brownish discoloration associated with
atrophy of gyri and sulcal widening were recorded in the dorsal and lateral cerebral hemispheres
in 3 dogs. Microscopically, in all dogs there was subacute to chronic superficial neocortical
degeneration affecting all cerebral lobes, ranging from loss of the molecular layer to less frequent
larger and deeper cavitations of variable size. Clinical signs probably resulted from a
combination of primary neocortical degeneration and secondary degeneration in the
corticobulbar and corticospinal tracts. The distribution pattern of gross and histologic
cerebrocortical lesions suggests that this is a novel degenerative canine cerebral disease.

Keywords brain, canines, cortical atrophy, dog, neocortex, degeneration

Cerebrocortical necrosis and atrophy in dogs have been diagnosed as idiopathic8,13 or

associatedwithleadpoisoning,17
cyanidepoisoning,9thiaminedeficiency,15cardiacarrest,14hypoglycaemia,10cranialtrauma,12foll
owingseizures,2,11orasacomponent of potentially hereditary degenerative central nervous
system(CNS)disease.1,3,4,6Typically,neuronaldegenerationand loss involve several laminae of
the neocortex, sometimes resultinginfull-thicknessnecrosis.Incontrast,theidiopathicsyndrome that
we report here is characterized by very superficial (but occasionally deeper) neocortical
degeneration and atrophy, encountered in 5 dogs in North America and the United Kingdom.

Materials and Methods

Four cases were in the personal collection of B.A.S., acquired from submissions to Cornell
University College of Veterinary Medicine, Ithaca, New York (19822006). A fifth case was
submitted to the necropsy service of the Royal Veterinary College, London, in 2012.
Clinical Histories and Examination

Case no. 1, a 2-year-old intact female Scottish deerhound, was electively euthanized following a
3-month history of progressive neurologic abnormalities, including staggering gait,
hyperextension of the thoracic limbs when walking, reduced proprioception especially on the
right side, knuckling of left thoracic limb, andoften behaving as if blind. The dog developed
difficulty eating and drinking 2 weeks prior to elective euthanasia Case no. 2, a 1-year-old male
neutered Great Dane, presented with a 4-week history of gradual onset of neurologic
abnormalities. He was first noted to have problems getting up and down stairs; over the
following 3 weeks, he became progressively more confused and ataxic. On clinical examination,
he was found to be hyperesthetic with loss of proprioception, mild ataxia, difficulty in
prehending food, and intermittent partial focal seizures involving the jaw and neck. Elective
euthanasia was performed. No clinical history was available for case no. 3. Case no. 4, a 2-year-
old female neutered Toy Poodle, presented with a history of progressive neurologic signs of
approximately 1-year duration. Signs ranged from loss of vision and hearing, self-mutilation,
severe obtundation, and severe aggression. Episodes lasted approximately 5 minutes and had
increased to 1 or 2 episodes per day. On clinical examination, she was depressed and
hyperesthetic, reacting violently to being touched. No menace response, pupillary light response,
or reaction to noise was detected. No hopping or patellar reflexes were elicited. Magnetic
resonance imaging (MRI) of the brain was performed, but details of the sequences are not
available. Elective euthanasia was performed. Case no. 5, a 1.5-year-old female Irish Wolfhound,
was electively euthanized following a 2-month history of progressive ataxia, hypermetria,
blindness, and behavioral changes. Magnetic resonance images were obtained with a 1.5-Tesla
magnet (Philips Acheiva). The following sequences were acquired: T2-weighted, sagittal,
transverse; T1 inversion recovery, transverse; T1 weighted, transverse, dorsal (pre- and
postcontrast); and fluid-attenuated inversion recovery (FLAIR), transverse. For summaries of
cases, see used at 1:100 with epitope retrieval solution 1 (ER-1; low pH) pretreatment. Neuron-
specific enolase was used at 1:200 with ER-1 pretreatment. Vimentin was used at 1:500 with ER-
1 pretreatment. Appropriate positive and negative controls were included. Cerebral tissue from
case No. 5 was formalin fixed and subsequently refixed in glutaraldehyde, postfixed in osmium
tetraoxide, and processed for transmission electron microscopy.

Necropsy and Histopathology

Case Nos. 2 and 4 had a complete necropsy; brain and cervical spinal cord were submitted in
case Nos. 1 and 5; only the brain was submitted for case No. 3. Brains and other tissue samples
were immersion fixed in 10% neutral buffered formalin, and selected samples were embedded in
paraffin, sectioned at 5 mm, and stained with hematoxylin and eosin for initial microscopic
evaluation. In case Nos. 3 and 5, additional stains used were reticulin, Massons trichrome, and
Perls Prussian blue. Formalin-fixed, paraffin-embedded sections from case Nos. 3 and 5 were
mounted on positively charged slides (Superfrost Plus, Menzl-Glaser) and immunolabeled for
reactivity to glial fibrillary acidic protein (GFAP; monoclonal antibody, Leica), neuron-specific
enolase (monoclonal antibody, Leica), and vimentin (monoclonal mouse antibody, Dako) through
a peroxidase-based method for indirect immunohistochemistry on a Leica Bondmax autostainer.
Diaminobenzidine chromogen was used for visualization of bound antibodies. GFAP was used at
1:100 with epitope retrieval solution 1 (ER-1; low pH) pretreatment. Neuron-specific enolase
was used at 1:200 with ER-1 pretreatment. Vimentin was used at 1:500 with ER-1 pretreatment.
Appropriate positive and negative controls were included. Cerebral tissue from case No. 5 was
formalin fixed and subsequently refixed in glutaraldehyde, postfixed in osmium tetraoxide, and
processed for transmission electron microscopy.

Results Hematology and Biochemistry

Biochemistry and hematology results were available for dogs Nos. 2, 4 and 5, including serum
resting and postprandial bile acids, and were within normal limits. Case No. 2 tested negative for
serum lead. Thiamine levels of 72.0 ng/ml (reference range, 46112 ng/ml) were detected in case
No. 5.

Serology and Polymerase Chain Reaction

No antibodies to Ehrlichia canis, Rickettsia rickettsii, Neospora caninum, and Toxoplasma gondii
agents were detected in serum from case No. 2. Real-time polymerase chain reaction testing on
cerebrospinal fluid (CSF) from case No. 5 for canine distemper virus, N. caninum, and T. gondii
was negative. CSF from case No. 2 had abnormalities, described as slightly elevated leukocytes
consisting mainly of macrophages and a few lymphocytes and normal protein content. Case No.
5 had increased proteins and a mild eosinophilic pleocytosis.

Magnetic Resonance Imaging

MRI examination was performed on case Nos. 4 and 5. Details are available only for case No. 5
(Figs. 1, 2), in which the T2-weighted images revealed hyperintense signal and widening of the
subarachnoid space overlying the gyri and sulci of the frontal, temporal, and occipital lobes. In a
similar distribution, the T1-weighted and FLAIR images revealed a hypointense (isointense to
the CSF) signal at this level. A thin hyperintense signal rim in the cortical gray matter was
present in the FLAIR sequences (laminar necrosis?). The thalamus (and interthalamic adhesion)
was severely reduced in size, and enlargement of the lateral and third ventricles was present. The
cerebellum did not show structural abnormalities. Postcontrast images revealed patchy irregular
uptake of the neocortical meninges. The images were suggestive of cortical atrophy/necrosis and
atrophy of the corona radiata, thalamus, and brainstem. In summary, MRI in dog Nos. 4 and 5
revealed severe bilateral cerebrocortical atrophy.

Pathologic Findings
Significant gross and histologic lesions were limited to the CNS in each case.

Macroscopic Lesions

In case No. 1, diffuse, markedly reduced neocortical gray matter was noted bilaterally, affecting
the frontal and parietal lobes. A diffusely reddish appearance to cortical gray matter was noted in
cross sections of cerebrum. In case No. 2, on transverse sections of brain, marked bilaterally
symmetrical atrophy affected the neocortex within the frontal, parietal, and temporal lobes of the
rostral two-thirds of the cerebral hemispheres. This lesion was most extensive in the dorsal and
dorsolateral gyri. The piriform lobes were atrophied and flattened with yellow discoloration.
Dense white discoloration was noted of the tracts comprising the crus cerebri, longitudinal fibers
of the pons, pyramids, and the pyramidal decussation. A round white spot was present bilaterally
in the lateral funiculi in the position of the lateral corticospinal tracts of the cervical spinal cord.
No gross report was available for case No. 3. In case No. 4, no gross abnormalities were
observed. In case No. 5, multiple firm adhesions were noted between the cerebral hemispheres
and the overlying dura mater throughout the cerebrum. A subtle patchy surface irregularity to the
rostral two-thirds of the neocortex was noted, most extensively in the dorsal and dorsolateral
gyri. On transverse sections of the brain, bilaterally symmetrical atrophy and patchy yellow
discoloration of the neocortical gray matter of the parietal and temporal lobes were observed
(Fig. 3). The lesions were most extensive in the dorsal and dorsolateral gyri.

Microscopic Lesions

Limited numbers of histology slides were available for examination in each case. Brain (and,
when available, spinal cord) lesions in all cases were of a similar nature and are presented as a
summary. Approximately bilaterally symmetrical degenerative lesions diffusely affected the
cerebral neocortex from the frontal to occipital lobes. These changes affected all surfaces of the
cerebrum but most consistently the dorsal and lateral surfaces. Cerebrocortical degeneration and
atrophy were sufficient to produce widespread marked widening of the sulci (Fig. 4). The
normally smooth, convex cerebrocortical surface was undulating due to superficial tissue loss,
producing scalloping or deeper cavitations, which extended into the molecular layer and
sometimes further (Figs. 5, 6). Areas of neuropil degeneration were pallid and multifocally
showed marked postnecrotic thinning or loss of the molecular layer (lamina 1) and occasional
necrosis and loss of the most superficial neurones. Affected neocortex showed marked superficial
astrogliosis astrocytes appeared activated with enlarged nuclei and expanded cytoplasm. Such
reactive astrocytes were found at all levels of the superficial to middle laminae and in denser
aggregates involving the junction of the white matter. Astrogliosis was evident in GFAP (Fig. 7)
and vimentin stains, mainly in superficial layers with middle to deeper layers largely of the
cerebral injury. Leptomeningeal fibroplasia with moderate collagen deposition and increased
vasculature was seen in case Nos. 3, 4, and 5 (Fig. 10). Involvement of areas of the brain beyond
the neocortex was seen occasionally. More acute lesions were observed in the hippocampal gray
matter of case No. 3 and in the region of the occipital cortex of case No. 5 where prominent
neutrophilic aggregates were noted in the leptomeninges, surrounding unaffected, although
deeper layers were notably affected in case No. 5. Mild neovascularization (capillaries and small
arterioles) was frequently observed in areas of cavitation. A minimal to mild diffuse
leptomeningeal and subarachnoid infiltrate of lymphocytes, plasma cells, and occasional
neutrophils was often observed (Fig. 9), and perivascular cuffing was observed within the
neocortex in case No. 5. Hemosiderinladen macrophages were observed throughout the
meninges in areas of neocortical necrosis in all cases in low to high numbers. Mature, debris-
laden gitter cells within the areas of neocortical loss were only occasional, attesting to the
chronicity small-caliber leptomeningeal vessels lined by prominent endothelial cells and
scattered in areas of necrosis. In case No. 5, focally extensive necrosis of gray matter of the
lateral aspect of the pons was characterized by loosening and rarefaction. Within the
mesencephalon, diffuse subtle mild rarefaction of the superficial parenchyma with mild gliosis
was noted. Similar lesions were observed affecting the gray matter on the surface of the
hypothalamus Gray matter changes were not observed within sections of medulla oblongata and
cerebellum, which were available for case Nos. 2, 3, and 5. White matter degeneration
characterized by myelin sheath ballooning, some loss of axons, rare intramyelinic macrophages,
and astrogliosis was present within the corpus callosum, internal capsule, periventricular white
matter, and bilaterally in the crus cerebri, longitudinal fibers of the pons, and the pyramids. This
was present also in the lateral corticospinal tract in the cervical spinal cord of case Nos. 1, 2, and
5.

Discussion

We describe a novel but rare incapacitating and progressively worsening degenerative disorder of
the CNS affecting young adult female and male dogs (3 were female [1 unknown sex])
presenting between 1 and 2 years of age that we encountered in the United States and the United
Kingdom. Two were Irish Wolfhounds and one was a Scottish Wolfhound, raising the possibility
of an hereditary basis. Onset of neurologic deficits was insidious and progressive, ranging from 1
month to 1 year. Neurologic signs included general proprioceptive and cerebellar ataxia, upper
motor neuron paresis, blindness, and behavioral abnormalities. In addition to the 5 cases
described, a further US case with strikingly similar lesions was assessed; however, signalment
and full case history retrieval was not available, and so it was not included in this report. Clinical
neurologic signs in these dogs indicated multifocal to diffuse CNS disease with likely
involvement of the prosencephalon (seizures, altered sensorium, central visual pathway) and
caudal fossa/spinal cord (difficulty in prehension, general proprioceptive ataxia, and upper motor
neuron paresis). Potential multifocal to widespread CNS disorders that were variously explored
included evaluations for infectious causes of meningoencephalomyelitis, such as canine
distemper, N. caninum, Neorickettsia, and encephalopathies, including lead poisoning, thiamine
deficiency, and portosystemic shunting. Two dogs received MRI evaluations, which identified
the resulting neocortical loss and subarachnoid expansion and will play an important role in the
diagnosis of any further cases. The pattern of superficial cortical degeneration that we report is
very unusual and differs from that commonly observed in cerebrocortical necrosis in dogs (or
other species). Canine cerebrocortical necrosis is typically a sporadic condition occurring either
alone or combined with gray matter lesions at other sites within the brain.4 The cause is
sometimes unknown2,8 or follows cyanide poisoning,9 hypoglycaemia,10 trauma,12 prolonged
hypoxia following cardiac arrest,14 lead poisoning,17 and thiamine deficiency.15
Cerebrocortical necrosis is also reported in disease processes, such as atherosclerosis,
thromboembolism, meningitis,2 infectious canine hepatitis, canine distemper encephalitis,8 and
gastroenteritis7 and in congenital cellular metabolic disorders, as reported in the encephalopathy
of Alaskan Huskies and Yorkshire Terriers.1,4 In contrast to the lesions reported here, in which
necrosis affected mainly superficial cerebrocortical laminae, canine cerebrocortical necrosis in
previously described instances affected deeper laminae.810,12,17 In 1 case of prolonged
hypoxia, all layers of the cerebral cortex were affected.14 In Alaskan Husky encephalopathy,
necrosis variably affected superficial to deep layers of the cerebral cortical laminae with lesions
occurring mainly at the base of the sulci.4 In the cases reported here, gray matter necrosis and
loss were specifically limited to the superficial neocortex, mainly the molecular layer (lamina 1)
affecting the neuropil with occasional neuronal necrosis. Lesions were present in the sulci and
gyri. Subtle gray matter rarefaction, necrosis, and gliosis were observed in areas of the
hypothalamus, mesencephalon, and pons from case Nos. 3 and 5, suggesting that lesions are not
limited to neocortical gray matter in these cases. This raises the possibility of the presence of a
CSF toxin; however, a toxin within the CSF would have access to the ventricles, and no evidence
of ependymal necrosis was noted. We interpret the widespread superficial neocortical
degeneration and loss as the primary lesions with bilateral white matter degeneration a
consequence of diffuse neocortical loss. This degeneration observed grossly in case No. 2 and
otherwise microscopically in the midbrain, pons, medulla, and spinal cord is bilateral and
symmetrical and anatomically consistent with the descending corticobulbar and corticospinal
tracts. These changes reflect degeneration of upper motor neuron axons and concurrently their
myelin sheaths or transsynaptic interneuron loss. The severity of the white matter degeneration
reflects the widespread bilateral neocortical lesion and the chronicity of these changes but is
surprising given their superficial nature. Bilateral and symmetrical CNS lesions in either gray or
white matter or affecting both simultaneously are generally caused by aberrations in global
vascular perfusion (hypoxiaischemia) preferentially affecting areas of highest sensitivity or
associated with metabolic dysfunction due to neurodegenerative disorders or toxicoses. Global
brain ischemia as can occur in cardiac arrest14 and anesthetic accidents targets areas of the
neocortex, hippocampus, and cerebellum. Cerebral circulatory disturbances in humans more
often occur in gray matter at the base of sulci rather than at the crest.5 Our cases showed gray
matter necrosis at the base and crest of sulci, affecting the outermost cortical laminae with
relative sparing of most laminae of neurones. Neocortical necrosis in human cases of cardiac
arrest is most evident in the occipital and parietal lobes where the first and second laminae are
usually preserved. In canine cases of cardiac arrest, all layers of the cerebral cortex are
involved.14 Furthermore, we are unaware of any antecedent events, such as cardiac arrest or
general anesthesia, in these 5 relatively young dogs. In addition, the clinical signs in these dogs
were progressive which would not be expected in most vascular disorders. The possibility of a
hypoxic, late gestation or periparturient injury was entertained, however given the lack of
neurological signs observed in these dogs as juveniles this was considered an unlikely etiology.
Superficial neurodegeneration (in addition to gross infarction) is seen in some cases of feline
ischemic encephalopathy caused by intracranial Cuterebramigration.16 It is presumed that an
excreted parasite product is neurotoxic. While this causes superficial erosive neocortical
degeneration and associated gliosis, lesions are asymmetric and involve the ventricular system
with ependymal loss (presumably, the putative toxin is spread in CSF); these changes are lacking
in these dogs. Superficial astrogliosis accompanied the disruption of the neocortex, well
demonstrated with GFAP and to a lesser degree with vimentin stains, and was evident on
ultrastructural examination. Sometimes astrocytic changes extended more deeply, most notably
in case No. 5, involving the gray-white matter junction, suggesting deeper injury in these
instances. Gitter cells were absent from the parenchyma, but some mononuclear macrophages
contained hemosiderin, attesting to prior hemorrhage. High numbers of neutrophils and lesser
numbers of histiocytes and occasional lymphocytes were observed in acutely affected regions in
case Nos. 3 and 5 within the leptomeninges and subarachnoid space. This is interpreted as
secondary to tissue necrosis. Leptomeningeal fibrosis was sometimes noted also. Intoxication by
an exogenous agent was considered unlikely, given the novel lesions, narrow age range of the
affected dogs, and sporadic occurrence of cases (5 in approximately 30 years). Cerebrocortical
lesions secondary to seizures have been described,11 but seizure activity was reported in only 1
of the 5 dogs in this report. Cortical necrosis, likely seizure induced, is seen in some cases of
canine distemper encephalitis selectively affecting the pyriform lobe and the hippocampus,2 and
it affects middle to deeper laminae of neurons. As 2 dogs were of Irish Wolfhound origin and one
of Scottish Wolfhound origin (related and not exceptionally common breeds), a hereditary basis
for the cases was entertained. Canine CNS disorders of unknown causes that are potentially
inherited and characterized by symmetrical gray matter degeneration and necrosis with neuronal
preservation include a neurodegenerative condition in Australian Cattle dogs,3 familial cerebellar
ataxia with hydrocephalus in Bull Mastiffs,6 and encephalopathy of Alaskan Huskies and
Yorkshire Terriers.1,4 While all these disorders present in early life, they are quite distinct
neuropathologically from the syndrome that we describe herein for which the cause and
pathogenesis remain to be elucidated.

Acknowledgements

We acknowledge the assistance of Professor Ken Smith, Department of Pathology and Pathogen
Biology, Royal Veterinary College, London, in providing support for this article.

Declaration
of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of
this article.

References

Baiker K, Hofmann S, Fischer A, et al. Leigh-like subacute necrotising encephalopathy in

Yorkshire Terriers: neuropathological characterisation, respiratory chain activities and
mitochondrial DNA. Acta Neuropathol. 2009;118:697709. 2. Braund KG, Vandevelde M.
Polioencephalomalacia in the dog. Vet Pathol. 1979;16:661672. 3. Brenner O, de Lahunta A,
Summers BA, et al. Hereditary polioencephalomyelopathy of the Australian cattle dog. Acta
Neuropathol. 1997;94:5466. 4. Brenner O, Wakshlag JJ, Summers BA, et al. Alaskan Husky
encephalopathy: a canine neurodegenerative disorder resembling subacute necrotizing
encephalomyelopathy (Leigh syndrome). Acta Neuropathol. 2000;100:5062. 5. Brierley JB,
Meldrum BS, Brown AW. The threshold and neuropathology of cerebral anoxic-ischemic cell
change. Arch Neurol. 1973;29:367374. 6. Carmichael S, Griffiths IR, Harvey MJ. Familial
cerebellar ataxia with hydrocephalus in bull mastiffs. Vet Rec. 1983;112:354358. 7. Fischer K.
Herdfoermige symmetrische Hirngewebsnekrosenbei Hunden mit epileptiformen Kraempfen.
Vet Pathol. 1964;1: 133160. 8. Hartley WJ. Polioencephalomalacia in dogs. Acta
Neuropathologica. 1963;2:271281. 9. Haymaker W, Ginzler AM, Ferguson RL. Residual
neuropathological effects of cyanide poisoning; a study of the central nervous system of 23 dogs
exposed to cyanide compounds. Mil Surg. 1952;111:231246. 10. Krook L, Kenney RM. Central
nervous system lesions in dogs with metastasizing islet cell carcinoma. Cornell Vet. 1962;52:
385415. 11. Morita T, Shimada A, Takeuchi T, et al. Cliniconeuropathologic findings of familial
frontal lobe epilepsy in Shetland sheepdogs. Can J Vet Res. 2002;66:3541. 12. Palmer AC.The
accident case: IV. The significance and estimation of damage to the central nervous system. J
Small Anim Pract. 1964;5:2533. 13. Palmer AC. Pathological changes in the brain associated
with fits in dogs. Vet Rec. 1972;90:167173. 14. Palmer AC, Walker RG. The neuropathological
effects of cardiac arrest in animals: a study of five cases. J Small Anim Pract. 1970; 11:779791.
15. Read DH, Jolly RD, Alley MR. Polioencephalomalacia of dogs with thiamine deficiency. Vet
Pathol. 1977;14:103112. 16. Williams KJ, Summers BA, de Lahunta A. Cerebrospinal
cuterebriasis in cats and its association with feline ischemic encephalopathy. Vet Pathol.
1998;35:330343. 17. Zook BC. The pathologic anatomy of lead poisoning in dogs. Veterinary
Pathol. 1972;9:310327.
TERJEMAHAN

Degenerasi dan Atrofi Cortical Idiopatik Novel Idiopatik pada Anjing Dewasa
Muda
S. D. Cahalan1, R. Cappello2, A. de Lahunta3, and B. A. Summers1

Veterinary Pathology 2015, Vol. 52(2) 344-350 The Author(s) 2014 Reprints and permission:
sagepub.com/journalsPermissions.nav DOI: 10.1177/0300985814531498 vet.sagepub.com

Abstrak

Degenerasi neokorteks yang menyebar dan kronis, yang mengakibatkan atrofi terdeteksi pada
lima sampai 2 tahun. Menyajikan tanda-tanda neurologis termasuk ataksia, disfagia, kebutaan,
dan perubahan mentasi. Pencitraan resonansi magnetik pada otak dari 2 anjing menunjukkan
atrofi serebrosortikal bilateral yang parah dan pembesaran lateral dan ventrikel ketiga. Secara
keseluruhan, multifokal, bilateral simetris, area yang luas dari perubahan warna kecoklatan
neokortikal yang terkait dengan atrofi gyri dan pelebaran sulkus dicatat pada belahan otak
serebral dan lateral pada 3 anjing. Secara mikroskopis, pada semua anjing ada subakut sampai
degenerasi neokortikal kronis superfisial yang mempengaruhi semua lobus serebral, mulai dari
hilangnya lapisan molekul hingga kavitasi yang lebih jarang dan lebih dalam dengan ukuran
variabel. Tanda klinis mungkin diakibatkan oleh kombinasi degenerasi neokorteks primer dan
degenerasi sekunder di kortikobulbar dan saluran kortikospinalis. Pola distribusi lesi
serebrokortikal bruto dan histologis menunjukkan bahwa ini adalah penyakit serebral canine
degeneratif baru.

Kata kunci otak, taring, atrofi korteks, anjing, neokorteks, degenerasi

Nekrosis serebrosortis dan atrofi pada anjing telah didiagnosis sebagai idiopatik 8,13 atau terkait
dengan keracunan timah, 17 sianidepoisoning, 9iaminedefisiensi, 15cardiacarrest,
14hypoglycaemia, 10cranialtrauma, 12followingseizures, 2,11 juga memiliki penyakit herediter
yang berpotensi menyebabkan sistem saraf pusat degeneratif (SSP). , 4,6 Secara tipikal,
neuronaldegenerasi dan kehilangan melibatkan beberapa lamina neokorteks, kadang-kadang
menghasilkan ketebalan-ketebalannecrosis. Ketidakcocokan, theidiopathicsyndrome yang kami
laporkan di sini ditandai oleh degenerasi neokortikal yang sangat dangkal (tapi kadang-kadang
lebih dalam) dan atrofi, ditemukan pada 5 anjing di Amerika Utara dan Inggris.
Bahan dan metodeEmpat kasus berada dalam koleksi pribadi B.A.S., diperoleh dari pengajuan ke
Cornell University College of Veterinary Medicine, Ithaca, New York (1982-2006). Kasus kelima
diajukan ke layanan necropsy dari Royal Veterinary College, London, pada tahun 2012.

Riwayat Klinis dan Pemeriksaan

Kasus no. 1, anjing betina betina betina berusia 2 tahun yang utuh, menjalani euthanasia secara
tradisional setelah riwayat kelainan neurologis progresif selama 3 bulan, termasuk gaya berjalan
yang mengejutkan, hiperekstensi tungkai toraks saat berjalan, mengurangi hak kepemilikan
terutama di sisi kanan, buku jari kiri Tungkai toraks, dan biasanya bersikap seolah buta. Anjing
berkembang kesulitan makan dan minum 2 minggu sebelum elektif euthanasia Kasus no. 2,
seorang pria berusia 1 tahun yang dikebiri Great Dane, diberi riwayat asma kelainan neurologis
bertahap selama 4 minggu. Dia pertama kali mengalami masalah saat naik turun tangga; Selama
3 minggu berikutnya, ia menjadi semakin bingung dan beracun. Pada pemeriksaan klinis, dia
ditemukan mengalami hiperesthetic dengan kehilangan proprioception, ataksia ringan, kesulitan
dalam prehending makanan, dan kejang fokal parsial intermiten yang melibatkan rahang dan
leher. Elutasia elektif dilakukan. Tidak ada riwayat klinis yang tersedia untuk kasus no. 3. Kasus
no. 4, seorang wanita 2 tahun dikebiri Toy Poodle, disajikan dengan riwayat tanda neurologis
progresif sekitar 1 tahun lamanya. Tanda-tanda berkisar dari kehilangan penglihatan dan
pendengaran, mutilasi diri, obtundasi parah, dan agresi berat. Episode berlangsung sekitar 5
menit dan meningkat menjadi 1 atau 2 episode per hari. Pada pemeriksaan klinis, dia mengalami
depresi dan hiperestetis, bereaksi keras karena disentuh. Tidak ada respon ancaman, respon
cahaya pupil, atau reaksi terhadap kebisingan terdeteksi. Tidak ada refleks melompat atau patella
yang muncul. Magnetic Resonance Imaging (MRI) otak dilakukan, namun rincian urutannya
tidak tersedia. Elutasia elektif dilakukan. Kasus no. 5, seekor anjing serigala Irlandia berusia 1,5
tahun, diseleksi secara elektronik setelah riwayat ataksia progresif 2 bulan, hipermetria,
kebutaan, dan perubahan perilaku. Gambar resonansi magnetik diperoleh dengan magnet 1,5-
Tesla (Philips Acheiva). Urutan berikut diperoleh: T2-weighted, sagittal, transverse; Pemulihan
inversi T1, melintang; T1 tertimbang, melintang, dorsal (pra dan pascakontrakan); Dan
pemulihan inversi yang dilemahkan cairan (FLAIR), melintang. Untuk ringkasan kasus, lihat
digunakan pada 1: 100 dengan larutan pengambilan epitop 1 (ER-1; pH rendah) pretreatment.
Neumon spesifik enolase digunakan pada 1: 200 dengan perlakuan awal ER-1. Vimentin
digunakan pada 1: 500 dengan perlakuan awal ER-1. Kontrol positif dan negatif yang tepat
disertakan. Jaringan serebral dari kasus No. 5 adalah formalin tetap dan kemudian disaring
kembali dalam glutaraldehida, dipasangkan dengan osmium tetraoksida, dan diproses untuk
mikroskop elektron transmisi.

Nekropsi dan Histopatologi

Kasus nomor 2 dan 4 memiliki nekropsi lengkap; Otak dan sumsum tulang belakang serviks
diajukan dalam kasus No. 1 dan 5; Hanya otak yang diajukan untuk kasus No. 3. Otak dan
sampel jaringan lainnya dicelupkan ke dalam formalin buffer netral 10%, dan sampel terpilih
disematkan pada parafin, dipotong 5 mm, dan diwarnai dengan hematoxylin dan eosin untuk
evaluasi mikroskopis awal. Dalam kasus No. 3 dan 5, noda tambahan yang digunakan adalah
reticulin, trichrome Masson, dan Perls Prussian blue. Bagian formal-fixed dan parafin dari butir 3
dan 5 dipasang pada selang bermuatan positif (Superfrost Plus, Menzl-Glaser) dan diberi
imunolabel untuk reaktif terhadap protein asam fibriler glial (GFAP; antibodi monoklonal,
Leica), spesifik neuron Enolase (antibodi monoklonal, Leica), dan vimentin (antibodi tikus
monoklonal, Dako) melalui metode berbasis peroksidase untuk imunohistokimia tidak langsung
pada autostainer Leica Bondmax. Diaminobenzidin kromogen digunakan untuk visualisasi
antibodi terikat. GFAP digunakan pada 1: 100 dengan larutan pengambilan epitop 1 (ER-1; pH
rendah) pretreatment. Neumon spesifik enolase digunakan pada 1: 200 dengan perlakuan awal
ER-1. Vimentin digunakan pada 1: 500 dengan perlakuan awal ER-1. Kontrol positif dan negatif
yang tepat disertakan. Jaringan serebral dari kasus No. 5 adalah formalin tetap dan kemudian
disaring kembali dalam glutaraldehida, dipasangkan dengan osmium tetraoksida, dan diproses
untuk mikroskop elektron transmisi.

Hasil Hematologi dan Biokimia

Hasil biokimia dan hematologi tersedia untuk anjing No.2, 4 dan 5, termasuk asam empedu
istirahat dan postprandial serum, dan berada dalam batas normal. Kasus No. 2 diuji negatif untuk
timbal serum. Tingkat tiamin 72,0 ng / ml (kisaran referensi, 46-112 ng / ml) terdeteksi pada
kasus No. 5.

Serologi dan Reaksi Rantai Polimerase

Tidak ada antibodi terhadap Ehrlichia canis, Rickettsia rickettsii, Neospora caninum, dan agen
Toxoplasma gondii terdeteksi dalam serum dari kasus No. 2. Uji reaksi berantai polimerase real-
time pada cairan serebrospinal (CSF) dari kasus No. 5 untuk virus distemper canine, N Caninum,
dan T. gondii adalah negatif. CSF dari kasus No. 2 memiliki kelainan, digambarkan sebagai
leukosit yang sedikit meningkat terutama terdiri dari makrofag dan beberapa limfosit dan
kandungan protein normal. Kasus No. 5 telah meningkatkan protein dan pleositosis eosinofilik
ringan.

Pencitraan Resonansi Magnetik

Pemeriksaan MRI dilakukan pada kasus No. 4 dan 5. Rincian hanya tersedia untuk kasus No. 5
(Gambar 1, 2), di mana gambar tertimbang T2 menunjukkan sinyal hyperintense dan pelebaran
ruang subarachnoid yang menutupi gyri dan sulci. Lobus frontal, temporal, dan oksipital. Dalam
distribusi yang sama, gambar T1-weighted dan FLAIR menunjukkan sinyal hypointense
(isointense to the CSF) pada level ini. Pelek sinyal hyperintense yang tipis dalam materi abu-abu
korteks hadir dalam rangkaian FLAIR (laminar necrosis?). Talamus (dan adhesi interthalamic)
sangat berkurang ukurannya, dan pembesaran ventrikel lateral dan ketiga ada. Cerebellum tidak
menunjukkan kelainan struktural. Gambar-gambar postcontrur menunjukkan serapan tak teratur
yang tidak teratur pada meninges neokorteks. Gambaran tersebut menunjukkan adanya atrofi
kortikal / nekrosis dan atrofi korona radiata, thalamus, dan batang otak. Singkatnya, MRI dalam
anjing No. 4 dan 5 mengungkapkan atrofi serebrosortikal bilateral yang parah.

Temuan patologis

Lesi kotor dan histologis yang signifikan terbatas pada SSP pada setiap kasus.

Lesi makroskopik

Dalam kasus No. 1, materi abu neokorteks yang difusif dan ditandai secara mencolok dicatat
secara bilateral, yang mempengaruhi lobus frontal dan parietal. Penampilan kemerahan yang
melintang pada materi abu-abu kortikal dicatat pada penampang otak serebri. Dalam kasus No. 2,
pada bagian melintang otak, ditandai atropi simetris bilateral yang mempengaruhi neokorteks di
dalam lobus frontal, parietal, dan temporal dari dua pertiga rektum belahan otak. Lesi ini paling
luas di gyri punggung dan dorsolateral. Lobus piriform di atrofi dan diratakan dengan warna
kuning berubah warna. Perubahan warna putih yang padat dicatat dari traktus yang terdiri dari
serebri crus, serat longitudinal pons, piramida, dan dekeminasi piramid. Bintik putih bulat hadir
secara bilateral di funikuli lateral pada posisi saluran kortikospinalis lateral dari sumsum tulang
belakang serviks. Tidak ada laporan kotor yang tersedia untuk kasus No. 3. Dalam kasus No. 4,
tidak ada kelainan gross yang diamati. Dalam kasus No. 5, adhesi beberapa perusahaan dicatat
antara hemisfer serebral dan dura mater di seluruh otak besar. Ketidakteraturan permukaan halus
yang tidak rata ke rostral dua pertiga neokorteks dicatat, paling umum di gyri dorsal dan
punggung. Pada bagian melintang otak, atrofi simetris bilateral dan perubahan warna kuning
tambal sulam dari materi abu-abu neokorteks dari lobus parietal dan temporal diamati (Gambar
3). Lesi paling banyak terjadi pada gyri punggung dan dorsolateral.

Lesi mikroskopik

Jumlah slide histologi yang terbatas tersedia untuk pemeriksaan dalam setiap kasus. Lesi otak
(dan bila tersedia, sumsum tulang belakang) dalam semua kasus memiliki sifat yang sama dan
disajikan sebagai ringkasan. Kira-kira lesi degeneratif bilateral simetris difus mempengaruhi
neokorteks serebral dari lobus frontal ke oksipital. Perubahan ini mempengaruhi semua
permukaan otak besar namun secara konsisten permukaan dorsal dan lateral. Degenerasi
serebrosortikal dan atrofi cukup untuk menghasilkan pelebaran jinak sulci yang luas (Gambar 4).
Permukaan serebrosortikal cembung yang normal dan halus bergelombang karena kehilangan
jaringan superfisial, menghasilkan kavitasi skalar atau lebih dalam, yang meluas ke lapisan
molekuler dan kadang-kadang lebih jauh (Gambar 5, 6). Daerah degenerasi neuropil pucat dan
multifokal menunjukkan penipisan postnekrotik atau kehilangan lapisan molekuler (lamina 1)
dan nekrosis dan hilangnya neuron paling dangkal. Neokorteks yang terkena menunjukkan
astroliosis superfisial-astrosit tampak diaktifkan dengan inti yang membesar dan sitoplasma yang
diperluas. Seperti astrosit reaktif ditemukan di semua tingkat dangkal ke laminae tengah dan
pada agregat padat yang melibatkan persimpangan materi putih. Astrogliosis tampak jelas pada
GFAP (Gambar 7) dan noda vimentin, terutama di lapisan superfisial dengan lapisan tengah
hingga dalam yang sebagian besar mengalami cedera serebral. Leptomeningeal fibroplasia
dengan deposisi kolagen moderat dan peningkatan vaskulatur terlihat pada kasus No. 3, 4, dan 5
(Gambar 10). Keterlibatan daerah otak di luar neokorteks kadang-kadang terlihat. Lesi yang
lebih akut diamati pada kasus abu-abu hippocampal dari kasus No. 3 dan di wilayah korteks
oksipital dari kasus No. 5 dimana agregat neutrofilik terkemuka tercatat di leptomeninges, yang
tidak terpengaruh, meskipun lapisan yang lebih dalam biasanya terpengaruh jika tidak ada 5.
Neovaskularisasi ringan (kapiler dan arteriol kecil) sering diamati di daerah kavitasi. Infiltrat
limfosit, sel plasma, dan neutrofil sesekali diminimalkan dan limfosit subarachnoid sering
diamati (Gambar 9) , dan perivascular cuffing diamati di neokorteks dalam kasus No. 5.
Makrofag hemosiderinladen diamati di seluruh meninges di daerah. Nekrosis neokorteks dalam
semua kasus di rendah ke angka tinggi. Sel gitter yang sudah matang dan puing-puing dalam area
kehilangan neokorteks hanya sesekali, dengan membuktikan ke kronisitas pembuluh
leptomeningeal kaliber kecil yang dilapisi oleh sel endotel yang menonjol dan tersebar di daerah
nekrosis. Dalam kasus No. 5, nekrosis naif luas dari bahan abu-abu dari aspek lateral pons
ditandai dengan pelonggaran dan penghisapan. Dalam mesencephalon, difffaction ringan difus
halus dari parenkim superfisial dengan gliosis ringan dicatat. Lesi serupa diamati yang
mempengaruhi materi abu-abu di permukaan perubahan warna abu-abu hipotalamus tidak
diamati di dalam bagian medula oblongata dan serebelum, yang tersedia untuk kasus No. 2, 3,
dan 5. Degenerasi materi putih yang ditandai dengan pelapis myelin yang membengkak. ,
Beberapa kehilangan akson, makrofag intramyelinik langka, dan astrogliosis hadir di dalam
korpus callosum, kapsul internal, materi putih periventrikular, dan bilateral di serebri crus, serat
longitudinal pons, dan piramida. Ini hadir juga di saluran kortikospinalis lateral di sumsum
tulang belakang serviks dari kasus No. 1, 2, dan 5.

Diskusi

Kami menggambarkan sebuah kelainan degeneratif yang jarang terjadi namun jarang terjadi dan
semakin memburuk dari SSP yang mempengaruhi anjing dewasa dan laki-laki dewasa muda (3
adalah perempuan [1 jenis kelamin tidak diketahui]) yang berusia antara 1 dan 2 tahun yang
kami temui di Amerika Serikat dan Amerika Serikat Kerajaan. Dua adalah anjing serigala
Irlandia dan satu lagi adalah seekor anjing serigala Skotlandia, meningkatkan kemungkinan dasar
turun-temurun. Timbulnya defisit neurologis itu berbahaya dan progresif, mulai dari 1 bulan
sampai 1 tahun. Tanda-tanda neurologis termasuk ataksia proprioseptif dan serebelum umum,
motor paresis motor atas, kebutaan, dan kelainan perilaku. Selain 5 kasus yang dijelaskan, kasus
AS lebih lanjut dengan lesi yang sangat mirip dinilai; Namun, sinyal dan pengambilan riwayat
kasus penuh tidak tersedia, dan karena itu tidak termasuk dalam laporan ini. Tanda neurologis
klinis pada anjing ini mengindikasikan multifokal untuk meredakan penyakit SSP dengan
kemungkinan keterlibatan prosencephalon (kejang, sensor sensasi, jalur visual sentral) dan fosa
kaudal / sumsum tulang belakang (kesulitan pada prehension, ataksia proprioseptif umum, dan
motor paresis motor atas). Potensi multifokal untuk gangguan SSP yang meluas yang
dieksplorasi dengan beragam mencakup evaluasi untuk penyebab meningoencephalomyelitis
menular, seperti distemper kanin, N. caninum, Neorickettsia, dan ensefalopati, termasuk
keracunan timbal, defisiensi tiamin, dan shunting portosystemic. Dua anjing menerima evaluasi
MRI, yang mengidentifikasi hilangnya neokorteks dan perluasan subaraknoid yang dihasilkan
dan akan memainkan peran penting dalam diagnosis kasus lebih lanjut. Pola degenerasi kortikal
superfisial yang kami laporkan sangat tidak biasa dan berbeda dari yang biasa diamati pada
nekrosis serebrokortikal pada anjing (atau spesies lainnya). Nekrosis serebrokortis Canine
biasanya merupakan kondisi sporadis yang terjadi baik sendiri atau dikombinasikan dengan lesi
materi abu-abu di tempat lain di dalam otak.4 Penyebabnya kadang tidak diketahui.2,8 atau
setelah keracunan sianida, 9 hipoglikemia, 10 trauma, 12 hipoksia berkepanjangan setelah
serangan jantung, Nekrosis serebrosortikal juga dilaporkan dalam proses penyakit, seperti
aterosklerosis, tromboemboli, meningitis, 2 hepatitis tifus menular, ensefalitis distemper anjing,
8 dan gastroenteritis7 dan gangguan metabolisme seluler kongenital, seperti yang dilaporkan
dalam Ensefalopati Alaska Huskies dan Yorkshire Terriers.1,4 Berbeda dengan lesi yang
dilaporkan di sini, di mana nekrosis mempengaruhi ligamentum serebrosortikal yang paling
dangkal, nekrosis cerebrocortical canine pada contoh yang telah dijelaskan sebelumnya
mempengaruhi lamina yang lebih dalam.8-10,12,17 Dalam 1 kasus Hipoksia berkepanjangan,
semua lapisan korteks serebral terpengaruh.14 Di Alaska Husky encephalopat Hy, nekrosis
bervariasi mempengaruhi lapisan dangkal ligan kortikal serebral dengan lesi yang terjadi
terutama di dasar sulci.4 Dalam kasus yang dilaporkan di sini, materi abu-abu Nekrosis dan
kehilangan secara khusus terbatas pada neokorteks superfisial, terutama lapisan molekul (lamina
1) yang mempengaruhi neuropil dengan nekrosis neuronal sesekali. Lesi hadir dalam sulci dan
gyri. Fragmen abrasi abu-abu halus, nekrosis, dan gliosis diamati di daerah hipotalamus,
mesenskon, dan pons dari kasus No.3 dan 5, menunjukkan bahwa lesi tidak terbatas pada materi
abu-abu neokortikal dalam kasus ini. Hal ini menimbulkan kemungkinan adanya toksin CSF;
Namun, toksin di dalam CSF akan memiliki akses ke ventrikel, dan tidak ada bukti nekrosis
ependymal yang dicatat. Kami menafsirkan degenerasi dan kerugian neokorteks superfisial yang
menyebar luas karena lesi primer dengan degenerasi materi putih bilateral merupakan
konsekuensi dari hilangnya neokorteks yang menyebar. Degenerasi ini diamati secara kasar
dalam kasus No. 2 dan sebaliknya secara mikroskopis di otak tengah, pons, medula, dan sumsum
tulang belakang bersifat bilateral dan simetris dan anatomis konsisten dengan kortikobulbar
turun dan saluran kortikospinalis. Perubahan ini mencerminkan degenerasi akson neuron motorik
atas dan bersamaan dengan selubung mielin atau kehilangan interneuron transsynaptic. Tingkat
keparahan degenerasi materi putih mencerminkan lesi neokorteks bilateral yang meluas dan
kronisitas perubahan ini namun mengejutkan mengingat sifat dangkal mereka. Lesi SSP bilateral
dan simetris baik dalam hal abu-abu atau putih atau yang mempengaruhi keduanya secara
bersamaan umumnya disebabkan oleh penyimpangan perfusi vaskular global (hipoksiazeremia)
yang secara istimewa mempengaruhi daerah dengan sensitivitas tertinggi atau terkait dengan
disfungsi metabolik karena gangguan neurodegeneratif atau toksosis. Iskemia otak global seperti
yang dapat terjadi pada serangan jantung14 dan kecelakaan anestesi menargetkan daerah
neokorteks, hippocampus, dan otak kecil. Gangguan peredaran cerebral pada manusia lebih
sering terjadi pada materi abu-abu di dasar sulci dan bukan pada puncaknya.5 Kasus kami
menunjukkan nekrosis materi abu-abu di dasar dan puncak sulci, yang mempengaruhi laminae
kortikal paling dalam dengan hemat relatif paling banyak pada neuron. . Nekrosis neokorteks
pada kasus henti jantung manusia paling banyak terlihat pada lobus oksipital dan parietal dimana
lamina pertama dan kedua biasanya diawetkan. Pada kasus taring serangan jantung, semua
lapisan korteks serebral dilibatkan.14 Selanjutnya, kita tidak mengetahui adanya kejadian
pendahuluan, seperti serangan jantung atau anestesi umum, pada 5 anjing yang relatif muda ini.
Selain itu, tanda klinis pada anjing ini progresif yang tidak diharapkan pada kebanyakan kelainan
vaskular. Kemungkinan hipoksia, kehamilan atau cedera periparturient terhibur, namun
mengingat kurangnya tanda-tanda neurologis yang diamati pada anjing ini sebagai remaja, ini
dianggap etiologi yang tidak mungkin terjadi. Neurodegenerasi superfisial (selain infark bruto)
terlihat pada beberapa kasus ensefalopati iskemik kucing yang disebabkan oleh Cuterebramacy
intrakranial.16 Diperkirakan bahwa produk parasit yang diekskresikan bersifat neurotoksik.
Sementara ini menyebabkan degenerasi neokorteks erosif superfisial dan gliosis yang terkait, lesi
bersifat asimetris dan melibatkan sistem ventrikel dengan kehilangan ependimal (mungkin,
toksin putatif menyebar dalam CSF); Perubahan ini kurang pada anjing ini. Astroliosis
superfisial menyertai gangguan neokorteks, juga ditunjukkan dengan GFAP dan pada tingkat
yang lebih rendah dengan noda vimentin, dan terbukti pada pemeriksaan ultrastruktural. Kadang-
kadang perubahan astrositik meningkat lebih dalam, terutama dalam kasus No. 5, yang
melibatkan sambungan materi abu-abu putih, menunjukkan luka yang lebih dalam pada kasus
ini. Sel gitter tidak ada di parenkim, namun beberapa makrofag mononuklear mengandung
hemosiderin, yang membuktikan pendarahan sebelumnya. Tingginya jumlah neutrofil dan
jumlah histiosit dan limfosit sesekali diamati di daerah yang terkena dampak akut dalam kasus
No. 3 dan 5 di dalam ruang leptomeninges dan subarachnoid. Ini ditafsirkan sebagai sekunder
akibat nekrosis jaringan. Fibrosis leptomeningeal kadang kala juga diperhatikan. Intoksikasi oleh
agen eksogen dianggap tidak mungkin, mengingat lesi baru, rentang usia yang sempit dari anjing
yang terkena, dan kejadian sporadis pada kasus (5 dalam waktu sekitar 30 tahun). Lesi
serebrokortikal yang sekunder akibat kejang telah dijelaskan, 11 namun aktivitas kejang
dilaporkan hanya pada 1 dari 5 anjing dalam laporan ini. Nekrosis kortikal, seizure seismik yang
mungkin terjadi, terlihat pada beberapa kasus ensefalitis distemper canine yang secara selektif
mempengaruhi lobus pyriform dan hippocampus, 2 dan ini mempengaruhi lamina neuron tengah
ke dalam. Karena 2 anjing berasal dari Irlandia Wolfhound dan salah satu asal Wolfhound asal
Skotlandia (keturunan terkait dan tidak sangat umum), sebuah basis turun-temurun untuk kasus-
kasus itu terhibur. Gangguan SSP pada anjing yang tidak diketahui penyebabnya yang berpotensi
diwariskan dan ditandai dengan degenerasi dan degenerasi abu-abu simetris dengan pelestarian
neuronal termasuk kondisi neurodegeneratif pada anjing Ternak Australia, 3 ataksia serebelum
familial dengan hidrosefalus pada Bull Mastiffs, 6 dan ensefalopati Alaska Huskies and
Yorkshire Terriers .1,4 Sementara semua kelainan ini terjadi pada awal kehidupan, mereka sangat
berbeda secara neuropatologis dari sindrom yang kami jelaskan di sini dimana penyebab dan
patogenesis tetap harus dijelaskan.

Ucapan Terima KasihKami mengetahui bantuan Profesor Ken Smith, Departemen Patologi dan
Biologi Patogen, Royal Veterinary College, London, dalam memberikan dukungan untuk artikel
ini.

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