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First published online October 12, 2010

Leukoencephalomalacia and Laminar Neuronal Necrosis Following Smoke Inhalation in a Dog


Acute respiratory and neurologic disease after smoke inhalation are well documented, but human patients may also develop delayed-onset neurologic symptoms associated with leukoencephalomalacia after exposure to smoke or carbon monoxide. In this case, a dog developed progressive neurologic signs 6 days after rescue from an apartment fire. At necropsy 9 days after smoke inhalation, leukoencephalomalacia of the central cerebral white matter was accompanied by laminar necrosis of cerebrocortical neurons. This is the first report of delayed posthypoxic leukoencephalopathy in a nonhuman animal.
Delayed posthypoxic leukoencephalopathy (DPHL) develops in human beings after smoke inhalation or exposure to carbon monoxide (CO),15,16 and it is attributed to anoxic anoxia (failure of blood oxygenation), anemic anoxia (low blood oxygen–carrying capacity, as in CO poisoning), or ischemic anoxia (low cerebral blood flow).16 Clinically, DPHL patients recover after an initial comatose state, only to develop neurologic symptoms 1 to 3 weeks later.16 Common lesions are leukoencephalomalacia of the central cerebral white matter with reactive astrogliosis,12,15,16 laminar necrosis of pyramidal neurons of the cerebral cortex, and necrosis of Purkinje cells and neurons of the basal nuclei.2,12,15
In veterinary medicine, only individual or small case series of neurologic disease after accidental smoke exposure have been reported.1,39,11,13,17 Some cases met the clinical criteria of DPHL, but the brain was not evaluated postmortem.11,13 To our knowledge, this is the first clinicopathologic description of delayed posthypoxic leukoencephalopathy in a nonhuman animal.

Case History

An 8.5-kg 5-year-old male mixed-breed dog was unconscious when rescued from a burning apartment building and so was administered oxygen via a face mask by the firefighters. Upon hospital admission a half hour later, the dog was conscious with normal rectal temperature but unable to stand. The heart rate was 140 beats per minute; mucous membranes were pale; capillary refill time was 1.5 seconds. Respiratory effort was increased; harsh lung sounds were ausculted; and a peribronchial lung pattern was detected radiographically. The dog had hypersalivation, vomited black mucus, and had black fluid feces. Plasma chemistry abnormalities included mild hypokalemia, hyperproteinemia, and elevated liver enzymes.
The dog recovered after oxygen therapy via an intranasal tube for several hours, intravenous lactated Ringer solution, plus short-acting glucocorticoids, furosemide, theophylline, ophthalmic ointment, and infrared treatment, and was discharged 1 day after presentation. The following day, the dog had lethargy and diarrhea, but its condition improved with intravenous fluid therapy. Six days after the fire, the dog developed neurologic signs with unresponsiveness, restlessness, and constant howling. It was treated with intravenous fluid, furosemide, mannitol, and prednisolone without improvement. On day 9, the dog was euthanized because it was still restless, unable to find food or water, and barking and pacing constantly.

Pathologic Findings

At necropsy, pulmonary parenchyma had moderate brownish discoloration, especially on the cranioventral aspect. Elsewhere, the lungs were reddened and wet with patchy overinflation. Both cardiac ventricles were moderately dilated; the heart weighed 75 g (0.88% body weight). The brain was grossly normal.
Tissue samples were fixed in 10% neutral buffered formalin for 24 hours; the complete brain, in 25% neutral buffered formalin for 7 days. Fixed tissues were processed routinely; paraffin sections were cut at 4 to 5 μm and stained with hematoxylin and eosin.
Histologically, finely granular, black, hydrogen peroxide–resistant pigment was in scattered alveolar macrophages, interstitial macrophages, and rare neutrophils (Fig. 1). Histologic lesions were not evident in sections of myocardium or liver.
Figure 1. Lung; dog. Hydrogen peroxide–resistant pigment in interstitial and scattered alveolar macrophages. HE.
Figure 2. Cerebrum; dog. Focal rarefaction (arrowheads) in central white matter of the frontal lobe with prominent blood vessels. HE (a). Luxol fast blue (b).
Figure 3. Cerebrum; dog. Prominent vasculature with hypertrophied endothelial cells. HE. Inset: Pericytes and/or smooth muscle cells of blood vessels in lesional tissue express smooth muscle actin. Immunohistochemistry with diaminobenzidine as chromogen; counterstain, hemalaun.
Figure 4. Cerebral white matter; dog. Astrogliosis with increased expression of glial fibrillary acidic protein around a necrotic focus. Immunohistochemistry with diaminobenzidine as chromogen; counterstain, hemalaun.
Figure 5. Cerebral white matter; dog. Scattered parenchymal and perivascular cells in rarefied white matter express activated caspase 3, indicating apoptosis. Immunohistochemistry with diaminobenzidine as chromogen; counterstain, hemalaun.
Figure 6. Cerebral cortex; dog. Necrotic neurons in layers II and III. HE. Inset: Necrotic (apoptotic) neurons express activated caspase 3. Immunohistochemistry with diaminobenzidine as chromogen; counterstain, hemalaun.
The central white matter of the cerebrum had marked pallor, especially in the frontal lobe, with marked focal rarefaction of the neuropil (Fig. 2a). The lesions were accentuated by Luxol fast blue stain (Fig. 2b). Only rare gitter cells or gemistocytic astrocytes were noted, but astrogliosis was obvious at the periphery of malacic foci. Blood vessels within the rarefied area were prominent with hypertrophied endothelial cells (Fig. 3).
Immunohistochemistry for smooth muscle actin (clone ASM-1, Progen, Heidelberg, Germany), glial fibrillary acidic protein (polyclonal, Dako, Hamburg, Germany), and activated caspase 3 (polyclonal, R&D Systems, Minneapolis, MN) was performed by standard avidin–biotin complex method. Expression of smooth muscle actin within vascular walls was enhanced in comparison to unaffected areas of the white matter (Fig. 3 inset). Expression of glial fibrillary acidic protein was diminished within the rarefied area but increased at its periphery (Fig. 4). Activated caspase 3 was expressed at the periphery of the rarefied foci and around vessels in the midst of rarefied tissue (Fig. 5).
Laminar necrosis of pyramidal neurons was noted in layers II and III of the cerebral cortex. Affected neurons were shrunken, hypereosinophilic, and karyolytic, and they expressed activated caspase 3 (Fig. 6). Scattered cerebellar Purkinje cells and hippocampal neurons also expressed activated caspase 3.


Delayed posthypoxic leukoencephalopathy is characterized by severe leukoencephalomalacia with reactive astrogliosis and, in some cases, laminar necrosis of cerebrocortical pyramidal neurons and other neurons.2,12,15 Excluding astrogliosis, which indicates a more protracted process, comparable lesions are encountered in the immediate response to CO or smoke inhalation.2,12 Consequently, DPHL must be differentiated from acute CO or smoke inhalation by the clinical history and the presence of reactive astrogliosis.
Because the lesions of DPHL are not diagnostic for smoke inhalation,2 it is essential to exclude other possible reasons for hypoxia. In this case, there was no evidence of inherent predisposition to hypoxia; for example, no evidence of preexisting heart disease was apparent in sections of myocardium, lung, or liver.
Leukoencephalomalacia of central cerebral white matter was reported in experimental CO poisoning of dogs and cats; however, neuronal necrosis was not observed,10,14 perhaps because of the rapid clinical course. Of the few reports of accidental CO or smoke exposure, only one includes gross and histologic findings. Smoke inhalation in the dog of that report was fatal within 36 hours; lesions included acute cerebrocortical necrosis, vasculitis, and hemorrhage.7
Carbon monoxide induces long-standing hypoxia by binding hemoglobin (replacing oxygen) and forming carboxyhemoglobin.11,15,16 Direct toxicity to myelin has also been suggested.2,15,16 By binding cytochrome oxidase, CO impairs cellular respiration and thereby ATP synthesis and energy-dependent myelin turnover.16 Furthermore, CO can cause vasodilation and, thereby, systemic hypotension that exacerbates cerebral hypoxia.15
Laminar neuronal necrosis can result from various insults, such as ischemia, hypoxia, and thiamine deficiency. In this case, the cause was probably hypoxia. Expression of activated caspase 3 by necrotic neurons suggests apoptosis as the means of cell death.2 However, neurons may survive the initial hypoxic episode, only to succumb after reoxygenation/reperfusion.2 This paradoxical cell death after reperfusion may explain the relatively acute appearance of the neuronal necrosis in this case.
Carbon monoxide, per se, does not induce pulmonary lesions, because it is not an irritant.12,15 In the setting of smoke inhalation, however, the lung is exposed to a variety of compounds. Myocardial lesions are reported in human CO poisoning and smoke inhalation.12,15 The biventricular cardiac dilation in this dog could have been secondary to CO-associated hypoxia because no evidence of preexisting cardiac disease was detected. Hypoxia and the binding of CO to myocardial myoglobin can result in heart failure, which would exacerbate systemic hypoxia and enhance cerebral, especially neuronal, injury.2 In conclusion, delayed posthypoxic leukoencephalopathy may develop after smoke inhalation in dogs.

Competing Interests

The authors declared no potential conflicts of interests with respect to the authorship and/or publication of this article.

Funding Information

The authors received no financial support for the research and/or authorship of this article.


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Article first published online: October 12, 2010
Issue published: September 2011


  1. delayed posthypoxic leukoencephalopathy
  2. demyelination
  3. dog
  4. neuronal necrosis

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© American College of Veterinary Pathologists 2011.
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Published online: October 12, 2010
Issue published: September 2011
PubMed: 20940447



A. Th. A. Weiss
Department of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany
C. Graf
Small Animal Clinic, Freie Universität Berlin, Berlin, Germany
A. D. Gruber
Department of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany
B. Kohn
Small Animal Clinic, Freie Universität Berlin, Berlin, Germany


Alexander Weiss, Department of Veterinary Pathology, Freie Universität Berlin, Robert-von-Ostertag-Str. 15, 14163 Berlin, Germany Email: [email protected]

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