Signalment:  

10-week-old female Swiss-Webster ICR/CD-1 (Institute of Cancer Research/Caesarean-Derived from ICR stock) mouse (Mus musculus).This mouse presented with an acute onset of intermittent rolling to the left separated by brief periods of lateral recumbency. The animals body weight/body condition score and coat were within normal limits and the mouse appeared to otherwise be in good health. After a brief period of observation, during which a video of the rolling behavior was recorded, humane euthanasia was elected and a necropsy was performed. The gross necropsy findings were unremarkable and selected tissues were submitted for histopathology.

Gross Description:  

No significant gross lesions were seen.

Histopathologic Description:

Extending from the caudal mesencephalon to the medulla oblongata there is unilateral, sharply-demarcated pallor and rarefaction of the neuropil with variable, mild to marked, multifocal vacuolization (malacia), neuronal cell loss and necrosis, capillary congestion, and mild, multifocal hemorrhage. This lesion is ventral and lateral in the caudal-most portions of the mesencephalon but unilateral and diffuse in the more caudal portions of the brainstem including the pons and medulla oblongata (involving trigeminal nerve sensory nucleus and motor fiber tracts, vestibulocochlear nuclei, and facial nerve motor nuclei and fiber tracts). 

Morphologic Diagnosis:  

Caudal mesencephalon to the medulla oblongata: Severe, subacute, unilateral encephalomalacia with neuronal cell necrosis and loss, and mild multifocal hemorrhage and edema.

Condition:  

Spontaneous unilateral brainstem infarction of Swiss mice

Contributor Comment:  

Our differential diagnoses in this mouse included otitis media and/or interna (bacterial: Mycoplasma pulmonis, Pasteurella pneumotropica, Pseudomonas aeruginosa, Streptococcus sp. or viral: reovirus) or, despite the young age of this mouse, a CNS tumor involving the brainstem. Although no occlusion was identified in the intracranial vertebral artery or its branches in this mouse, the histopathologic lesions in the brainstem are consistent with subacute, unilateral brainstem infarction. The vestibular clinical signs (intermittent rolling to one side) are secondary to severe, unilateral ischemia affecting the pontine or vestibulocochlear nuclei, resulting in central vestibular disease. There were no lesions in the outer, middle, or inner ears in this mouse. 

This lesion has been previously reported by Southard and Brayton in Swiss ICR/CD-1 mice as spontaneous vestibular syndrome and spontaneous unilateral brainstem infarction in Swiss mice.(11) Spontaneous vestibular syndrome in this outbred mouse stock is thought to be secondary to occlusion or dissection of the extracranial or intracranial vertebral artery and/or its branches. 

The paired extracranial vertebral arteries arise from the subclavian artery, or rarely, directly from the aortic arch. The largest branch of the intracranial vertebral artery supplies the dorsal medulla and cerebellum and is termed the posterior inferior cerebellar artery (PICA). At the base of medulla oblongata the two intracranial vertebral arteries merge at the midline to form the basilar artery which then branches to form the posterior cerebral arteries and the posterior communicating arteries comprising the Circle of Willis.(1-3)

The clinical and histopathologic features of this syndrome in Swiss ICR/CD-1 mice have been compared by Southard and Brayton to a constellation of clinical signs seen secondary to occlusion or dissection of the intracranial vertebral artery or posterior inferior cerebellar artery in humans termed Wallenberg syndrome or lateral medullary syndrome.(9,10,12) However, these Swiss mice do not share the most common risk factors associated with stroke in humans, including hypertension, diabetes mellitus, smoking, and hyperlipemia leading to atherosclerosis(1,6,8) (in humans this constellation of clinical signs is sometimes also attributed to neoplasia involving the brainstem(12)). Currently, the underlying etiology in these Swiss mice, such as an underlying congenital intravertebral artery stenosis, is not known and deserves further investigation.  Vertebral artery occlusions leading to medullary infarction in humans are associated with both gender and race predilections. Intracranial vertebral artery occlusions or dissections are more common in women and people of African and Asian descent, while extracranial vertebral artery occlusions or dissections are more common in white males.(1) Medullary infarctions are further classified as lateral medullary infarctions (LMI, Wallenberg, or Wallenbergs syndrome) and medial medullary infarctions (MMI or Dejerine syndrome).(4,5,7) The major symptoms associated with LMI include sensory disturbances affecting the face, dysarthria, vertigo, Horners syndrome, cerebellar ataxia, and decreased pharyngeal reflexes. The major symptoms associated with MMI include motor weakness and sensory disturbances of the extremities, however, the clinical signs of LMI and MMI commonly overlap depending on the areas and extent of the brainstem affected.(4,5) It is not surprising that the vascular supply to the medial and lateral medulla differs (and sometimes varies). As mentioned above, the lateral medulla receives its arterial supply from the intracranial vertebral artery and PICA, while the upper and lower medial medulla receives arterial blood from the anteromedial medullary arteries. These arise from the intracranial vertebral artery in the upper medulla and from the anterior spinal artery in the lower medulla.(5) The reported prevalence of medullary infarctions in humans varies widely and is continually changing owing to the development and widespread use of magnetic resonance imaging as a diagnostic tool, which has improved anatomic localization of the lesions. The incidence of spontaneous medullary infarction in Swiss ICR/CD-1 mouse is not known. 

JPC Diagnosis:  

Brainstem: Necrosis, unilateral, focally extensive, with edema.

Conference Comment:  

The contributor provides an excellent summary of unilateral brainstem infarction, a spontaneous condition rarely described in young Swiss mice. The histological lesions in this case are consistent with an early infarct, however, thrombi are not detected within examined sections, so the etiology cannot be confirmed. Examination of serial step sections of the head and neck may be helpful in definitively determining the underlying cause of these lesions. Many thrombi dissolve or break down and the affected area is reperfused, which causes additional damage, so the absence of thrombi does not necessarily indicate that they were not the inciting cause of the necrosis. 

A Laxol Fast Blue (LFB) stained virtual slide is available here.

References:

1. Caplan L, Wityk R, Pazdera L, Chang HM, Pessin M, Dewitt L. New England Medical Center Posterior Circulation Stroke Registry II. Vascular lesions. J Clin Neurol. 2005;1:31-49.

2. Caplan LR. The intracranial vertebral artery: a neglected species. The Johann Jacob Wepfer Award 2012. Cerebrovasc Dis. 2012;34:20-30.

3. Cloud GC, Markus HS. Diagnosis and management of vertebral artery stenosis. QJM. 2003;96:27-54.

4. Fukuoka T, Takeda H, Dembo T, Nagoya H, Kato Y, Deguchi I, et al. Clinical review of 37 patients with medullary infarction. J Stroke Cerebrovasc Dis. 2012;21:594-599.

5. Kameda W, Kawanami T, Kurita K, Daimon M, Kayama T, Hosoya T, et al. Lateral and medial medullary infarction: a comparative analysis of 214 patients. Stroke. 2004;35:694-699.

6. Lantelme P, Rohrwasser A, Gociman B, Hillas E, Cheng T, Petty G, et al. Effects of dietary sodium and genetic background on angiotensinogen and Renin in mouse. Hypertension. 2002;39:1007-1014.

7. Lee MJ, Park YG, Kim SJ, Lee JJ, Bang OY, Kim JS. Characteristics of stroke mechanisms in patients with medullary infarction. Eur J Neurol. 2012;19:1433-1439.

8. Lemini C, Jaimez R, Franco Y. Gender and inter-species influence on coagulation tests of rats and mice. Thromb Res. 2007;120:415-419.

9. Razak A, Clark D, Farooq MU, Kassab MY. Wallenberg's syndrome with extradural-extracranial origin of the posterior inferior cerebellar artery. Neurol Sci. 2011;32:711-713.

10. Sameshima T, Morita A, Yamaoka Y, Ichikawa Y. Ipsilateral sensorimotor deficits in lateral medullary infarction: a case report. J Stroke Cerebrovasc Dis. 2012.

11. Southard T, Brayton CF. Spontaneous unilateral brainstem infarction in Swiss mice. Vet Pathol. 2011;48:726-729.

12. van den Bergh P, Dom R. Wallenberg's syndrome caused by a craniopharyngioma "en plaque". J Neurol. 1983;229:61-64.

Click the slide to view.

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4-1. Brainstem

4-2. Brainstem

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