False-negative diagnostic imaging of Wallenberg’s syndrome by diffuse-weighted imaging: a case report and literature review
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Here, we report a case of a 64-year-old female with acute-onset vertigo, nausea, and vomiting. In an emergency imaging examination, the results of computed tomography (CT) and diffusion weighted imaging (DWI) were negative. However, on 1 day post-hospital admission, a small acute infarct in the posterolateral aspect of the left medulla was detected by DWI. Extra attention should be payed to the false-negative imaging results to avoid diagnosis and treatment delay.
KeywordsDiffusion weighted imaging Wallenberg’s syndrome Brain stem infarction
Wallenberg’s syndrome (WS), also known as the lateral medullary syndrome, is caused by occlusion of the vertebral artery, most frequently followed by obstruction of the posterior inferior cerebellar artery, and least often, of the medullary arteries. It is the most common type of infarction in the brain stem, causing a range of symptoms due to ischemia in the lateral part of the medulla oblongata. However, clinical examinations by diffusion weighted imaging with magnetic resonance imaging (DWI-MRI or DWI) can produce false-negative results. Once the disorder is neglected, the treatment is inevitably delayed, which can have detrimental effects on the patient’s health.Case report
It has been reported that patients with posterior circulation ischemia are five times more likely to present with a negative DWI scan than patients with anterior circulation ischemia [1, 2]. The medulla oblongata has a more abundant blood supply and its lateral circulation is more efficient than in other parts of the brain stem; therefore, infarctions in medulla oblongata are rare. Nonetheless, when medulla oblongata infarctions occur, they are commonly located in the dorsolateral medulla, mostly due to occlusion of the posterior inferior cerebellar artery (PICA).
PICA supplies the olivary bodies in the medulla oblongata. PICA passes between the origins of the hypoglossal nerve and the accessory nerve. The branches of the PICA are divided into the cerebellar branch, the choroidal branch, and the medulla branch. The medullary branch and its terminal branches consistently supply 1/3 of the Wallenberg’s region, including many nerve nuclei, nerve conduction bundle, reticular structures, and sympathetic nerve fibers between the branches. Therefore, when the PICA is blocked, the dorsolateral region of the medulla oblongata can become damaged. However, when Kim  performed angiography on 123 patients with simple dorsolateral medullary lesions, it was revealed that 67% of the cases were caused by vertebral artery lesions, and only 10% of the cases were due to posterior inferior cerebellar artery lesions. Nonetheless, the clinical manifestations of this disease are complicated because of the high anatomic variability of the posterior inferior cerebellar artery.
(1) dizziness, nausea, vomiting, and nystagmus (impaired vestibular nerve); (2) hoarseness, dysphagia, choking cough, and ipsilateral pharyngeal reflex diminished or disappeared (suspected nucleus damage); (3) ipsilateral Horner sign (impaired sympathetic pathway); (4) ipsilateral facial and contralateral somatic superficial sensory impairment (loss of spinal trigeminal nucleus and spinal cord tract); (5) ipsilateral limb ataxia (damage to the cerebellar peduncle, posterior spinocerebellar tract);(6)palatal myoclonus (disruption of the central tegmental tract). Other symptoms include paresis of the contralateral limb, contralateral pathology, and upper gastrointestinal bleeding. [4, 5]. The typical cases are rare, and the clinical manifestations are very complicated and variable.
In our patient’s case, many of the above symptoms were observed; however, CT and DWI analysis did not reveal any infarction on the day of admission. Therefore, we have investigated the cause of these sustained DWI negative results and here we further discuss the possible reasons of this diagnostic error. In the head CT examination, due to interference by the posterior fossa bone and the brain volume effect, the detection error is more prominent. In addition, the brain stem infarction contains smaller lesions and less edema, which can lead to a great reduction in the diagnostic efficiency of CT for brain stem infarction. Nuclear magnetic resonance greatly avoids the inefficiency of CT imaging and has become the most sensitive imaging modality available for ischemic stroke detection. [6, 7]. MRI is a great tool for accurate diagnosis of acute or hyper-acute ischemic stroke.  Lebihan  used diffusion-weighted imaging in clinical examinations for the first time in 1986, and since then, it has been the only method to detect microscopic motion of water molecules in living tissues. MRI is not affected by the bone mass; therefore, its diagnostic accuracy for lateral medullary infarction is superior to CT imaging.
The head MRI can clearly display the anatomy and the clinical features of the brain stem, and detect obvious morphological changes, which can provide valuable information for accurate early diagnosis and treatment of cerebral infarction, hence improve the prognosis of the disease. However, early studies have confirmed that the false-negative detection rate of DWI ranged from 3.5 to 31% [10, 11, 12]. Furthermore, Rahul et al.  suggested that DWI does not display 100% of the lesions in acute ischemic infarctions, especially in the basilar artery. Oppenheim and other studies  have shown that the basilar artery blood supply area had a high incidence of misdiagnosis, but a specific explanation for this observation was not provided by the authors. Julio et al.  performed MRI examinations in 356 patients with suspected acute ischemic stroke, including ischemic stroke patients with no signs of cerebral infarction by an earlier DWI examination, which accounted for 17% of the cases. Multivariate regression analysis in that study indicated that the stroke onset time of 3 h is the main factor of the false-negative results obtained by DWI. Moreover, the authors demonstrated that there was a significant inverse correlation between the false-negative rate of the DWI results and the onset of the disease.  Hossman et al.  analyzed the ischemic threshold of brain tissue retrospectively. The analysis revealed that the perfusion of the ischemic region decreased slightly at the early stages of ischemic stroke, leading to the loss of neurological function, even though the threshold of the diffusion limit had not been reached yet [10, 16, 17]. This may result in early false-negative DWI results.
At present, both animal experiments and clinical retrospective studies have confirmed that recanalization of the obstructed vessels and the compensatory collateral circulation after intravenous thrombolysis in early stage of cerebral infarction can also contribute to the normal appearance of the diffusion limited brain tissue by DWI. [18, 19, 20, 21, 22] However, although these early changes can affect the DWI results, they cannot prevent delayed brain damage. 
So far, many relevant case reports and clinical studies have shown that the infarct location and the affected area can influence the incidence of early false-negative results by DWI [11, 12, 14]. This is because they are important factors for the development of brain stem lacunar infarction at the early stages of stroke [11, 12, 14]. Furthermore, there are anatomical differences between the brain stem and the cerebral hemisphere, and the neurons in the gray and the white matter tracts are clearly separated. Considering that the brain stem nuclei can be interspersed between the nerve fibers and the brain stem infarction, an abnormal signal could mask the delayed signal generated by the cerebral hemisphere, resulting in early false-negative DWI findings.  Studies have found that ischemic preconditioning can mobilize the protection and repair mechanisms in the body, thereby increasing the tolerance of the brain tissue to damage caused by ischemia [25, 26]. Therefore, patients with ischemia, in the white matter region of the brain might undergo an equivalent ischemic preconditioning, thus preventing the formation of cytotoxic edema, and leading to the formation of early false-negative DWI results. [27, 28] Under good local collateral circulation, the involvement of the brain tissue might become less obvious since the degree of local ischemia is mild, and DWI can produce false-negative results. Therefore, the patient’s condition should be carefully assessed by combining the symptoms, signs, and the DWI analysis results, and the imaging examination method should be reviewed further. The patients with early dizziness accompanied by nausea, vomiting, cough, and other drinking-related symptoms should get extra attention. Although patients examined by DWI do not display diffuse limitation of the infarct size in 6 h, early thrombolytic treatment should not be considered a treatment taboo and can still be administered according to the patient’s physical examination. In addition, early dysphagia training and low-frequency electric pulse treatment can significantly improve the swallowing and dysarthria of patients. Cerebral angiography (DSA) examination is usually required to further assess whether the vascular lesions, the vascular distribution, and the collateral circulation are responsible for the severity of the infarction. In our case, the patient underwent MRA examination, which indicated multiple stenosis of the cerebral arteries and no posterior inferior cerebellar artery infarction. However, we were not able to identify the responsible blocked vessels since no further cerebral angiography (DSA) examination was performed.
Although MRI examination is valuable for the diagnosis of acute cerebral infarction, it can also provide the basis for the appropriate clinical treatment selection, disease progress assessment, and prognosis.  Clinically, there was a false-negative DWI result in the diagnosis of acute cerebral infarction, which should raise the awareness of the clinicians when assessing the condition of stroke patients. Accurate detection of acute cerebral infarction and early administration of thrombolytic treatment are of great importance for the reduction of mortality rates in stroke patients.
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Conflict of interest
The authors declare that they have no conflict of interest.
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