Transient Cerebral Arteriopathy in a Child Associated With Cytomegalovirus Infection

Transient Cerebral Arteriopathy in a Child Associated With Cytomegalovirus Infection

cerebral palsy(sərē`brəl pôl`zē), disability caused by brain damage before or during birth or in the first years, resulting in a loss of voluntary muscular control and coordination. The usual presentation includes a high temperature, headache and confusion associated with convulsions and signs of a focal neurological deficiency. We present a case of acute central retinal artery obstruction in association with Herpes zoster ophthalmicus and delayed cerebral vasculopathy. The authors report a 2.5-year-old girl with sudden left hemiplegia and aphasia. Neurons are highly susceptible to the hypoxia–ischemia that occurs during stroke. Therapeutically acyclovir, anticoagulation, and steroids have been used in the treatment of the zoster associated with stroke. Although the clinical symptoms had improved significantly over three months, the high signal intense lesions on T1-weighted MR images were also detected in the left medial temporal lobe, the right insula, and the straight gyrus.

Two months later, T2-weighted MRI visualized a diffuse lesion of increased signal intensities involving the white matter of both hemispheres, while both CSFprotein and myelin basic protein were significantly elevated. To our knowledge, this is the first report of a cytomegalovirus-associated transient cerebral arteriopathy in an immunocompetent child. For example, several viral proteins, such as the Rabies virus P-protein and chicken anemia virus VP3, regulate their NLS/NES activity via phosphorylation [6]. Transient cerebral arteriopathy is a unilateral monophasic arteriopathy frequently recognized in children with arterial ischemic stroke. Transient cerebral arteriopathy typically results in lenticulostriate infarcts as a result of a nonprogressive unilateral intracranial arteriopathy of the distal internal carotid artery and proximal middle cerebral artery or the anterior cerebral artery. The confirmatory diagnosis of transient cerebral arteriopathy requires follow-up cerebrovascular imaging, indicating stabilization or improvement in the arterial lesions, with or without residual stenosis.1 In regard to the pathognomonic mechanism of transient cerebral arteriopathy, the cerebral arterial wall is thought to be affected by an inflammatory process related to certain infections. The previously reported infectious agents associated with transient cerebral arteriopathy include varicella-zoster virus, enterovirus, human immunodeficiency virus (HIV), and Borrelia burgdorferi.2 However, the association of transient cerebral arteriopathy with a cytomegalovirus infection has never been reported.

Here, the authors report a child with transient cerebral arteriopathy associated with a cytomegalovirus infection, which can be a causative agent. A girl, aged 2 years and 6 months, had previously been in good health. She presented to our emergency department with a chief complaint of the sudden onset of left hemiplegia and aphasia, heralded by left-sided headaches. Test the good eye first and then the affected eye. She received Japanese B encephalitis vaccine 3 days prior to this episode. The relevant feature in her past history was a mild febrile episode associated with a transient maculopapular skin rash and elevated serum hepatic transaminase levels 1 month previously: aspartase aminotransferase = 85 IU/L (normal reference: 10-42 IU/L) and alanine aminotransferase = 102 IU/L (normal reference: 10-40 IU/L). She was fully conscious and afebrile, and there were no respiratory or digestive signs.

Her neurological examination on admission revealed an expressive aphasia, left facial droop, and hemiparesis, with her leg being weaker than her arm. A brain computerized tomography scan revealed diffusely edematous changes with enhanced meninges in the right fronto–parieto–temporal lobes and the left parietal lobe. A cranial magnetic resonance imaging showed infarction in the region of the right middle cerebral artery (Figure 1A). The magnetic resonance angiography showed loss of signal in the proximal middle cerebral artery, suggestive of occlusion (Figure 1B). In addition, the magnetic resonance angiography showed stenoses of bilateral supraclinoid internal carotid arteries and a reminiscent feature of Moyamoya disease in the right basal ganglion, which was demonstrated by “puff-of-smoke” network of vessels (Figure 1C). Routine investigations for a possible underlying cause of the childhood ischemic stroke, including tests for a possible thrombotic tendency (factor V Leiden mutations, homocysteine, protein S and C, antithrombin III levels, antiphospholipid antibodies, and lactic acid), inborn errors of metabolism (plasma amino acids and urine organic acids), or congenital heart disease (echocardiogram), were all normal. A lumbar puncture showed 45 nucleated cells per mm3 with 80% lymphocytes and normal glucose and protein.

Transient Cerebral Arteriopathy in a Child Associated With Cytomegalovirus Infection
Tests for a viral infection were performed, including detection of viral material in the cerebrospinal fluid using polymerase chain reaction (PCR) techniques and detection of antibodies (immunoglobulin G and M). Serum cytomegalovirus immunoglobulin M and immunoglobulin G tests were positive in early and late sera. Cytomegalovirus immunoglobulin M was positive in cerebrospinal fluid; however, no cytomegalovirus DNA was detected by PCR either in the cerebrospinal fluid or in the blood. Cytomegalovirus antigen pp65 was not found in cerebrospinal fluid or serum samples. Polymerase chain reaction was negative for human immunodeficiency virus, varicella-zoster virus, herpes simplex virus type 1 and 2, and enterovirus. The cryptococcal antigen was not detected. A, T2-weighted magnetic resonance imaging showing hypersignal of the right middle cerebral artery territory.

B, Magnetic resonance angiography showing an occlusion of the right middle cerebral artery (white arrow). C, Note a “puff-of-smoke” network of vessels, reminiscent of Moyamoya disease, was also depicted in the territory supplied by right lateral lenticulostriate arteries (black arrow). Treatment with anticytomegalovirus immunoglobulin for 3 days and ganciclovir for 2 weeks in addition to prednisolone resulted in gradual improvement in clinical symptoms. She is currently on long-term aspirin therapy and has made a good functional recovery with no recurrent events. The parents refused a further survey via conventional cerebral arteriography. Follow-up magnetic resonance angiography performed 3 months later showed stabilization of the previous vascular lesions and further improvement at the 6-month follow-up. Magnetic resonance angiography showed partial recanalization of the right middle cerebral artery with increased distal flow and improvement in the internal carotid artery stenosis.

Twelve months later, her neurological examination was normal and a follow-up magnetic resonance angiography was unchanged. Transient cerebral arteriopathy is emerging as one of the main arteriopathies underlying childhood stroke. A comparison of the titer of the infused vector stock and an estimate of the total number of successfully targeted neurons in unoccluded control cell fields indicated that there was variability in the number of neurons successfully infected as result of each microinfusion, but the overall efficiency of infection was ∼10%. Among the previously reported infectious origins in transient cerebral arteriopathy, varicella-zoster virus accounts for the most common (approximately one-third) identifiable pathogen. Herein, we describe a child with a prior cytomegalovirus infection and ischemic stroke who fulfilled the criteria of a transient cerebral arteriopathy.2 Furthermore, the fact that the child’s arteriopathy is in complete remission after antiviral therapy and treatment with prednisolone also favors a diagnosis of cytomegalovirus-associated transient cerebral arteriopathy. To our knowledge, this is the first reported case of transient cerebral arteriopathy manifestly associated with a cytomegalovirus infection. Our report highlights that a cytomegalovirus infection should be considered in children diagnosed with transient cerebral arteriopathy.

In the present case, the causal relationship between transient cerebral arteriopathy and cytomegalovirus infection is defined by the detection of seroconversion against cytomegalovirus in the patient’s early and late sera and positive immunoglobulin M in the cerebrospinal fluid. Cytomegalovirus is a ubiquitous herpesvirus with the capacity to cause various clinical syndromes. Although postnatal cytomegalovirus infection is common, clinically apparent cytomegalovirus infection is uncommon in healthy children. Most immunocompetent children infected by cytomegalovirus can manifest a self-limited course of either hepatitis or an infectious mononucleosis-like syndrome (cytomegaloviral mononucleosis). The immunocompromised hosts are particularly at risk for life-threatening complication of an acute cytomegalovirus infection, such as encephalitis and pneumonitis. In addition, a cytomegalovirus infection appears to have a specific tropism for vascular endothelium. Indeed, cytomegalovirus-associated vasculitis has been reported; however, it is an extremely rare condition.

Vasculitis caused by cytomegalovirus occurs predominantly in immunocompromised patients and represent a broad spectrum of disease involving the gastrointestinal tract, skin, lung, eyes, heart, kidneys, central nervous system, and peripheral nervous system.5 On rare occasions, cytomegalovirus infection can also cause vasculitis in nonimmunocompromised patients and can be either a causative agent or an opportunistic infection. The underlying state of host immunocompetence probably plays a pivotal role in determining the outcome of cytomegalovirus-associated vasculitis.5 Such postulation can further explain the self-limited course of arteriopathy in our patient. Infection with cytomegalovirus has been associated with several childhood neurologic conditions, including infantile spasms, Guillain-Barre syndrome, encephalitis, and myelitis. Similarly, cytomegalovirus-associated vasculitis can complicate a variety of neurologic defects.6 A severe case of cytomegalovirus-associated vasculitis resulting in widespread infarction of the brain and spinal cord was described in a patient with an underlying lymphoma.7 The arteriopathy can be explained either by direct cytomegalovirus infection of the cerebral vascular wall or by an indirect immunological effect of systemic cytomegalovirus infection. In accordance with past hypotheses,5,6 the present case showing the presence of pleocytosis and the positive immunoglobulin M for cytomegalovirus in the cerebrospinal fluid makes the former mechanism more plausible. The exact mechanism of varicella-zoster virus-associated transient cerebral arteriopathy is unclear; however, transaxonal migration of reactivated varicella-zoster virus from the trigeminal ganglion along the trigeminal nerve to the cerebral arteries, leading to vasculitis, is likely. We postulate a similar mechanism in which cytomegalovirus spread to the affected arterial wall occurs through the ophthalmic branch of the trigeminal nerve.

In conclusion, the present case highlights the need to include cytomegalovirus infections as possible causative factors in the differential diagnosis and classification of children with transient cerebral arteriopathy. We suggest the necessity for performing an extensive infectious disease evaluation for possible viral pathogens of the cerebral involvements when the cause of the childhood stroke remains indefinite. Author Contribution Wei-Tsun Kao contributed to conception of report, acquisition of data, or analysis and interpretation of data, comments upon the manuscript, and drafting the manuscript for intellectual content. Wei-Chen Lin contributed to analysis and interpretation of imaging. Yong-Hao Tseng contributed to acquisition of the data and comments upon the manuscript. Tai-Heng Chen contributed to conception and design, acquisition of data, revising the manuscript critically for important intellectual content, comments upon the manuscript, and final approval of the version to be published.

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