The Neuroradiology Journal 27: 327-333, 2014 - doi: 10.15274/NRJ-2014-10037
www.centauro.it
Varicella Zoster CNS Vascular Complications A Report of Four Cases and Literature Review FRANCISCO CHIANG1, THEERAPHOL PANYAPING1, GUSTAVO TEDESQUI1, DANIEL SOSSA1, CLAUDIA COSTA LEITE1,2, MAURICIO CASTILLO1 1 2
Department of Radiology, Neuroradiology Division, University of North Carolina at Chapel Hill; Chapel Hill, NC, USA Department of Radiology, University of São Paulo, School of Medicine; São Paulo, Brazil
Key words: varicella zoster, complication, vasculitis, MRI, imaging
SUMMARY – This study explored the neurologic vascular complications of varicella zoster virus (VZV). We describe four patients presenting at our institution with neurologic involvement by VZV. MR and MRA studies of the intracranial arterial circulation in the head were read by board-certified radiologists using standard clinical procedures. On MRI, three patients had acute infarcts and in two instances irregularities and narrowings of vessels were visible. Many of these complications are recognized to be due to a vasculopathy affecting small or large vessels and resulting in cerebral infarctions and rarely hemorrhages. The pattern of cerebral infarction and vascular abnormalities is not specific and resembles those of vasculitis/vasculopathy from other causes. The central nervous system (CNS) vascular complications of VZV should be considered in the patients with simultaneous primary or prior VZV infection whose imaging studies show cerebral infarction and/ or vasculitic appearing intracranial arteries.
Introduction Systemic varicella zoster virus (VZV) infection is very common. Although rare, neurological complications of primary infection are well-described in the literature and with the advent of the polymerase chain reaction (PCR) the recognized spectrum of neurological disorders associated with VZV has widened. The VZV virus can infect a broad variety of cells in the CNS, including neurons, oligodendrocytes, meningeal cells, ependymal cells and the blood vessel wall cells. The wide range of susceptible cells explains the diversity of clinical and pathological nervous system manifestations of VZV. Lesions caused by small-vessel vasculopathy show central cavitation and macrophage influx secondary to the initial ischemic event or to the additional damage caused by VZV infection of astrocytes and neurons. Disruption of the internal elastic lamina in cerebral arteries infected with VZV can result in a weakened vessel wall that leads to dolichoectasia or aneurysm with subarachnoid or intracerebral hemorrhage, or to arterial dissection 1.
Accurate recognition of the vascular complications of CNS Varicella Zoster is important as early treatment with antiviral agents may be beneficial. Here we describe four patients with vascular complications due to VZV infection with emphasis in their imaging characteristics and a pertinent literature review. Case 1 A 26-year-old African-American man was diagnosed with systemic lupus erythematosus and three years ago developed end stage kidney disease requiring dialysis. One year ago he was diagnosed with zoster ophthalmicus and VZV meningitis successfully treated with retroviral medication. Four months later he reported right eye swelling, pain, and rash consistent with VZV recurrence with right trigeminal distribution confirmed by CSF PCR. MRI and MRA of the brain revealed severe stenosis (70% stenosis) of the right MCA near its origin with generalized asymmetric narrowing of multiple arteries consistent with vasculi327
Varicella Zoster CNS Vascular Complications
A
Francisco Chiang
B
Figure 1 A) TOF 3D reconstruction shows severe stenosis (70% stenosis) of the right MCA at its origin, moderate irregular stenosis of the left MCA and bilateral stenosis of the A1 segments, worse on the right. B) FLAIR axial image shows abnormal hyperintensity in the right centrum semiovale.
tis. A subacute right occipital lobe infarct was demonstrated (Figure 1). The patient is stable without any additional brain symptoms. Case 2 A three-year-old boy with a history of medulloblastoma resection was admitted with seizures and fever. One-year before admission, he had a herpetic skin rash on the left trunk and the diagnosis of VZV infection was made. Contrastenhanced MRI performed at that time demonstrated a posterior pontine subacute infarct (Figure 2). The patient was treated with acyclovir therapy for 20 days. No follow-up is available. Case 3 A 28-year-old woman presented with a rapid onset encephalopathy and altered mental status. Brain MRI showed bilateral basal ganglia T2-weighted bright lesions with high DWI signal and restricted diffusion on ADC maps. MRA of the circle of Willis showed mild ir328
regularities in the right MCA (Figure 3). VZV infection was diagnosed by CSF PCR and the patient was started on antiviral antibiotics and steroids. Clinically she improved and was discharged home. Case 4 An 11-month-old boy with previously normal neurodevelopment and motor skills presented with right hemiparesis 15 days after VZV infection. MRI showed left basal ganglia acute infarcts with restricted diffusion on ADC maps. No abnormalities were identified on MRA of the circle of Willis (Figure 4). At 24 hours follow-up, the hemiparesis had improved greatly and after viral antibiotics he was discharged. Materials and Methods Multiplanar, multisequence MR was done including DWI in all cases. Intracranial arterial circulation MRA was performed using
www.centauro.it
The Neuroradiology Journal 27: 327-333, 2014 - doi: 10.15274/NRJ-2014-10037
A
B
C
Figure 2 A) Axial T2-weighted image shows increased signal intensity in the posterior pons anteriorly to the 4th ventricle. B) Pre (left) and post contrast-enhanced (right) sagittal images show heterogeneous enhancement of the lesion in the posterior pons. Note post-operative cerebellar changes from previous medulloblastoma resection. C) DWI image shows the high signal focus in the posterior pons corresponding to the area of infarction. The ADC maps did not show restricted diffusion suggesting an subacute infarct.
329
Varicella Zoster CNS Vascular Complications
A
Francisco Chiang
B C
Figure 3 A) Axial FLAIR image shows abnormal hyperintensities in the caudate head bilaterally and in the left lentiform nucleus. B) DWI image shows a hyperintense signal in corresponding regions. The ADC maps showed restricted diffusion suggesting an acute infarct. C) TOF 3D reconstruction of the brain shows severe stenosis (70% stenosis) at the distal M1 segment of the right MCA and A1 segment of the left ACA.
the 3D TOF (time of flight) sequence. In the 11-month-old patient the field-of-view was changed from 28 to 26 cm, and the slice thickness was decrease from 7 to 5 mm compared to the MRA parameters of the adult patients. The studies were read by board-certified radiologists using standard clinical procedures. Conventional angiography was not performed in these patients. 330
Discussion Varicella zoster (VZV) is a human αherpesvirus. The primary infection causes chickenpox or varicella after which it becomes latent in the brain, dorsal nerve roots, and autonomic ganglia and may reactivate to cause herpes zoster. Nervous system complications can follow either primary VZV infection or its
www.centauro.it
The Neuroradiology Journal 27: 327-333, 2014 - doi: 10.15274/NRJ-2014-10037
A
B
Figure 4 A) Sequential DWI images show a high signal in the left caudate and putamen and restricted diffusion in the ADC maps consistent with acute infarcts. B) TOF 3D reconstruction shows no abnormality of the intracranial vessels.
reactivation 2. After reactivation, VZV occasionally invades the spinal cord or cerebral arteries producing severe neurological manifestations such as myelitis, encephalitis, aseptic meningitis, acute cerebellar ataxia, Reye syndrome, Ramsay Hunt syndrome, and rarely stroke 2,3. All of these complications are recognized to be due to vasculitis affecting small and/or large vessels.
Large and small vessel vasculopathies are due to direct infection of the vessel wall and vasculitis causing thrombosis resulting in cerebral infarctions and rarely hemorrhages 3. VZV has been detected in large and small CNS blood vessels using PCR. VZV DNA can be detected in arteries of both the anterior and posterior circulations but not in the brain substance suggesting that VZV infection is prima331
Varicella Zoster CNS Vascular Complications
rily a vasculopathy that affects blood vessels. CNS vasculopathy due to VZV may involve small and large vessels depending on the immune status of the patients. Large vessel-associated encephalitis occurs mostly in immunocompetent patients while small vessel-mediated encephalitis is found in immunodeficient patients 4. Large vessel vasculitis is also called “unifocal vasculopathy” or “granulomatous arteritis” and has usually an acute onset. Small vessel vasculitis, also called “multifocal vasculopathy”, commonly has a subacute presentation 2-4. Both small and large vessel disease can occur together in HIV-positive patients 3. Serious manifestations arise when VZV invades the spinal cord or cerebral arteries after reactivation causing severe disease especially myelitis and focal vasculopathies. Neurologic involvement may also develop in the absence of rash. Neurological complications of primary VZV infection are rare and those associated with reactivation are even less common. With the introduction of PCR, the recognized clinical spectrum of acute and chronic neurological disorders associated with VZV reactivation has widened 2,3. Special conditions like advanced age or immunosuppression that produce some degree of immune compromise may lead to virus reactivation. The possible manifestations of this reactivation are diverse and include multifocal VZV vasculopathy. VZV vasculopathy is probably not unusual given that VZV affects >50% of individuals by 80 years of age, increasing the risk of stroke by 30% within the following year. Nearly 40% of such patients have no history of zoster or varicella rash. Thus, VZV must be considered a possible cause of TIA or stroke either in adults or children even without a history of rash. When a rash has occurred, there is often a long delay from its onset to the occurrence of neurologic symptoms 4,5. Pathological and virological analysis of affected arteries from cases of clinically unifocal vasculopathy after zoster or varicella reveal multinucleated giant cells, Cowdry type A inclusion bodies, and herpesvirus particles as well as VZV DNA antigen in affected vessels 3,6. Most patients with VZV vasculopathy have findings on brain imaging. MRI reveals multiple cortical infarcts, infarcts at gray/white matter junctions, and deep infarcts in central gray and white matter as well as in the brainstem. Most lesions are ischemic and in the subacute phase enhance partially or completely with 332
Francisco Chiang
gadolinium 3,6. Catheter angiography or MRA may reveal narrowing in the middle and anterior cerebral arteries in patients with infarcts. A large vessel vasculitis of the circle of Willis can lead, in some instances, to hemorrhagic infarcts 5. Occlusion of the retinal vessels or posterior circulation arteries can also occur 7. Rarely, subarachnoid hemorrhage can occur due to VZV vasculopathy 8. In our cases, the patients were not immunocompromised and one of them had varicella recurrence along right trigeminal nerve distribution, which was confirmed by CSF PCR detection. In accordance with the previous discussion, all have large vessel-related disease. Brain MRI in the first, third and fourth patients showed acute infarcts in the basal ganglia. In our first patient there was also a small subacute infarction at the right occipital lobe and in our second patient a posterior pontine infarct. MRA of the brain in three patients showed a high-grade stenosis of the right MCA near its origin with generalized asymmetric small calibers of multiple vessels and a small right occipital lobe infarction in case 1 and high-grade stenosis of the distal M1 segment of the right MCA in case 3 with acute bilateral basal ganglia infarctions. MRA may not have the spatial resolution needed to detect abnormalities in all affected arteries, as in our fourth case where the MRA was normal. The presence of brain infarctions in both deep gray and cortical-subcortical areas, accompanying the vascular abnormality on MRA, was consistent with large vessel vasculopathy with focal vascular involvement. In these patients the evaluation of CSF may reveal moderate lymphocytic predominant pleocytosis, red blood cells, and mildly elevated protein with IgG oligoclonal bands against VZV. PCR analysis of CSF is a sensitive and specific test for VZV DNA. Detection of VZV antibody in CSF, even in the absence of PCR-amplifiable VZV DNA, supports the diagnosis in cases of suspected VZV infection of the nervous system 9,10. IgG antibody against VZV is the diagnostic method of choice as it is better than VZV DNA PCR. This is due to the time lag between the varicella infection and the onset of vascular symptoms making VZV DNA undetectable in CSF after 14-50 days of infection 10,11. The few protean complications associated with VZV include aneurysms, vascular ectasia formation, and carotid dissection due to infec-
www.centauro.it
The Neuroradiology Journal 27: 327-333, 2014 - doi: 10.15274/NRJ-2014-10037
tion of the tunica media of the arteries with disruption of their internal elastic lamina. VZV vasculopathy may be associated with other complications such as subarachnoid hemorrhage, spinal cord infarction, peripheral artery disease, and polyneuritis cranialis 8,12. The vasculitic changes can be partly reversed with the use of acyclovir and methylprednisolone 8. Early diagnosis of CNS and peripheral nervous system complications of VZV reactivation is important as aggressive treatment with intravenous acyclovir can be beneficial. The use of intravenous acyclovir for 14 days accompanied by a short course of steroid for five days reduces inflammation in cerebral vessels 3,8,12.
Conclusion Reactivation of VZV occasionally invades the cerebral arteries producing severe neurological manifestations such as VZV-related focal vasculopathies. MRI and MRA are essential to diagnose VZV vasculopathy disclosing brain infarcts sometimes with accompanying stenosis or occlusion of major cerebral arteries especially those of the circle of Willis. The presence of anti-VZV antibody in CSF is strongly suggestive of VZV even in the absence of PCR-amplifiable VZV DNA. Early diagnosis of more serious CNS VZV reactivation is important as treatment with intravenous acyclovir is beneficial.
References 1 Kleinschmidt-DeMasters BK, Gilden DH. VaricellaZoster virus infections of the nervous system: clinical and pathologic correlates. Arch Pathol Lab Med. 2001; 125 (6): 770-780. 2 Gilden D. Varicella Zoster Virus and CNS Syndromes. Herpes. 2004; 11 (Suppl 2): 89A-94A. 3 Nagel MA, Cohrs RJ, Mahalingam R, et al. The varicella zoster virus vasculopathies. Clinical, CSF, imaging, and virologic features. Neurology. 2008; 70 (11): 853-60. doi: 10.1212/01.wnl.0000304747.38502.e8. 4 Nagel MA, Gilden D. The challenging patient with varicella-zoster virus disease. Neurol Clin Pract. 2013; 3 (2): 109-117. doi: 10.1212/CPJ.0b013e31828d9f92. 5 McKelvie P, Collins S, Thyagarajan D. Meningoencephalomyelitis with vasculitis due to varicella zoster virus: a case report and review of the literature. Pathology. 2002; 34 (1): 88-93. doi: 10.1080/00313020120105705. 6 Gilden DH, Mahalingam R, Cohrs RJ, et al. The protean manifestations of varicella-zoster virus vasculopathy. J Neurovirol. 2002; 8 (Suppl. 2): 75-79. doi: 10.1080/13550280290167902. 7 Nagel MA, Russman AN, Feit H. VZV ischemic optic neuropathy and subclinical temporal arterial infection without rash. Neurology. 2013; 80 (2): 220-222. doi: 10.1212/WNL.0b013e31827b92d1. 8 Jain R, Deveikis J, Hickenbottom S, et al. Varicellazoster vasculitis presenting with intracranial hemorrhage. Am J Neuroradiol. 2003; 24 (5): 971-974. 9 Verma R, Lalla R, Patil TB. Extensive extracranial and intracranial varicella zoster vasculopathy. BMJ Case Rep. 2012; 2012. doi: 10.1136/bcr-2012-006845. 10 Russman AN, Lederman RJ, Calabrese LH, et al. Multifocal varicella zoster virus vasculopathy without rash. Arch Neurol. 2003; 60 (11): 1607-1609. doi: 10.1001/archneur.60.11.1607.
11 Nagel MA, Forghani B, Mahalingam R, et al. The value of detecting anti-VZV antibody in CSF to diagnose VZV vasculopathy. Neurology. 2007; 68 (13): 1069-1073. doi: 10.1212/01.wnl.0000258549.13334.16. 12 Gilden D, Cohrs RJ, Mahalingam R, et al. Varicella zoster virus vasculopathies: diverse clinical manifestations, laboratory features, pathogenesis and treatment. Lancet Neurol. 2009; 8 (8): 731-740. doi: 10.1016/ S1474-4422(09)70134-6.
Dr Francisco Chiang Neuroradiology Division Department of Radiology University of North Carolina at Chapel Hill 101 Manning Drive Chapel Hill, NC 27154, USA E-mail: [email protected]
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Varicella Zoster CNS Vascular Complications A Report of Four Cases and Literature Review FRANCISCO CHIANG1, THEERAPHOL PANYAPING1, GUSTAVO TEDESQUI1, DANIEL SOSSA1, CLAUDIA COSTA LEITE1,2, MAURICIO CASTILLO1 1 2
Department of Radiology, Neuroradiology Division, University of North Carolina at Chapel Hill; Chapel Hill, NC, USA Department of Radiology, University of São Paulo, School of Medicine; São Paulo, Brazil
Key words: varicella zoster, complication, vasculitis, MRI, imaging
SUMMARY – This study explored the neurologic vascular complications of varicella zoster virus (VZV). We describe four patients presenting at our institution with neurologic involvement by VZV. MR and MRA studies of the intracranial arterial circulation in the head were read by board-certified radiologists using standard clinical procedures. On MRI, three patients had acute infarcts and in two instances irregularities and narrowings of vessels were visible. Many of these complications are recognized to be due to a vasculopathy affecting small or large vessels and resulting in cerebral infarctions and rarely hemorrhages. The pattern of cerebral infarction and vascular abnormalities is not specific and resembles those of vasculitis/vasculopathy from other causes. The central nervous system (CNS) vascular complications of VZV should be considered in the patients with simultaneous primary or prior VZV infection whose imaging studies show cerebral infarction and/ or vasculitic appearing intracranial arteries.
Introduction Systemic varicella zoster virus (VZV) infection is very common. Although rare, neurological complications of primary infection are well-described in the literature and with the advent of the polymerase chain reaction (PCR) the recognized spectrum of neurological disorders associated with VZV has widened. The VZV virus can infect a broad variety of cells in the CNS, including neurons, oligodendrocytes, meningeal cells, ependymal cells and the blood vessel wall cells. The wide range of susceptible cells explains the diversity of clinical and pathological nervous system manifestations of VZV. Lesions caused by small-vessel vasculopathy show central cavitation and macrophage influx secondary to the initial ischemic event or to the additional damage caused by VZV infection of astrocytes and neurons. Disruption of the internal elastic lamina in cerebral arteries infected with VZV can result in a weakened vessel wall that leads to dolichoectasia or aneurysm with subarachnoid or intracerebral hemorrhage, or to arterial dissection 1.
Accurate recognition of the vascular complications of CNS Varicella Zoster is important as early treatment with antiviral agents may be beneficial. Here we describe four patients with vascular complications due to VZV infection with emphasis in their imaging characteristics and a pertinent literature review. Case 1 A 26-year-old African-American man was diagnosed with systemic lupus erythematosus and three years ago developed end stage kidney disease requiring dialysis. One year ago he was diagnosed with zoster ophthalmicus and VZV meningitis successfully treated with retroviral medication. Four months later he reported right eye swelling, pain, and rash consistent with VZV recurrence with right trigeminal distribution confirmed by CSF PCR. MRI and MRA of the brain revealed severe stenosis (70% stenosis) of the right MCA near its origin with generalized asymmetric narrowing of multiple arteries consistent with vasculi327
Varicella Zoster CNS Vascular Complications
A
Francisco Chiang
B
Figure 1 A) TOF 3D reconstruction shows severe stenosis (70% stenosis) of the right MCA at its origin, moderate irregular stenosis of the left MCA and bilateral stenosis of the A1 segments, worse on the right. B) FLAIR axial image shows abnormal hyperintensity in the right centrum semiovale.
tis. A subacute right occipital lobe infarct was demonstrated (Figure 1). The patient is stable without any additional brain symptoms. Case 2 A three-year-old boy with a history of medulloblastoma resection was admitted with seizures and fever. One-year before admission, he had a herpetic skin rash on the left trunk and the diagnosis of VZV infection was made. Contrastenhanced MRI performed at that time demonstrated a posterior pontine subacute infarct (Figure 2). The patient was treated with acyclovir therapy for 20 days. No follow-up is available. Case 3 A 28-year-old woman presented with a rapid onset encephalopathy and altered mental status. Brain MRI showed bilateral basal ganglia T2-weighted bright lesions with high DWI signal and restricted diffusion on ADC maps. MRA of the circle of Willis showed mild ir328
regularities in the right MCA (Figure 3). VZV infection was diagnosed by CSF PCR and the patient was started on antiviral antibiotics and steroids. Clinically she improved and was discharged home. Case 4 An 11-month-old boy with previously normal neurodevelopment and motor skills presented with right hemiparesis 15 days after VZV infection. MRI showed left basal ganglia acute infarcts with restricted diffusion on ADC maps. No abnormalities were identified on MRA of the circle of Willis (Figure 4). At 24 hours follow-up, the hemiparesis had improved greatly and after viral antibiotics he was discharged. Materials and Methods Multiplanar, multisequence MR was done including DWI in all cases. Intracranial arterial circulation MRA was performed using
www.centauro.it
The Neuroradiology Journal 27: 327-333, 2014 - doi: 10.15274/NRJ-2014-10037
A
B
C
Figure 2 A) Axial T2-weighted image shows increased signal intensity in the posterior pons anteriorly to the 4th ventricle. B) Pre (left) and post contrast-enhanced (right) sagittal images show heterogeneous enhancement of the lesion in the posterior pons. Note post-operative cerebellar changes from previous medulloblastoma resection. C) DWI image shows the high signal focus in the posterior pons corresponding to the area of infarction. The ADC maps did not show restricted diffusion suggesting an subacute infarct.
329
Varicella Zoster CNS Vascular Complications
A
Francisco Chiang
B C
Figure 3 A) Axial FLAIR image shows abnormal hyperintensities in the caudate head bilaterally and in the left lentiform nucleus. B) DWI image shows a hyperintense signal in corresponding regions. The ADC maps showed restricted diffusion suggesting an acute infarct. C) TOF 3D reconstruction of the brain shows severe stenosis (70% stenosis) at the distal M1 segment of the right MCA and A1 segment of the left ACA.
the 3D TOF (time of flight) sequence. In the 11-month-old patient the field-of-view was changed from 28 to 26 cm, and the slice thickness was decrease from 7 to 5 mm compared to the MRA parameters of the adult patients. The studies were read by board-certified radiologists using standard clinical procedures. Conventional angiography was not performed in these patients. 330
Discussion Varicella zoster (VZV) is a human αherpesvirus. The primary infection causes chickenpox or varicella after which it becomes latent in the brain, dorsal nerve roots, and autonomic ganglia and may reactivate to cause herpes zoster. Nervous system complications can follow either primary VZV infection or its
www.centauro.it
The Neuroradiology Journal 27: 327-333, 2014 - doi: 10.15274/NRJ-2014-10037
A
B
Figure 4 A) Sequential DWI images show a high signal in the left caudate and putamen and restricted diffusion in the ADC maps consistent with acute infarcts. B) TOF 3D reconstruction shows no abnormality of the intracranial vessels.
reactivation 2. After reactivation, VZV occasionally invades the spinal cord or cerebral arteries producing severe neurological manifestations such as myelitis, encephalitis, aseptic meningitis, acute cerebellar ataxia, Reye syndrome, Ramsay Hunt syndrome, and rarely stroke 2,3. All of these complications are recognized to be due to vasculitis affecting small and/or large vessels.
Large and small vessel vasculopathies are due to direct infection of the vessel wall and vasculitis causing thrombosis resulting in cerebral infarctions and rarely hemorrhages 3. VZV has been detected in large and small CNS blood vessels using PCR. VZV DNA can be detected in arteries of both the anterior and posterior circulations but not in the brain substance suggesting that VZV infection is prima331
Varicella Zoster CNS Vascular Complications
rily a vasculopathy that affects blood vessels. CNS vasculopathy due to VZV may involve small and large vessels depending on the immune status of the patients. Large vessel-associated encephalitis occurs mostly in immunocompetent patients while small vessel-mediated encephalitis is found in immunodeficient patients 4. Large vessel vasculitis is also called “unifocal vasculopathy” or “granulomatous arteritis” and has usually an acute onset. Small vessel vasculitis, also called “multifocal vasculopathy”, commonly has a subacute presentation 2-4. Both small and large vessel disease can occur together in HIV-positive patients 3. Serious manifestations arise when VZV invades the spinal cord or cerebral arteries after reactivation causing severe disease especially myelitis and focal vasculopathies. Neurologic involvement may also develop in the absence of rash. Neurological complications of primary VZV infection are rare and those associated with reactivation are even less common. With the introduction of PCR, the recognized clinical spectrum of acute and chronic neurological disorders associated with VZV reactivation has widened 2,3. Special conditions like advanced age or immunosuppression that produce some degree of immune compromise may lead to virus reactivation. The possible manifestations of this reactivation are diverse and include multifocal VZV vasculopathy. VZV vasculopathy is probably not unusual given that VZV affects >50% of individuals by 80 years of age, increasing the risk of stroke by 30% within the following year. Nearly 40% of such patients have no history of zoster or varicella rash. Thus, VZV must be considered a possible cause of TIA or stroke either in adults or children even without a history of rash. When a rash has occurred, there is often a long delay from its onset to the occurrence of neurologic symptoms 4,5. Pathological and virological analysis of affected arteries from cases of clinically unifocal vasculopathy after zoster or varicella reveal multinucleated giant cells, Cowdry type A inclusion bodies, and herpesvirus particles as well as VZV DNA antigen in affected vessels 3,6. Most patients with VZV vasculopathy have findings on brain imaging. MRI reveals multiple cortical infarcts, infarcts at gray/white matter junctions, and deep infarcts in central gray and white matter as well as in the brainstem. Most lesions are ischemic and in the subacute phase enhance partially or completely with 332
Francisco Chiang
gadolinium 3,6. Catheter angiography or MRA may reveal narrowing in the middle and anterior cerebral arteries in patients with infarcts. A large vessel vasculitis of the circle of Willis can lead, in some instances, to hemorrhagic infarcts 5. Occlusion of the retinal vessels or posterior circulation arteries can also occur 7. Rarely, subarachnoid hemorrhage can occur due to VZV vasculopathy 8. In our cases, the patients were not immunocompromised and one of them had varicella recurrence along right trigeminal nerve distribution, which was confirmed by CSF PCR detection. In accordance with the previous discussion, all have large vessel-related disease. Brain MRI in the first, third and fourth patients showed acute infarcts in the basal ganglia. In our first patient there was also a small subacute infarction at the right occipital lobe and in our second patient a posterior pontine infarct. MRA of the brain in three patients showed a high-grade stenosis of the right MCA near its origin with generalized asymmetric small calibers of multiple vessels and a small right occipital lobe infarction in case 1 and high-grade stenosis of the distal M1 segment of the right MCA in case 3 with acute bilateral basal ganglia infarctions. MRA may not have the spatial resolution needed to detect abnormalities in all affected arteries, as in our fourth case where the MRA was normal. The presence of brain infarctions in both deep gray and cortical-subcortical areas, accompanying the vascular abnormality on MRA, was consistent with large vessel vasculopathy with focal vascular involvement. In these patients the evaluation of CSF may reveal moderate lymphocytic predominant pleocytosis, red blood cells, and mildly elevated protein with IgG oligoclonal bands against VZV. PCR analysis of CSF is a sensitive and specific test for VZV DNA. Detection of VZV antibody in CSF, even in the absence of PCR-amplifiable VZV DNA, supports the diagnosis in cases of suspected VZV infection of the nervous system 9,10. IgG antibody against VZV is the diagnostic method of choice as it is better than VZV DNA PCR. This is due to the time lag between the varicella infection and the onset of vascular symptoms making VZV DNA undetectable in CSF after 14-50 days of infection 10,11. The few protean complications associated with VZV include aneurysms, vascular ectasia formation, and carotid dissection due to infec-
www.centauro.it
The Neuroradiology Journal 27: 327-333, 2014 - doi: 10.15274/NRJ-2014-10037
tion of the tunica media of the arteries with disruption of their internal elastic lamina. VZV vasculopathy may be associated with other complications such as subarachnoid hemorrhage, spinal cord infarction, peripheral artery disease, and polyneuritis cranialis 8,12. The vasculitic changes can be partly reversed with the use of acyclovir and methylprednisolone 8. Early diagnosis of CNS and peripheral nervous system complications of VZV reactivation is important as aggressive treatment with intravenous acyclovir can be beneficial. The use of intravenous acyclovir for 14 days accompanied by a short course of steroid for five days reduces inflammation in cerebral vessels 3,8,12.
Conclusion Reactivation of VZV occasionally invades the cerebral arteries producing severe neurological manifestations such as VZV-related focal vasculopathies. MRI and MRA are essential to diagnose VZV vasculopathy disclosing brain infarcts sometimes with accompanying stenosis or occlusion of major cerebral arteries especially those of the circle of Willis. The presence of anti-VZV antibody in CSF is strongly suggestive of VZV even in the absence of PCR-amplifiable VZV DNA. Early diagnosis of more serious CNS VZV reactivation is important as treatment with intravenous acyclovir is beneficial.
References 1 Kleinschmidt-DeMasters BK, Gilden DH. VaricellaZoster virus infections of the nervous system: clinical and pathologic correlates. Arch Pathol Lab Med. 2001; 125 (6): 770-780. 2 Gilden D. Varicella Zoster Virus and CNS Syndromes. Herpes. 2004; 11 (Suppl 2): 89A-94A. 3 Nagel MA, Cohrs RJ, Mahalingam R, et al. The varicella zoster virus vasculopathies. Clinical, CSF, imaging, and virologic features. Neurology. 2008; 70 (11): 853-60. doi: 10.1212/01.wnl.0000304747.38502.e8. 4 Nagel MA, Gilden D. The challenging patient with varicella-zoster virus disease. Neurol Clin Pract. 2013; 3 (2): 109-117. doi: 10.1212/CPJ.0b013e31828d9f92. 5 McKelvie P, Collins S, Thyagarajan D. Meningoencephalomyelitis with vasculitis due to varicella zoster virus: a case report and review of the literature. Pathology. 2002; 34 (1): 88-93. doi: 10.1080/00313020120105705. 6 Gilden DH, Mahalingam R, Cohrs RJ, et al. The protean manifestations of varicella-zoster virus vasculopathy. J Neurovirol. 2002; 8 (Suppl. 2): 75-79. doi: 10.1080/13550280290167902. 7 Nagel MA, Russman AN, Feit H. VZV ischemic optic neuropathy and subclinical temporal arterial infection without rash. Neurology. 2013; 80 (2): 220-222. doi: 10.1212/WNL.0b013e31827b92d1. 8 Jain R, Deveikis J, Hickenbottom S, et al. Varicellazoster vasculitis presenting with intracranial hemorrhage. Am J Neuroradiol. 2003; 24 (5): 971-974. 9 Verma R, Lalla R, Patil TB. Extensive extracranial and intracranial varicella zoster vasculopathy. BMJ Case Rep. 2012; 2012. doi: 10.1136/bcr-2012-006845. 10 Russman AN, Lederman RJ, Calabrese LH, et al. Multifocal varicella zoster virus vasculopathy without rash. Arch Neurol. 2003; 60 (11): 1607-1609. doi: 10.1001/archneur.60.11.1607.
11 Nagel MA, Forghani B, Mahalingam R, et al. The value of detecting anti-VZV antibody in CSF to diagnose VZV vasculopathy. Neurology. 2007; 68 (13): 1069-1073. doi: 10.1212/01.wnl.0000258549.13334.16. 12 Gilden D, Cohrs RJ, Mahalingam R, et al. Varicella zoster virus vasculopathies: diverse clinical manifestations, laboratory features, pathogenesis and treatment. Lancet Neurol. 2009; 8 (8): 731-740. doi: 10.1016/ S1474-4422(09)70134-6.
Dr Francisco Chiang Neuroradiology Division Department of Radiology University of North Carolina at Chapel Hill 101 Manning Drive Chapel Hill, NC 27154, USA E-mail: [email protected]
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