Original article M- G- Hausler' V. Th. ~arnaekers' I- ~ e u l ~ R. ~ e i l i c k e ~ G. Heimann' '~ivisionof Pediatric Neurology and Department of Pediatrics. Departments of '~euroradiology and 31mmunology. University of Aachen. Aachen. Germany Early and Late Onset Manifestations of Cerebral Vasculitis Related to Varicella Zoster Abstract The clinical, radiologic and immunologic findings i n four children w i t h VZCV will be reported. Clinical manifestations included sudden onset of hemiparesis. motor aphasia and disturbed consciousness in previously healthy children. Only one child had a history of chickenpox six weeks prior to the onset of stroke, whereas a latency period of up t o four years between chickenpox and the onset of stroke was found i n the other three children. Diagnosis of VZCV was confirmed repeatedly by demonstrating intrathecal production of varicefla-zoster IgC antibodies i n three children or a four-fold increase of Gricella-roster serum IgA-antibodies i n one child. lntrathecal production of antibodies against other latent viruses and borreliosis could be excluded. PCR for varicella on CSF. performed i n t w o patients, remained negative. No intrathecal production of varicella-zoster antibodies has been found in a control group of twenty clinically healthy children (age range from 2-18 years) w i t h a previous varicella infection. During follow-up t w o children recovered completely whereas two children still suffer from serious neurological deficits. lmrnunological investigations. performed i n three children, showed circulating immune-complexes with slightly lowered complement concentrations i n t w o patients. i n addition a lowered T-helperlT-suppressor cell ratio of unknown origin was found in three children. These immunological findings will be discussed i n the light of the pathophysiology of VZCV. Key words: Ischemic stroke - Varicella zoster - Vasculitis Since 1994 extensive CSF investigations with regard to specific newotropic viruses (herpes simplex, varicella zoster, mumps, The incidence of ischemic stroke in childhood has been consid- measles, m,rubella and Epstein-Barr virus) have been included ered rare in comparison with the adult age group. Although the in the list of putative causes underlying pediatric ischemic stroke. etiology in many childhood cases can be attributed to a broad Thereupon the diagnosis VZCV due to reactivated zoster virus spectrum of illnesses includmg metabolic, cardiac, genetic or was suspected and then confirmed by demonstration of specific acquired conditions, the cause remains unknown in up to 56% intrathecal antibody production in the first two patients (Cases 1 of all patients (3, 18, 21, 30, 33). and 3).After this interestmg finding a diagnosis VZCV could be established in retrospect in two other patients (28). The paper Cerebral vasculitis as a cause of ischemic stroke has been will present and discuss our findings in more detail. estimated to occur in about 4 1 2 % of all childhood cases (18, 24). Cerebral vasculitis related to varicella zoster infection (VZCV) has been reported very rarely Most cases of ischemic stmke after chickenpox have been reported to occur during the reconvalescence phase. A Japanese study in 1990 suggested that Patients and methods stroke complicates 1:6500 cases of childhood varicella infection Between January 1994 and September 1995 four previously (16). The majority of VZCV cases reported in the literature did healthy cluldren (between four and fourteen years of age), have occur during reconvalescence from a chcally apparent varicella- been treated for varicella-zostes-associated cerebral vasculitis. zoster virus (VZV) infection. The minority of cases suffered from There was no evidence for oncological, metabolic, hematological, herpes zoster ophthalmicus or developed stroke and systemic thromboembolic or cardiovascular dlsease. A follow-up was varicella-zoster nfection during acute lyrnphoblasticleukemia (1, available for all children, including clinical examination, trans4, 8, 13, 17, 20, 25, 31, 32, 35). Other predisposing factors cranial duplex sonography (TCD) and neuroimaging. Neuroleading to VZCV in previously healthy children are unknown. radiological imaging included emergency- and follow-up CCT in Compared with other cases of ischemic stroke in childhood, the dl patients. Digital subtraction angiography was performed prognosis seems to be good. initially in two and MRI in the remaining two cases (Cases 1 and 4). During follow-up MRT examinations were done in three cases (Cases 1, 3 and 4). Introduction Received June 5, 1997; revised, accepted March 30. 1998 The intrathecal production of antibodies against VZV in cerebmspinal fluid (CSF) was determined by calculation of antibody indices (AI). The antibody index has been calculated according to the following formula: Downloaded by: University of British Columbia. Copyrighted material. Varicella-zoster associated cerebral vasculitis (VZCV) as a cause of cerebral infarction has hitherto been considered a rare condition. Ischemic stroke i n previously healthy children has occurred during recovery from chickenpox or has been attributed t o virus reactivation among immunosuppressed patients. Neuropediotrics 29 (7 998) Early and Late Onset Manifestations of Cerebml Vasculitis Related to Varicella Zoster CSF/sem ratio of total IgG Evaluation of CSF and serum was performed by two different laboratories: laboratory I (AI-I)or laboratory I1 (AI-II). AI-I values > 1.5 or AI-I1 values > 3 prove intrathecal antibodyproduction in CSF (laboratory-relatedreference ranges, for detailed description of this method see references 6 and 29). The A1 against VZV has also been calculated for the serum and CSF samples drawn from a control group of 20 healthy children (age range between 2 and 18 years) with a clinically and serologically proven varicella infection without complications which had occurred many months or years prior to the time of admission during which a diagnostic lumbar puncture was done to rule out CNS infection or borreliosis. In the patients the specific A1 was determined simultaneously for other latent vinses (rubella, coxsackie v i n ~ ,cytomegalovirus, herpes simplex, mumps and measles) and borreliosis. Extensive laboratory investigations, including lymphocyte phenotyping by FACS-analysis, have been performed in three children. Reference ranges for lymphocyte subsets were defined according to the findings described in the literature (5, 12, 15). arteria cerebri m&a were fluctuating probably indicating the occurrence of vasospasm with compromised circulation of the left lenticulostnate arteries. The VZV M-I1 of 17.2 was clearly increased. Initial treatment consisted of prednisolone and administration of subcutaneous heparin. After five months steroids were withdrawn and heparin was replaced by acetylsalicylic acid. Despite the absence of further stroke-like events duplex sonography remained abnormal, indicating a persisting narrowing of the vessel lumen of the left medial cerebral artery. On follow-up, MRI documented residual lesions localized to the left putamen and nucleus caudatus head. Case 2 A fowyear-old boy, who had recovered from chickenpox one year before, manifested three short-lasting, transient ischemic attacks with right-sided hemiparesis, aphasia and disturbed consciousness. Although TCD and neurological examination between the attacks were normal, neuroimaging showed leR-sided basal gan&a mfarhon. The VZV AI-II of 8.8 was markedly elevated. During follow-up over one year after discharge from hospital stroke-hke episodes chd not recur and treatment was not necessary. Clinical examination and TCD remained completely normal. Follow-up MRI showed residual scarring of the left-sided basal gangha. The VZV AI after one year remained increased at 4. Case reports Case 3 The individual clinical course, treatment and follow-up data are presented in more detail, while the most relevant laboratory A 16-year-old girl had recovered from chickenpox four years before admission to our hospital. Since the age of three years she findings have been summarized in Table 1. was treated with insulin for diabetes mellitus type I elsewhere. However, treatment was not optimal as reflected by the HbAlc Case 1 level of 13.2%. Additionally, hyperlipidernia and arterial hyperAn eight-year-oldboy, who had recovered horn chickenpox two tension were present and there was also mild diabetic nephroyears previously, was adrmtted to our hospital because of three pathy and early neuropathy. She was admitted because of a transient and short-lasting episodes with impaired speech and sudden complete lefL-sided hemiparesis with impaired vigilance. vegetative symptoms occurring during meals. On admission hls One week after admission she regained consciousness. Persisting neurological examination was completely normal. A left-sided dysarthria, acalculia, retrograde amnesia and impairment of ischemic lesion of the putamen and nucleus caudatus head was short-term memory mflected significant cognitive dysfunction. documented by MRI neuroimaging. Transcranial Doppler sono- On TCD and angiography, a bilateral suprachoid carotid artery graphy (TCD) revealed raised cerebral blood-flow velocities in- occlusion was found which had resulted in multiple right hemidicating a sigruficant stenosis of the left medial cerebral artery. spheric white-rnatter lesions and an additional lesion in the left On several occasions Doppler flow velocity signals h r n the left internal capsule as detected by MRI (Fig. la-d). The bilateral Table 1 lrnrnunological and serologic data. CSF blood-brain-barrier CSF-VZV-PCR lntrathecal anti-VZVantibodies Anti VZV-1gA in serum 19c (gll) IgM (911) IgA (911) C3 (mgll) C4 (mgll) C l q IgG CIC C3d I g t CIC T-cellslpl 8-cells/pl CD41p1 (Helper) CDB/pI (Suppressor) Cd41CD8 ratio I normal I n.d. n.d. n.d. Al-ll positive n.d. (17.2) negative n.d. 9.5 0.91 1.23 600 220 negative negative CIC: circulatinq immune complexes: n.d.: not done normal I n.d. I discretely disturbed n.d. n.d. negative (twice) Al-ll positive Al-l positive Al-ll negative (0.84) (8.8) (4.0) max. 1:4069 n.d. negative 6.5 6.86 5.321 1.07 1.19 1.63 0.37 0.33 1.9 600 600 1050 410 150(1) 130(1) negative negative negative negative elevated negative 11851 10621 363 23 5 5731 631 0.91 1 51 11 552 0.931 normal I normal n.d. negative Al-l positive (7.2): Al-ll positive (3.27) negative 12.3 1.78 1.05 680 14'4 1) negative elevated 1752 3 84 864 912 0.951 Al-l positive (5.3) n.d. 11.4 1.09 0.78 720 180 negative elevated Downloaded by: University of British Columbia. Copyrighted material. AI = CSF/serum ratio of anti VZV specific IgG Fig. I b Fig. l c Fig. Id Fig. l a to d Case 3: a) (coronal TI-weighted image) and b) (coronal T,weighted image) show a high signal lesion in the right basal ganglia and periventricular white matter. The differential diagnosis includes an inflammatory or a vascular lesion. The TI-weighted image is acquired after intravenous administration of contrast media (Cad-DTPA). It demonstrates a pathological leptomeningeal enhancement which corresponds t o the abnormal leptomeningeal collateralization caused by the bilateral occlusion of the internal carotid artery. Note the small diameter of the lumen of the carotid artery in its cavernous extradural portion (arrows). c) and d) demonstrates the angiographic findings with bilateral occlusion of the C1 portion of the internal carotid artery and extensive collateral flow via the posterior communicating arteries and the leptomeningeal collaterals, which can explain the abnormal vascular enhancement on MRI scans. occlusion of the internal carotid arteries was associated with development of sigmficant leptomeningeal collateral circulation, which provided an adequate collateral neovascularisation network as demonstrated by SPECT studies. Serial CSF-examinations showed a discrete disturbance of the blood-brain-barrier, Upon admission CSF-VZV-PCR and AI-II were repeatedly negative. Since a slowly progressive cerebral vasculitis was suspected, treatment was started with subcutaneous heparin and oral prednisolone. During the ensuing two months anti-VZV IgA-antibody levels in serum increased from 1:512 to 1:4096, suggesting VZV reactivation. Seven months after the onset of stroke she has been put on a low-dose acetykalicylic acid, lopirine and an appropriate dose of insulin.Despite significant recovery of her herniparesis ten months after the primary manifestations, her cognitive function still remains impaired. TCD shows further evidence of extensive intracranial arterial stenosis. Case 4 Six weeks after recovery from chickenpox, an eight-year-oldboy developed a complete right-sided hemiparesis and somnolence. Neuroimaging and angiography indicated a lef-sided basal ganglia infarction and a circumscribed ipsilateral cortical ischemic lesion in the presence of a long-distance narrowing within the lumen of the left medial cerebral artery and vasospasms within the distal branches (Fig. 2a-c). The AI-I for VZV was raised at 5.3. Low serum but absent CSF-antibody levels for Borrelia burgdorferi suggested a recent Borrelia infection. Significant elevation of anti-HSV1-and anti-HSV2 IgG- and IgM antibodies in serum in the absence of CSF antibodies were interpreted as recent HSV-reactivation.The boy was treated with a combination of cephalosporins (10 days), prednisolone (120 days), acetylsalicylic acid (2 days), acyclovir (2 days) and low doses of heparin (10 months). Three days after hospital admission he regained consciousness. Although stroke-like events did not recur, TCD Downloaded by: University of British Columbia. Copyrighted material. Fig. l a Fig. 2a Neuropediatrics 29 (7998) Downloaded by: University of British Columbia. Copyrighted material. Early and Late Onset Manifestations of Cerebral Vosculitis Related to Varicello Zoster Fig. 2b CAR Flg. 2c flg. 2d Fig. 2a to d Case 4: a) and b) demonstrate the ischemic infarction of the left basal ganglia. A lenticular stroke of this size is usually caused by an occlusion of the middle cerebral artery (MCA). Angiography detects a highgrade stenosis of the MCA (arrow, c) which remains nearly unchanged after one year (d). However. the vaswlitic changes visible on several intracranial vessels in c) have disappeared. Now the peripheral vascular territories appear normal, suggesting that the inflammatory process has regressed. and follow-up angiography, performed eight weeks after admission, suggested a slowly progressive vasculitis confined to the left medial artery and its branches. Now, 14 months later, the persistence of a circumscribed left-sided middle cerebral &ry stenosis has been confirmed by angiography (Fig. 2d). Subcutaneous administration of heparin is continued. Right-sided herniparesis without cogutive impairment persists. Laboratory invertigations Homocystinuria and inborn errors of metabolism, thrombernbolisrn, cardiovascular abnormalities, infections by other neumtropic infectious agents (including HIV and toxoplasmosis) and coagulation disorders (including antithrombin HI, protein C and S deficiency) have been ruled out in all children. Patients 1,2and 4 showed normal levels of biglycerides and cholesterol. Initial CSF examination was normal and oligoclonal bands were absent in all children. On admission and follow-up the A1 for VZV was clearly increased in Patients 1,2 and 4, while in Patient 3 reactivation of VZV was suggested by the four-fold rise of IgA titers. On two occasions CSF analysis using the PCR for VZV was negative. Simultaneous measurements of the A1 for measles, rubella, mumps, herpes simplex, cytomegalovirus, coxsackie virus and borreliosis showed negative results thereby excluding intrathecal IgG production for other latent viruses or a generalized reactivation due to for instance failing immune surveillance. M. G. Hiiusler et a/ as in Case 4. Our most important and new finding in three of our four patients was the very late onset of VZCVafter a latency of up to four years following the initial VZV infection. m s contrasts with most reports in the literature where ischemic stroke manifests within weeks to four months afkr chickenpox. The history of our patients indicated that the initial illness ran an uncomplicated course. In none of our chddren clinical evidence for impaired immune defense mechanisms was present. None of our patients showed a significant elevation of common markers for autoimmune-vasculihs like ANA, ANCA, or antiphospholipid-antibodies. The two patients with slightly reduced C4-complement values also showed slightly increased levels of circulating immune complexes in serum. This does not exclude VZV as the etiologic agent but might indicate that active and long-lasting immune processes are contributing to the vasculitis. Among the control group of 20 clinically healthy children with previous uncomplicated varicella infection (months to years before the actual lumbar puncture), the maximum value of the A1 against VZV was 1.24, thereby excluding intrathecal produc- The traditional concept of VZV reactivation envisages replication tion of specific VZZ antibodies. Immunological investigation in and spread of dormant virus particles in ganglion cells, leading to all patients showed negative antinuclear antibodies (ANA), anti- formation of skin lesions within inne~vateddermatames (23). neutrophil cytoplasmic antibodies (ANCA)or anti-phospholipid Corresponding with this concept acute VZV reactivation withm antibodies. Two children (Cases 2 and 4) had slightly lowered C4- autonomous or sensory nerves surrounding brain vessels might complement values and elevated levels of circulating immune also promote spread of virus towards i n t r a d a l arteries. This complexes. HLA-typing did not show a common HLA-constella- can evoke an immediate and specific immune response with local tion (Table 2). inflammation or final destruction of the vessel wall. The findings In Patients 2 and 3 the absolute count of B- and T-cells was low on admission of increased intrathecal production of specific on several occasions. The absolute count of CD4+-Thelper and antibodies did indeed suggest an immunological response against CD8+-T-suppressorcells was at the lower range of normal. The varicella zoster. Fluctuating blood flow in affected intracranial calculated CD4+/CD8+ ratio was reduced in Patients 2 , 3 and 4. vessels suggests vasospasm occurring within inflamed arteries. The history of all patients did not reveal clinical evidence for The presence of extensive leptomeningeal collateralization in Case 3, as shown by angiography and SPECT, suggests a slowly immune dysfunction (Table 1). progressive and bilateral occlusion of the internal carotid arteries. Although VZV-PCR was negative in Patients 3 and 4, this does not exclude the possibdity of active virus replication within their Discussion vessel walls. Compared with adults, ischemic and silent strokes in childhood are rare events with a dfferent etioloa. Two of our patients The literature on post-mortem histopathological examinations (Cases 1 and 2) only marufested symptoms of transient hemipa- aRer VZCV (7, 9, 10, 14, 19, 34) does not mention common resis and speech impairment. Neuroirnaging disclosed lesions histopathological characteristics. The inflammatory process was confined to the basal ganglia which could be explained by characterized by mononuclear a t r a t i o n s , histiocytes, giant cells ischemia witkin the territory of lenticulostriate arteries. The or the formation of granulomas. Arterial wall destruction ranged two other patients (Cases 3 and 4) suffered from long-lasting hom intimal proliferation to complete infiltration of the vessel neurological and cognitive deficit. In patients with transient wall with formation of microabscesses and aneurysms. Viral symptomatology due to stroke-like events the correct diagnosis inclusion bodies were found inside the histiocytes and inside may be delayed. Therefore, in the presence of transient symptoms the smooth muscular cells of the affected vessels. These reports development of basal ganglia lesions should be carefully sought and our own findings suggest that VZCV is not a homogenous for by combination of Doppler studies, EEG and MR imaging. pathophysiological entity. Different predisposing factors might contribute to a variable suscepthility for VZV and lead to All patients had focal EEG slowing and abnormal MRI-or CCT different forms of vascular inflammation. Although the expresfindings. Rapidly fluctuating flow velocity signals detected by sion "variceua-zoster-associatedcerebrovascuhtis" does imply a transcranial Doppler investigations in three patients apparently histological diagnosis, lustopathological proof in our patients reflected superimposed vasospasm within inflamed cerebral ar- could not be obtained since a biopsy from affected intracranial terial vessels. The initial CSF cell count, glucose and protein level vessels is not possible. Hanky (ll),who reviewed 100 cases of were normal in all patients. The elevated antibody-index con- isolated angiopathy of the central nervous system in children, firmed intrathecal VZV-antibody production in CSF in Patients I, even proposed that dagnosis of angiitis of the central nervous 2 and 4, suggesting that VZV-associatedimmunological processes system should be restricted to hstologically proven cases, were involved in the vascular alterations. In Patient 3, the whereas cerebrovascular processes without histologically conelevated and fourfold increase of VZV IgA-antbody levels in firmed diagnosis should be called angiopathy. In some cases serum reflected VZV reactivation. The specfic A1 for other latent affected leptomeningeal vessels can be used for biopsy, when viruses and bomliosis remained negative. Moreover, the control the diagnosis remains obscure and is warranted for the purpose group of 20 children, who had recovered without complications of treatment. However, in our cases leptomeningeal arteries did after chickenpox before lumbar puncture, showed negative re- not seem to be involved. sults for the specific AT against VZVl In adults, VZCV has been described &ng imrn~o~orn~rornised or occurred In the adult, VZCV has especially been described in immunosimultaneously during ophthalmic herpes zoster (2, 14, 22). In compromised patients (9, 14, 26). Although none of our children childhood, most reported cases followed shortly after chickenpox did have clinical evidence for immune dysfunction, our data Downloaded by: University of British Columbia. Copyrighted material. Neuropediotrics 29 (7998) Early and Late Onset Manifestations of Cerebral Vasculitis Related to Varicella Zoster Neuropediotricr 29 (7 998) might indicate dsturbed immunological surveillance predominantly due to inadequate Thelper cell function. Even long after the acute clinical presentation and after &scontinuation of steroid therapy the three investigated patients showed a slightly reduced CD4CD8 ratio, predominantly caused by an absolute or relative lower count of T-helper cells. In addition Patients 2 and 3 showed lowered absolute counts of B- and Tcells. Together with other factors llke diabetes mellitus, arterial hypertension and hyperlipidemia (Patient 3) or recent Borrelia infection (Patient 4), these changes might have influenced appropriate immune surveillance and have promoted a common final pathway with inadequate defence against dormant VZV Finally, the low CD4+ICD8+ ratio as a consequence of ongoing dammatory activity within affected cerebral vessels, seems &ely because an increase of CD8+ T-suppressor cells and not a decrease of Thelper cellcounts would have to be expected. " Hankey, G . 1. Isolated angiitidangiopathy of the mlralnervous system. Focusing on ischemic stroke due to vasculiticprocesses, Har~keyet al (11) found a better outcome in patients treated with a combination of prednisolone and cyclophosphamide, whereas Paulakis and Bourdette (2, 27) could not establish a correlation between special therapeutic strategies and sunrival rate. During the acute phase Uuee of our patients (Patients 1, 3 and 4) have been treated with prednisolone and heparin. After varying intervals prednisolone has been discontinued. In two patients (Patients 3 and 4) heparin was replaced by acetykalicylic acid. Although hemiparesis and cognitive dysfunction persist in two patients (Patients 3 and 4) the clinical course was self-limited. The question whether acyclovir treatment would have been effective cannot be judged from the available data. Acyclovir can only reduce virus replication and not prevent persistence of dormant virus DNA within neuronal cells. 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