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Varicella with delayed hemiplegia
Varicella with Delayed Hemiplegia Takashi Ichiyama, MD*, Sadataka Houdou, MD*, Toshiro Kisa, MD*, Kousaku Ohno, MD*, and Kenzo Takeshita, MD*
We report 4 children who developed acute hemiplegia 7 w e e k s to 4 m o n t h s a f t e r v a r i c e l l a i n f e c t i o n . In 2 patients, c a r o t i d a n g i o g r a p h y d e m o n s t r a t e d s e g m e n t a l n a r r o w i n g a n d occlusion of t h e m i d d l e c e r e b r a l a r t e r y . T h e i r clinical and a n g i o g r a p h i c f e a t u r e s w e r e s i m i l a r to t h o s e a s s o c i a t e d w i t h c o n t r a l a t e r a l h e m i p l e g i a a f t e r h e r p e s z o s t e r o p h t h a l m i c u s , t h e p a t h o g e n e s i s of w h i c h c o m p r i s e s c e r e b r a l angiitis d u e to v a r i c e l l a z o s t e r v i r a l i n f e c t i o n . W e believe t h a t o u r p a t i e n t s h a d t h e s a m e p a t h o g e n e s i s . In a s u r v e y o f infectious diseases in o u r region, the f r e q u e n c y of v a r i c e l l a w i t h d e l a y e d h e m i p a r e s i s was r o u g h l y 1:6,500 v a r i c e l l a p a t i e n t s . l c h i y a m a T, Houdou S, Kisa T, O h n o K, Takeshita K. Varicella with delayed hemiplegia. Pediatr Neurol 1990;6: 279-81.
Introduction
Herpes zoster ophthalmicus (HZO) with delayed contralateral hemiparesis is a distinct central nervous system s y n d r o m e caused by the varicella zoster virus (VZV). It is characterized by unilateral vasculopathy affecting larger cerebral arteries and appears a few days to 6 months after H Z O [1-11 ]. The pathogenesis comprises cerebral angiitis due to direct V Z V infection [4-6]. We report 4 children with varicella infection and delayed hemiplegia. Because the clinical and angiographic features were similar to those of hemiplegia after H Z O , the pathogenesis of both syndromes may be the same. Case Reports Patient 1. This 4-year-old boy suddenly experienced fight-sided hemiconvulsions and then developed gait disturbance 11 weeks after varicella infection which included generalized vesicular exanthema. The course had been uncomplicated. On admission, neurologic examination revealed marked fight hemiplegia and motor aphasia. Computed tomography (CT) performed 10
From the *Division of Child Neurology; Institute of Neurological Sciences; Tottofi University School of Medicine; Yonago, Japan; *Department of Pediatrics; Shimane Prefectural Central Hospital; Izumo, Japan.
~ ~ =:~:_,,...I a ~lightly low-density lesion in the left striatocapsular region. The serum antivaricella virus antigen IgG titer determined by an indirect fluorescent antibody (IFA) method was positive at 1:40 dilution: however, the IgM titer was not elevated. Neither titer was elevated in the cerebrospinal fluid (CSF). CSF contained 3 leukocytes/mm3 Call mononuclear cellsL 17 mg/dl protein. 70 mg/dl glucose, and 1.28 mg/dl lgG. Antinuclear antibody was negative. The coagulation studies were normal, including platelets (286.000/mm3), bleeding time (3 minL fibrinogen (255 mg/dlL prothrombin time (107%). activated partial thromboplastin time (35 sec; control: 28-37 secl. and fibfinogen degradation products (< I mg/dl). Echocardiography disclosed no abnormality. Three weeks later, the low-density lesion had resolved on CT (Fig IAI. Carotid angiography revealed segmental narrowing of the left middle cerebral artery (MCA: Fig 2A). Eight months later he was normal except for clumsiness of the right arm. Patient 2. This l-year-old girl developed acute right-sided weakness 4 months after vaficella infection. Vesicular exanthema had been mainly on the trunk with a little on the face and head. On admission, she exhibited mild right hemiparesis. CT revealed a low-density lesion in the left anterior limb of the internal capsule (Fig I B). CSF contained 2 leukocytes/mm3 (mononuclear cells), glucose 54 mg/dl, and protein 8 mg/dl. The serum complement-fixation titer for varicella was positive at 1:16 dilution. Electrocardiography revealed no arrhythmia. Carotid angiography disclosed occlusion of the proximal segment of the left MCA (Fig 2B). Five months later, her neurologic deficits had disappeared completely. Patient 3. This 7-year-old boy developed varicella which had an uncomplicated, typical course. Several vesicles appeared on the face. Two months later, he developed acute right-sided weakness with aphasia lasting about 5 rain. Subsequently, the same type of attack occurred 4 times. He developed slurred speech and fight-sided weakness within I day. On admission, he had a right hemiparesis. Tendon reflexes were normal. On day 19 of hospitalization, c'r revealed a low-density lesion in the left lenticular nucleus (Fig IC). CSF contained I leukocyte/mm3 (mononuclear), glucose 63 mg]dl, and protein 19 mg/dl. Results of bleeding time (3.5 rain), coagulation time (7 mio), and aggregation of blood platelets by adenosine diphosphate, collagen, and epinephrine were normal. Carotid angiography and echocardiography did not reveal any abnormalities. One month later he was asymptomatic. Patient 4. This 2-year-old girl developed varicella following measles. On recovery from varicella, she was believed to be normal. Seven weeks after the onset of varicella, she complained of fatigue and dizziness. She rapidly developed weakness in the right arm and leg and could not walk. On admission, she exhibited fight hemiplegia. CT revealed a hypodensity in the left striatocapsular region (Fig ID). Carotid angiography was not performed. Four months later, she was discharged with residual hemiparesis and dystonia of the fight upper extremity. Discussion
H Z O with delayed contralateral hemiparesis was first recognized in 1919 [1]. Since then, there have been reports o f more than 30 patients [2-11]. T h e r e is an interval of a few days to 6 months (average: 8 weeks) between H Z O onset and the neurologic disorder [2]. In most instances, C T demonstrates small, low-density lesions in the deep central region (i.e., basal ganglia,, internal capsule, and thalamus), occasionally referred to as lacunar infarcts [3,4,
Communications should be addressed to: Dr. Ichiyama; Division of Child Neurology; Institute of Neurological Sciences; Tottori University School of Medicine; Nishi-machi 86; Yonago 683, Japan. Received February 6. 1990; accepted March 19, 1990.
Ichiyama et al" Varicella and Hemjplegia 279
Figure 1. CT scans of Patients 1-4 reveal low-density lesions in the left basal ganglia (at'rows). (A) Patient 1. (B) Patient 2. (C) Patient 3. (D) Patient 4.
8,11]. Carotid angiography demonstrates segmental constriction and/or occlusion of the proximal middle and anterior cerebral arteries [2,3,7,8]. Pathologic studies reveal virus-like particles and viral antigens in vessel walls [4-6], which suggest vasculitis due to direct VZV infection. Acute hemiplegia, appearing 1-3 months after varicella infection, was first reported by Eda et al., but without angiographic evidence [12]. A patient was reported with varicella followed by hemiparesis with angiographic evidence of vasculitis [13]. In previously reported patients, lacunar infarcts were detected on CT. All of our patients also had attacks of acute hemiplegia 7 weeks to 4 months after varicella infection; infarcts were also revealed on CT. In addition, carotid angiography demonstrated segmental narrowing and occlusion of the MCA in 2 patients. Clinical and radiographic findings in our patients and others are very similar to those with HZO and delayed contralateral hemiparesis in terms of the interval from the onset of the eruption to the onset of hemiparesis, CT findings, and carotid angiographic findings. Considering that varicella and herpes zoster are different clinical manifestations of the same causative agent, the occasional association of acute hemiparesis with antecedent varicella strongly suggests a causal relationship.
280
PEDIATRIC NEUROLOGY
Vol. 6 No. 4
The cerebral angiographic findings, which are similar to those in HZO with delayed hemiparesis, suggest that the
n.
Figure 2. (A) A left internal carotid angiogram of Patient 1 demonstrates segmental narrowing of the left MCA (arrowhead). (B) A left internal carotid angiogram of Patient 2 reveals occlusion of the left MCA (arrowhead).
pathogenesis o f acute hemiplegia after varicella results from vasculitis due to V Z V infection. Although the distribution of vascular lesions in patients with H Z O is consistent with what is known about patterns o f trigeminovascular connections, cerebral vasculopathies have been reported in patients with segmental herpes zoster infection without clinical e v i d e n c e of trigeminal or disseminated herpes zoster infection [3,4,91. This finding suggests other m e c h a n i s m s for viral access to the cerebral vessels, including trigeminal infection without a rash, hematogenous seeding o f nerves, or spreading via sympathetic nervous system pathways [4]. In our region (the San-in district, Japan), 4 patients were observed between 1979 and 1986. A survey of infectious diseases in this area disclosed that there were 26,001 varicella patients in the same period; therefore, the frequency of varicella with delayed hemiplegia is roughly 1:6,500 varicella patients.
References
[1] Cope S. Jones AT. Hemiplegia complicating ophthalmic zoster. Lancet 1954;2:898-9. [2] Bourdette DN. Rosenbcrg NL, Yatsu FM. Herpes zoster ophthalmicus and delayed ipsilateral cerebral infarction. Neurology 1983; 33:1428-32.
[3] Hilt DC, Buchholz D, Krumholz A, Weiss H, Wolinsky JS. Herpes zoster ophthalmicus and delayed contralateral hemiparesis caused by cerebral angiitis: Diagnosis and management approaches. Ann Neurol 1983;14:543-53. [4] Eidelberg D, Sotrel A, Horoupian DS, Neumann PE, PumarolaSune T, Price RW. Thrombotic cerebral vasculopathy associated with herpes zoster. Ann Neurol 1986;19:7-14. 151 Linnemann CC Jr, Alvira MM. Pathogenesis of varicella-zoster angiitis in the CNS. Arch Neurol 1980;37:239-40. [6] Doyle PW. Gibson G. Dolman CL. Herpes zoster ophthalmicus with contralateral hemiplegia: Identification of cause. Ann Neurol 1983; 14:84-5. 17] MacKenzie RA, Forbes GS, Karnes WE. Angiographic findings in herpes zoster arteritis. Ann Neurol 1981;10:458-64. 181 Kuroiwa Yo Furukawa T. Hemispheric infarction after herpes zoster ophthalmicus: Computed tomography and angiography. Neurology 1981;31:1030-2. [91 Rosenblum WIo Hadfield MG. Granulomatous angiitis of the nervous system in cases of herpes zoster and lymphosarcoma. Neurology 1972;22:348-54. [10] Snow BJ, Simcock JP. Brainstem infarction following cervical herpes zoster. Neurology 1988;38:1331. [lll Leis AA, Butler IJ. Infantile herpes zoster ophthalmicus and acute hemiparesis following intrauterine chickenpox. Neurology 1987; 37:1537-8. [12] Eda I, Takashima S, Takeshita K. Acute hemiplegia with lacunar infarct after varicella infection in childhood. Brain Dev 1983;5: 494-9. [131 Kamholz J, Tremblay G. Chickenpox with delayed contralateral hemiparesis caused by cerebral angiitis. Ann Neurol 1985;18: 358-60.
Ichiyama et ai: Varic¢lla and Hemiplegia 281
We report 4 children who developed acute hemiplegia 7 w e e k s to 4 m o n t h s a f t e r v a r i c e l l a i n f e c t i o n . In 2 patients, c a r o t i d a n g i o g r a p h y d e m o n s t r a t e d s e g m e n t a l n a r r o w i n g a n d occlusion of t h e m i d d l e c e r e b r a l a r t e r y . T h e i r clinical and a n g i o g r a p h i c f e a t u r e s w e r e s i m i l a r to t h o s e a s s o c i a t e d w i t h c o n t r a l a t e r a l h e m i p l e g i a a f t e r h e r p e s z o s t e r o p h t h a l m i c u s , t h e p a t h o g e n e s i s of w h i c h c o m p r i s e s c e r e b r a l angiitis d u e to v a r i c e l l a z o s t e r v i r a l i n f e c t i o n . W e believe t h a t o u r p a t i e n t s h a d t h e s a m e p a t h o g e n e s i s . In a s u r v e y o f infectious diseases in o u r region, the f r e q u e n c y of v a r i c e l l a w i t h d e l a y e d h e m i p a r e s i s was r o u g h l y 1:6,500 v a r i c e l l a p a t i e n t s . l c h i y a m a T, Houdou S, Kisa T, O h n o K, Takeshita K. Varicella with delayed hemiplegia. Pediatr Neurol 1990;6: 279-81.
Introduction
Herpes zoster ophthalmicus (HZO) with delayed contralateral hemiparesis is a distinct central nervous system s y n d r o m e caused by the varicella zoster virus (VZV). It is characterized by unilateral vasculopathy affecting larger cerebral arteries and appears a few days to 6 months after H Z O [1-11 ]. The pathogenesis comprises cerebral angiitis due to direct V Z V infection [4-6]. We report 4 children with varicella infection and delayed hemiplegia. Because the clinical and angiographic features were similar to those of hemiplegia after H Z O , the pathogenesis of both syndromes may be the same. Case Reports Patient 1. This 4-year-old boy suddenly experienced fight-sided hemiconvulsions and then developed gait disturbance 11 weeks after varicella infection which included generalized vesicular exanthema. The course had been uncomplicated. On admission, neurologic examination revealed marked fight hemiplegia and motor aphasia. Computed tomography (CT) performed 10
From the *Division of Child Neurology; Institute of Neurological Sciences; Tottofi University School of Medicine; Yonago, Japan; *Department of Pediatrics; Shimane Prefectural Central Hospital; Izumo, Japan.
~ ~ =:~:_,,...I a ~lightly low-density lesion in the left striatocapsular region. The serum antivaricella virus antigen IgG titer determined by an indirect fluorescent antibody (IFA) method was positive at 1:40 dilution: however, the IgM titer was not elevated. Neither titer was elevated in the cerebrospinal fluid (CSF). CSF contained 3 leukocytes/mm3 Call mononuclear cellsL 17 mg/dl protein. 70 mg/dl glucose, and 1.28 mg/dl lgG. Antinuclear antibody was negative. The coagulation studies were normal, including platelets (286.000/mm3), bleeding time (3 minL fibrinogen (255 mg/dlL prothrombin time (107%). activated partial thromboplastin time (35 sec; control: 28-37 secl. and fibfinogen degradation products (< I mg/dl). Echocardiography disclosed no abnormality. Three weeks later, the low-density lesion had resolved on CT (Fig IAI. Carotid angiography revealed segmental narrowing of the left middle cerebral artery (MCA: Fig 2A). Eight months later he was normal except for clumsiness of the right arm. Patient 2. This l-year-old girl developed acute right-sided weakness 4 months after vaficella infection. Vesicular exanthema had been mainly on the trunk with a little on the face and head. On admission, she exhibited mild right hemiparesis. CT revealed a low-density lesion in the left anterior limb of the internal capsule (Fig I B). CSF contained 2 leukocytes/mm3 (mononuclear cells), glucose 54 mg/dl, and protein 8 mg/dl. The serum complement-fixation titer for varicella was positive at 1:16 dilution. Electrocardiography revealed no arrhythmia. Carotid angiography disclosed occlusion of the proximal segment of the left MCA (Fig 2B). Five months later, her neurologic deficits had disappeared completely. Patient 3. This 7-year-old boy developed varicella which had an uncomplicated, typical course. Several vesicles appeared on the face. Two months later, he developed acute right-sided weakness with aphasia lasting about 5 rain. Subsequently, the same type of attack occurred 4 times. He developed slurred speech and fight-sided weakness within I day. On admission, he had a right hemiparesis. Tendon reflexes were normal. On day 19 of hospitalization, c'r revealed a low-density lesion in the left lenticular nucleus (Fig IC). CSF contained I leukocyte/mm3 (mononuclear), glucose 63 mg]dl, and protein 19 mg/dl. Results of bleeding time (3.5 rain), coagulation time (7 mio), and aggregation of blood platelets by adenosine diphosphate, collagen, and epinephrine were normal. Carotid angiography and echocardiography did not reveal any abnormalities. One month later he was asymptomatic. Patient 4. This 2-year-old girl developed varicella following measles. On recovery from varicella, she was believed to be normal. Seven weeks after the onset of varicella, she complained of fatigue and dizziness. She rapidly developed weakness in the right arm and leg and could not walk. On admission, she exhibited fight hemiplegia. CT revealed a hypodensity in the left striatocapsular region (Fig ID). Carotid angiography was not performed. Four months later, she was discharged with residual hemiparesis and dystonia of the fight upper extremity. Discussion
H Z O with delayed contralateral hemiparesis was first recognized in 1919 [1]. Since then, there have been reports o f more than 30 patients [2-11]. T h e r e is an interval of a few days to 6 months (average: 8 weeks) between H Z O onset and the neurologic disorder [2]. In most instances, C T demonstrates small, low-density lesions in the deep central region (i.e., basal ganglia,, internal capsule, and thalamus), occasionally referred to as lacunar infarcts [3,4,
Communications should be addressed to: Dr. Ichiyama; Division of Child Neurology; Institute of Neurological Sciences; Tottori University School of Medicine; Nishi-machi 86; Yonago 683, Japan. Received February 6. 1990; accepted March 19, 1990.
Ichiyama et al" Varicella and Hemjplegia 279
Figure 1. CT scans of Patients 1-4 reveal low-density lesions in the left basal ganglia (at'rows). (A) Patient 1. (B) Patient 2. (C) Patient 3. (D) Patient 4.
8,11]. Carotid angiography demonstrates segmental constriction and/or occlusion of the proximal middle and anterior cerebral arteries [2,3,7,8]. Pathologic studies reveal virus-like particles and viral antigens in vessel walls [4-6], which suggest vasculitis due to direct VZV infection. Acute hemiplegia, appearing 1-3 months after varicella infection, was first reported by Eda et al., but without angiographic evidence [12]. A patient was reported with varicella followed by hemiparesis with angiographic evidence of vasculitis [13]. In previously reported patients, lacunar infarcts were detected on CT. All of our patients also had attacks of acute hemiplegia 7 weeks to 4 months after varicella infection; infarcts were also revealed on CT. In addition, carotid angiography demonstrated segmental narrowing and occlusion of the MCA in 2 patients. Clinical and radiographic findings in our patients and others are very similar to those with HZO and delayed contralateral hemiparesis in terms of the interval from the onset of the eruption to the onset of hemiparesis, CT findings, and carotid angiographic findings. Considering that varicella and herpes zoster are different clinical manifestations of the same causative agent, the occasional association of acute hemiparesis with antecedent varicella strongly suggests a causal relationship.
280
PEDIATRIC NEUROLOGY
Vol. 6 No. 4
The cerebral angiographic findings, which are similar to those in HZO with delayed hemiparesis, suggest that the
n.
Figure 2. (A) A left internal carotid angiogram of Patient 1 demonstrates segmental narrowing of the left MCA (arrowhead). (B) A left internal carotid angiogram of Patient 2 reveals occlusion of the left MCA (arrowhead).
pathogenesis o f acute hemiplegia after varicella results from vasculitis due to V Z V infection. Although the distribution of vascular lesions in patients with H Z O is consistent with what is known about patterns o f trigeminovascular connections, cerebral vasculopathies have been reported in patients with segmental herpes zoster infection without clinical e v i d e n c e of trigeminal or disseminated herpes zoster infection [3,4,91. This finding suggests other m e c h a n i s m s for viral access to the cerebral vessels, including trigeminal infection without a rash, hematogenous seeding o f nerves, or spreading via sympathetic nervous system pathways [4]. In our region (the San-in district, Japan), 4 patients were observed between 1979 and 1986. A survey of infectious diseases in this area disclosed that there were 26,001 varicella patients in the same period; therefore, the frequency of varicella with delayed hemiplegia is roughly 1:6,500 varicella patients.
References
[1] Cope S. Jones AT. Hemiplegia complicating ophthalmic zoster. Lancet 1954;2:898-9. [2] Bourdette DN. Rosenbcrg NL, Yatsu FM. Herpes zoster ophthalmicus and delayed ipsilateral cerebral infarction. Neurology 1983; 33:1428-32.
[3] Hilt DC, Buchholz D, Krumholz A, Weiss H, Wolinsky JS. Herpes zoster ophthalmicus and delayed contralateral hemiparesis caused by cerebral angiitis: Diagnosis and management approaches. Ann Neurol 1983;14:543-53. [4] Eidelberg D, Sotrel A, Horoupian DS, Neumann PE, PumarolaSune T, Price RW. Thrombotic cerebral vasculopathy associated with herpes zoster. Ann Neurol 1986;19:7-14. 151 Linnemann CC Jr, Alvira MM. Pathogenesis of varicella-zoster angiitis in the CNS. Arch Neurol 1980;37:239-40. [6] Doyle PW. Gibson G. Dolman CL. Herpes zoster ophthalmicus with contralateral hemiplegia: Identification of cause. Ann Neurol 1983; 14:84-5. 17] MacKenzie RA, Forbes GS, Karnes WE. Angiographic findings in herpes zoster arteritis. Ann Neurol 1981;10:458-64. 181 Kuroiwa Yo Furukawa T. Hemispheric infarction after herpes zoster ophthalmicus: Computed tomography and angiography. Neurology 1981;31:1030-2. [91 Rosenblum WIo Hadfield MG. Granulomatous angiitis of the nervous system in cases of herpes zoster and lymphosarcoma. Neurology 1972;22:348-54. [10] Snow BJ, Simcock JP. Brainstem infarction following cervical herpes zoster. Neurology 1988;38:1331. [lll Leis AA, Butler IJ. Infantile herpes zoster ophthalmicus and acute hemiparesis following intrauterine chickenpox. Neurology 1987; 37:1537-8. [12] Eda I, Takashima S, Takeshita K. Acute hemiplegia with lacunar infarct after varicella infection in childhood. Brain Dev 1983;5: 494-9. [131 Kamholz J, Tremblay G. Chickenpox with delayed contralateral hemiparesis caused by cerebral angiitis. Ann Neurol 1985;18: 358-60.
Ichiyama et ai: Varic¢lla and Hemiplegia 281