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Movement Disorder Following Herpes Simplex Encepha I itis Daniel E. Shanks Peter A . BIasco David P. Chason
Herpes simplex virus (HSV) encephalitis is the most commonly identified form of severe focal encephalitis in man. Before the availability of specific antiviral therapy, mortality was greater than 70 per cent (Olson el af. 1967, Whitley et al. 1977). Acyclovir has reduced mortality to between 19 and 28 per cent, but morbidity among survivors remains as high as 34 per cent (Skoldenberg et al. 1984, Whitley et a/. 1986). Recurrence of neurological symptoms after initial improvement has been described following discontinuation of antiviral therapy (Koenig et af. 1979, Dix el af. 1983, Knezevic and Carroll 1983, Abramson et al. 1984, Whitley et al. 1986). The development of a movement disorder has been reported in one fouryear-old girl after recovery from HSV encephalitis (Abramson et al. 1984). We present two children who developed severe hyperkinetic movement disorders following antiviral treatment and improvement of their initial illness.
Case reports
348
CASE 1 A previously healthy eight-year-old girl presented with a six-day history of progressive fever, pharyngitis, vomiting and disorientation. On admission to hospital she had a temperature of 39.1 "C and neurological findings including stupor, dysarthria, profuse drooling and meningismus. Physical examination was otherwise normal. A head CT was normal. Blood counts and serum electrolytes were also normal and plasma glucose was 8.3mmol/L. A lumbar puncture produced clear, colorless fluid with the abnormalities listed in Table 1 . An EEG demonstrated high-amplitude, irregular spike and sharp wave activity in the left temporal and frontal regions. Acyclovir was started at a dose of 25mg/kg/day and continued for 21 days. As alertness increased
over several days, she manifested behavioral aberrations. She compulsively begged for food and drink and tried to eat non-food objects. Her longterm memory was intact, but short-term memory was severely disturbed. On day six a repeat head CT scan showed abnormalities involving the white matter of the left frontal lobe and the cortex of the left temporal lobe. On day nine a lumbar puncture was still abnormal (Table I). Cranial MRI showed areas of increased signal intensity in the left frontal and temporal cortex, and bilaterally in the white matter adjacent to the insulae and Sylvian fissures (Fig. 1). She had irregular fevers for the first 14 days in hospital. By day 26 she had improved, but continued to demonstrate confusion and disturbed eating behavior. All CSF viral cultures were negative after three weeks. On day 31 her mental status deteriorated and she had a generalized motor seizure, which was treated with phenytoin. The next day continuous choreic and ballismic movements appeared while she was awake, and she was unable to produce meaningful vocalizations or follow commands. The movement disorder precluded oral feeding, so a gastrostomy tube was inserted. Follow-up MRI scans showed that grey and white matter changes had progressed to involve the anterior left parietal lobe. No lesions were identified in the basal ganglia, thalami or subthalamic nuclei. The lumbar puncture on day 42 showed improvement (Table I). A brain biopsy of the left anterior temporal lobe on day 66 demonstrated mononuclear cell infiltration. No neural elements were identified and no viral particles were noted on electron microscopy. The PAP immunoperoxidase for HSV type 1 capsid antigen was positive in many monocytes and glia. Viral cultures of the biopsy material were negative. Over the subsequent months, treatment with haloperidol, acyclovir, prednisone, diazepam and lorazepam had no effect on the movement disorder. She gradually improved, and eight months after initial presentation she was ambulatory, with good extremity function and no adventitious movements. The gastrostomy tube was removed and she could speak clearly. Residual deficits of short-term memory, mild anomia and impulsivity persisted. An MRI scan 18 months after onset showed no change from the previous study (Fig. 2). CASE 2 This seven-month-old boy presented with fever, irritability, and seizures that were generalized tonicclonic as well as focal clonic. Physical examination was normal, except for lethargy. A lumbar puncture produced xanthochromic fluid, containing the abnormalities listed in Table 1. White blood cell count was 17.1 x 109/L, with 2 per cent band neutrophils, 53 per cent segmented neutrophils, 38 per cent lymphocytes and 6 per cent monocytes. Serum electrolytes and plasma glucose were normal, as was the initial unenhanced CT scan. Ceftriaxone was started on day one, and on day two acyclovir was added at a dose of 30mg/kg/day and continued for 10 days. An EEG showed left-hemisphere slowing, maximal in the anterior temporal region. Repeat head CT scan showed low density in the superior left temporal lobe. Repeat lumbar puncture on day 12 was improved (Table 1). He gradually
Fig. 2. Axial M R I scan of case I , 18 months after onset. Tz-weighted image, showing bilateral temporal and posterior frontal lobe involvement, with atrophy greater on left, and bilateral insular and parahippocampal involvement, again more extensive on left. Basal ganglia are not involved.
Fig. 1. Axial MRI scan of case I on day 10. Tz-weighted image, showing confluent areas of increased signal throughout medial temporal lobes and insulae, more extensive on left.
TABLE 1
Lumbar puncture findings WBCmm3
RBCmm3
Glucose fmmol/L)
Protein (g/L)
Patient I Day 1 Day 9 Day 42
38 (16184) 221 (100/0) 3
36 221 16
6 .0 3 .6 3.6
0.16 0.99 0.29
Patient 2 Day 1 Day 12 Day 28t
111 (13/ 87) 66 (15,435) 10 (90/10)
3150
4.0 3.3 3.5
0.88 0.56 0.59
f %PMN/Mono) *
1
120
*PMN = polymorphonuclear cells: Mono = mononuclear cells. TTraumatic tap. improved, and at discharge was alert and interactive. His only neurological residuum was a mild motor deficit on the right. On day 28 he had an onset of involuntary choreic and ballismic movements which involved the trunk and extremities and which ceased during sleep. His medications at that time were carbamazepine and phenobarbital. A lumbar puncture did not suggest recurrent infection (Table 1). A head CT scan revealed a new low-density lesion in the right temporal lobe and increased left temporal changes. On day 34 he began another 10-day course of
acyclovir. Neither discontinuation of the carbamazepine nor institution of haloperidol or sodium valproate influenced the movement disorder. Severe oral-motor dysfunction necessitated the placement of a gastrostomy tube. He was most comfortable, and partially able to feed by mouth, when tightly swaddled. MRI scan on day 89 demonstrated excessive signal intensity within the temporal lobes. There was atrophy of the left temporal lobe and insula. The thalami, subthalamic nuclei and basal ganglia were normal (Fig. 3). A presumptive diagnosis of HSV
349
Fig. 3. Coronal MRI scan of case 2 on day 89. Tz-weighted image, showing left parietal and periventricular white matter involvement, with cortical extension in left parietotemporal region.
encephalitis was based on the clinical picture and the results of immunological testing. The HSV antibody index was calculated from paired CSF and serum samples from days four and 29. No antibody was detected in the CSF from the first sample, but the latter showed HSV type 1 antibody of 1.51 enzyme immunoassay (EIA) units (normal < 0 . 6 ) and an antibody index of 4 . 0 (normal
d .
0
8
d
Movement Disorder Following Herpes Simplex Encepha I itis Daniel E. Shanks Peter A . BIasco David P. Chason
Herpes simplex virus (HSV) encephalitis is the most commonly identified form of severe focal encephalitis in man. Before the availability of specific antiviral therapy, mortality was greater than 70 per cent (Olson el af. 1967, Whitley et al. 1977). Acyclovir has reduced mortality to between 19 and 28 per cent, but morbidity among survivors remains as high as 34 per cent (Skoldenberg et al. 1984, Whitley et a/. 1986). Recurrence of neurological symptoms after initial improvement has been described following discontinuation of antiviral therapy (Koenig et af. 1979, Dix el af. 1983, Knezevic and Carroll 1983, Abramson et al. 1984, Whitley et al. 1986). The development of a movement disorder has been reported in one fouryear-old girl after recovery from HSV encephalitis (Abramson et al. 1984). We present two children who developed severe hyperkinetic movement disorders following antiviral treatment and improvement of their initial illness.
Case reports
348
CASE 1 A previously healthy eight-year-old girl presented with a six-day history of progressive fever, pharyngitis, vomiting and disorientation. On admission to hospital she had a temperature of 39.1 "C and neurological findings including stupor, dysarthria, profuse drooling and meningismus. Physical examination was otherwise normal. A head CT was normal. Blood counts and serum electrolytes were also normal and plasma glucose was 8.3mmol/L. A lumbar puncture produced clear, colorless fluid with the abnormalities listed in Table 1 . An EEG demonstrated high-amplitude, irregular spike and sharp wave activity in the left temporal and frontal regions. Acyclovir was started at a dose of 25mg/kg/day and continued for 21 days. As alertness increased
over several days, she manifested behavioral aberrations. She compulsively begged for food and drink and tried to eat non-food objects. Her longterm memory was intact, but short-term memory was severely disturbed. On day six a repeat head CT scan showed abnormalities involving the white matter of the left frontal lobe and the cortex of the left temporal lobe. On day nine a lumbar puncture was still abnormal (Table I). Cranial MRI showed areas of increased signal intensity in the left frontal and temporal cortex, and bilaterally in the white matter adjacent to the insulae and Sylvian fissures (Fig. 1). She had irregular fevers for the first 14 days in hospital. By day 26 she had improved, but continued to demonstrate confusion and disturbed eating behavior. All CSF viral cultures were negative after three weeks. On day 31 her mental status deteriorated and she had a generalized motor seizure, which was treated with phenytoin. The next day continuous choreic and ballismic movements appeared while she was awake, and she was unable to produce meaningful vocalizations or follow commands. The movement disorder precluded oral feeding, so a gastrostomy tube was inserted. Follow-up MRI scans showed that grey and white matter changes had progressed to involve the anterior left parietal lobe. No lesions were identified in the basal ganglia, thalami or subthalamic nuclei. The lumbar puncture on day 42 showed improvement (Table I). A brain biopsy of the left anterior temporal lobe on day 66 demonstrated mononuclear cell infiltration. No neural elements were identified and no viral particles were noted on electron microscopy. The PAP immunoperoxidase for HSV type 1 capsid antigen was positive in many monocytes and glia. Viral cultures of the biopsy material were negative. Over the subsequent months, treatment with haloperidol, acyclovir, prednisone, diazepam and lorazepam had no effect on the movement disorder. She gradually improved, and eight months after initial presentation she was ambulatory, with good extremity function and no adventitious movements. The gastrostomy tube was removed and she could speak clearly. Residual deficits of short-term memory, mild anomia and impulsivity persisted. An MRI scan 18 months after onset showed no change from the previous study (Fig. 2). CASE 2 This seven-month-old boy presented with fever, irritability, and seizures that were generalized tonicclonic as well as focal clonic. Physical examination was normal, except for lethargy. A lumbar puncture produced xanthochromic fluid, containing the abnormalities listed in Table 1. White blood cell count was 17.1 x 109/L, with 2 per cent band neutrophils, 53 per cent segmented neutrophils, 38 per cent lymphocytes and 6 per cent monocytes. Serum electrolytes and plasma glucose were normal, as was the initial unenhanced CT scan. Ceftriaxone was started on day one, and on day two acyclovir was added at a dose of 30mg/kg/day and continued for 10 days. An EEG showed left-hemisphere slowing, maximal in the anterior temporal region. Repeat head CT scan showed low density in the superior left temporal lobe. Repeat lumbar puncture on day 12 was improved (Table 1). He gradually
Fig. 2. Axial M R I scan of case I , 18 months after onset. Tz-weighted image, showing bilateral temporal and posterior frontal lobe involvement, with atrophy greater on left, and bilateral insular and parahippocampal involvement, again more extensive on left. Basal ganglia are not involved.
Fig. 1. Axial MRI scan of case I on day 10. Tz-weighted image, showing confluent areas of increased signal throughout medial temporal lobes and insulae, more extensive on left.
TABLE 1
Lumbar puncture findings WBCmm3
RBCmm3
Glucose fmmol/L)
Protein (g/L)
Patient I Day 1 Day 9 Day 42
38 (16184) 221 (100/0) 3
36 221 16
6 .0 3 .6 3.6
0.16 0.99 0.29
Patient 2 Day 1 Day 12 Day 28t
111 (13/ 87) 66 (15,435) 10 (90/10)
3150
4.0 3.3 3.5
0.88 0.56 0.59
f %PMN/Mono) *
1
120
*PMN = polymorphonuclear cells: Mono = mononuclear cells. TTraumatic tap. improved, and at discharge was alert and interactive. His only neurological residuum was a mild motor deficit on the right. On day 28 he had an onset of involuntary choreic and ballismic movements which involved the trunk and extremities and which ceased during sleep. His medications at that time were carbamazepine and phenobarbital. A lumbar puncture did not suggest recurrent infection (Table 1). A head CT scan revealed a new low-density lesion in the right temporal lobe and increased left temporal changes. On day 34 he began another 10-day course of
acyclovir. Neither discontinuation of the carbamazepine nor institution of haloperidol or sodium valproate influenced the movement disorder. Severe oral-motor dysfunction necessitated the placement of a gastrostomy tube. He was most comfortable, and partially able to feed by mouth, when tightly swaddled. MRI scan on day 89 demonstrated excessive signal intensity within the temporal lobes. There was atrophy of the left temporal lobe and insula. The thalami, subthalamic nuclei and basal ganglia were normal (Fig. 3). A presumptive diagnosis of HSV
349
Fig. 3. Coronal MRI scan of case 2 on day 89. Tz-weighted image, showing left parietal and periventricular white matter involvement, with cortical extension in left parietotemporal region.
encephalitis was based on the clinical picture and the results of immunological testing. The HSV antibody index was calculated from paired CSF and serum samples from days four and 29. No antibody was detected in the CSF from the first sample, but the latter showed HSV type 1 antibody of 1.51 enzyme immunoassay (EIA) units (normal < 0 . 6 ) and an antibody index of 4 . 0 (normal
