Choreoathetosis After Herpes Simplex Encephalitis With Basal Ganglia Involvement on MRI
【摘要】 Children with herpes simplex virus encephalitis have a relapse in 25% of cases, which rarely may present as a movement disorder, most often choreoathetosis. The anatomic basis for herpes simplex virus encephalitis-associated movement disorders has been poorly understood, because neuroimaging, to date, has not been able to show the direct involvement of the areas of the brain that typically govern such movements. We present a patient with abnormal involuntary movements after herpes simplex virus encephalitis, with new lesions on MRI between the time of initial presentation and the development of choreoathetosis. To our knowledge, this is the first patient with a post-herpes simplex virus encephalitis movement disorder with neuroradiographic evidence of thalamic involvement correlating with the onset of abnormal involuntary movements. We describe this patient and review the literature on movement disorders and herpes simplex virus encephalitis. Current understanding of the pathophysiology of post-herpes simplex virus encephalitis movement disorders proposes 2 possible mechanisms that may be responsible: reinfection with the resumption of viral replication, or a postinfectious, immune-mediated process.
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【关键词】 acyclovir antiviral therapy movement disorder encephalitis pediatric disease
Movement disorders associated with post-herpes virus encephalitis (HSE) have been infrequently reported in the literature; scattered case reports exist, and the most recent reviews of the topic date back nearly a decade. Advances in neuroimaging, the understanding of disease mechanisms, and epidemiologic updates have prompted a review of the literature encompassing this morbid condition.
We describe an 8-month-old infant girl who presented post-HSE with 4 extremity ballismus and choreoathetosis, tongue-thrusting, and involuntary vocalizations. On evaluation she was found to have new signal abnormality in the medial thalamus on a comparison brain MRI and a negative cerebrospinal fluid (CSF) herpes simplex virus (HSV) polymerase chain reaction (PCR).
To our knowledge, this is the first case of post-HSE choreoathetosis/ballismus with a demonstrated anatomic correlate in the acute phase. These findings, as characterized on additional detailed MRI studies, add to the understanding of the mechanism of post-HSE movement disorders.
CASE REPORT
An 8-month-old previously healthy girl was brought to the emergency department with 4 days of fever where the peak temperature reached 104°F, with increasing lethargy, and 1 day of vomiting. On arrival, she was noted to have mild extensor posturing and upward eye deviation. Initial cranial computed tomography (CT) scan results revealed a hypodense lesion in the right frontal lobe without evidence of midline shift or intracranial bleed.
Lumbar puncture results were suggestive of viral meningoencephalitis: total protein, 37 mg/dL; glucose, 90 mg/dL; white blood cell count, 93 mg/dL; (3 neutrophils, 44 lymphocytes, 53 phagocytes, and 0 other cells), red blood cell count, 9 mg/dL. Fluid was clear, colorless, and negative for xanthochromia. The patient was initially treated with 20 mg/kg intravenous acyclovir every 8 hours for 21 days.
The results of an bedside electroencephalogram confirmed subclinical status epilepticus. The patient was treated with lorazepam and loaded with fosphenytoin and phenobarbital, then intubated and treated with fentanyl and midazolam infusions. The patient was extubated after 24 hours, maintained on phenobarbital monotherapy, and had no additional seizures after the first several days.
MRI results on hospital day 1 with and without contrast revealed edema of the frontal lobes on the right greater than left side, with involvement of the cingulate gyrus and parahippocampal gyrus on the right (Fig 1). Serum immunoglobulin G (IgG) results were mildly low at 228 mg/dL (range of 232–1411 mg/dL) and, given the concern for possible West Nile virus encephalitis, the patient received 1 mg/kg of intravenous immunoglobulin.
FIGURE 1 Initial MRI (hospital day 1) demonstrating bilateral frontal edema with involvement of the cingulate and parahippocampal gyri. (fluid-attenuated inversion recovery [FLAIR] axial image.)
The CSF qualitative HSV PCR results were positive (not typed). Toxoplasma IgG and IgM, varicella virus PCR, Bartonella henselae IgG and IgM, cytomegalovirus PCR, arbovirus panel (West Nile, Eastern equine, and Saint Louis encephalitis PCR), and enterovirus PCR results were negative. Positive measles IgG and mumps IgG results indicated immunity.
The patient showed dramatic clinical improvement during a 3-week hospitalization. By the time of discharge, she had regained the majority of previously learned developmental motor skills and was verbal and interactive. Of interest is the fact that the patient's mother had observed that the patient had stopped expressing angry emotions or a pain response. Painful stimuli, such as a blood draw needle stick, did not elicit a response.
The patient was readmitted to the hospital 6 days after discharge because of severe choreoathetoid and ballistic movements of the upper and lower extremities, tongue thrusting, and involuntary vocalizations, which had developed over a 3-day period. She did not track and did not seem to respond to voices (see Movie 1, which is published as supporting information on www.pediatrics.org/content/full/121/4/e1003). Results of a repeat lumbar puncture revealed the following: total protein, 130 mg/dL; glucose, 42 mg/dL; white blood cell count, 74 mg/dL (0 neutrophils, 95 lymphocytes, 5 phagocytes); red blood cell count, 1 mg/dL. Fluid was clear, colorless, and negative for xanthochromia. The results of a repeat CSF qualitative HSV PCR were negative.
Electroencephalographic test results did not reveal any abnormal correlate during the choreoathetoid and ballistic movements. Repeat brain MRI results 4 days after onset of symptoms revealed the evolution of the intracranial injury with encephalomalacia in the bilateral frontal and temporal lobes and patchy involvement of the medial occipital and parietal regions. In addition, there was new involvement of the medial thalamus bilaterally (Fig 2). On the advice of the Infectious Disease service, the patient was started on an additional course of 10 mg/kg per day of intravenous acyclovir for 10 days.
FIGURE 2 A, MRI, 2 weeks after initial MRI, showing dramatic involution of frontal lobes with new involvement of bilateral thalami at the time of presentation with movement disorder (FLAIR axial image). B, DWI from MRI 2 weeks after initial MRI, with lack of signal changes in the thalamus, suggesting inflammation as opposed to infarction.
Because of the possibility that her symptoms were related to an adverse drug effect, phenobarbital was discontinued and levetiracetam substituted for anticonvulsant coverage. The patient was treated with maximal doses of clonazepam, which was only partly effective in reducing the movements. After several days, risperidone at 0.2 mg, orally, 3 times a day was added. She developed a fever on day 2 of risperidone, prompting its discontinuation. She received a 7-day burst of prednisone, beginning with 6 mg orally 1 time per day (0.9 mg/kg per dose), and tapering by 1 mg per day, which was repeated consecutively when the first dose showed little benefit. The second burst was likewise ineffective. The patient was discharged from the hospital on levetiracetam and clonazepam. At the time of discharge, she demonstrated mild improvement of the abnormal movements. The patient continued to have tongue thrusting, poor muscle tone, and poor responses to visual and auditory stimuli.
The patient was readmitted 2 weeks later because of persistent, disabling choreoathetosis. During this brief admission, a third MRI was taken 30 days after the onset of movement disorder. The MRI results demonstrated continued gross involution of the frontal cortex and persistent signal abnormality in the basal ganglia (Fig 3). In the subsequent 6 months after this final admission, the patient continued to have 1 to 2 seizures per day, but an improvement in her movement disorder. The patient has not regained lost developmental skills and is unable to sit unassisted, track, or speak.
FIGURE 3 A, MRI performed 5 weeks after initial MRI, with striking frontal lobe involution and enhancement of the right parietal lobe (FLAIR axial image). B, Third MRI, performed 3 weeks after second MRI, showing dramatic involution of frontal lobes with evolving bilateral thalamic involvement, correlating with persistent choreoathetosis (FLAIR axial image).
At our institution, standard MRI protocols include a diffusion-weighted imaging (DWI) sequence, which is recognized as a means of separating cytotoxic edema from vasogenic edema, with cytotoxic edema generally being interpreted as a reflection of acute infarction. DWI results in our patient distinguish the signal changes seen in the cortex (frontal, temporal, occipital) from those in the thalamus; the former are consistent with areas of infarction (cytotoxic edema) and the latter with inflammation (vasogenic edema). DWI from the second series of MRI images also revealed no changes in the thalamus (Fig. 2B).
DISCUSSION
Choreoathetosis has been infrequently cited in the literature as a clinical presentation of HSV encephalitis relapse.1 The majority of reported cases predate neuroimaging or are from the CT era, where a small number of MRI results have been reported. To our knowledge, none of the cases of HSV encephalitis with movement disorder have demonstrated involvement of the basal ganglia, thalamus, or subthalamic nuclei.2,3,5,7,9 Given the lack of structural and functional abnormalities on imaging, and the generally bland CSF with little evidence of reinfection, the mechanism underlying post-HSE movement disorders remains enigmatic. Some sources speculate that damage to the frontal, parietal, and temporal lobes may injure neural connections to the basal ganglia and thalamic structures.2,5,8 The demonstrated involvement of thalamic structures in this patient can help shed light on the underlying mechanism of movement disorders associated with the relapse of HSV encephalitis.
In 1994, Lee and Marsden10 reviewed movement disorders after lesions of the thalamus or subthalamic region. They analyzed 62 cases of movement disorder associated with a focal lesion of the thalamus and/or subthalamic region. Nine case results revealed bilateral paramedian thalamic involvement, 7 patients of whom developed bilateral dyskinesia, and 2 who had unilateral dyskinesia; 1 patient with paramedian thalamic infarction had bilateral chorea involving abnormal tongue movements. Some of these case results occurred in children, but the authors did not stratify the data according to age. Their results underscore the many connections that the thalamus has with basal ganglia and other brain structures governing movement.
Arguably the most comprehensive literature review of proven HSV encephalitis associated with involuntary movements in pediatric patients was performed by Hargrave and Webb in 1998.5 Hargrave and Webb identified 19 published case studies with a median age at presentation of 11 months and a slight female: male preponderance. Eighteen of the 20 patients developed the movement disorder as part of a "clinical relapse." Relapse, as defined by seizure, altered consciousness, or fever, developed at a median of 28 days after the initial illness. Choreoathetosis of the limbs occurred in all 20 patients, and tongue writhing with orofacial dyskinesia developed in 7. Only 2 of the patients had normal CSF findings. CT scan results were normal in 5 patients and revealed either unilateral or bilateral temporal lobe lesions in 11. The basal ganglia and thalamus were reported to be normal in all cases studied (N = 16), both acutely and at the time of clinical relapse when abnormal involuntary movements occurred.
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HSV was isolated in 2 children with "early relapse" (defined as within 2 weeks of onset) but in only 1 of 13 cases with relapse at 1 month after onset.5 The authors concluded that inadequate antiviral therapy was not likely the cause of relapse, and that reinfection seemed to be an unlikely cause of the movements in the majority of cases. They additionally concluded that antiepileptic drug (AED) adverse effects were unlikely to contribute to presentation, because various AEDs were used in the case studies. They further note that although neuroimaging studies were not suggestive of anatomic damage to the basal ganglia, additional neuroimaging studies would likely be informative. Finally, they hypothesize that the biphasic pattern of the illness suggests an immune-mediated postinfectious cause of the post-HSE movement disorder.5
A recent study revealed the presence of antibasal ganglia antibodies in the CSF of a 2-year-old girl who was admitted with post-HSE chorea.6 Similar to the results of this article, this child presented with severe chorea 3 weeks after initial HSE. CSF HSV-PCR results were negative. Of interest is the fact that MRI results demonstrated bilateral temporal edema and cortical necrosis without evident involvement of the basal ganglia or thalamus. This article sheds light on the etiology of post-HSE movement disorders by revealing an antibody-mediated effect that involves brain structures governing movement.
An interesting correlate to the latter study is a 1990 case report by Takahashi et al11 that reveals neonatal HSE with calcifications of the thalamus and basal ganglia. In this case, the infant developed myoclonus and fever as presenting symptoms of HSE. A CT scan 5 days after presentation was normal, and the diagnosis of HSE was not made until 3 weeks after presentation. A follow-up CT scan performed 12 days after the initial CT scan showed calcification of the thalamus, basal ganglia, and right frontal lobe. However, it is important to note that neither a clinical relapse nor a post-HSE movement disorder was reported in this infant. Furthermore, some clinicians would classify neonatal HSE and HSE acquired after 4 to 6 weeks of age as distinct entities; most neonatal HSE is herpes virus type II children and most nonneonatal HSE is herpes virus type I.
A retrospective analysis from a tertiary hospital in Pakistan reviewed 68 cases of HSE from 1990 to 2002.7 Subjects' ages ranged from 1 to 82 years with a mean age of 31 years. Results were not classified according to age. Clinical encephalitis was defined as having fever, seizures, altered mental status, aphasia, and/or hemiparesis. Fifty percent of patients had a CT scan, 42% had an MRI, and 8% had both. Sixty-six percent of affected patients had an abnormal CT or MRI scan. Of these patients, 34 (50%) had abnormalities of the temporal lobes, and 11 had extratemporal lesions (16% of all patients, 24% of those with neuroimaging abnormalities). The study did note " basal ganglia and brainstem were involved in a few cases," although also stating that "the regions typically spared include white matter and basal ganglia." This study represents 1 of the largest and most recent comprehensive analyses of HSV encephalitis in all ages, although it did not distinguish data for pediatric patients nor did it specifically address movement disorders. Nevertheless, it is significant in that it underscores the not uncommon finding of HSV lesions outside of the temporal lobes.
The mechanism of post-HSE choreoathetosis has been hotly debated in the literature, especially given the absence of gross pathology on imaging in the areas of the brain that control movement. Early studies implicated anticonvulsant medication adverse effects, and recommended the avoidance of AEDs, especially phenobarbital and carbamazepine.8 This recommendation has been contested, because patients present with symptoms after being treated with a wide range of AEDs. Moreover, patients have continued with abnormal involuntary movements despite the discontinuation of AED therapy. In our patient, phenobarbital was discontinued on readmission with the concern that the choreoathetosis was related to her AED therapy. However, she showed no improvement when taken off phenobarbital.
The current theories regarding the etiology of relapse involve 2 mechanisms that may be responsible: resumption or reinfection by HSV with active viral replication, or an immune-mediated postinfectious process. De Tiège et al3 analyzed 42 pediatric patients with HSE between 1990 and 1997 with relapse and temporal, parietal, or temporoparietal lesions on CT. The authors concluded that relapse occurs as 2 separate entities: postinfectious (immune-mediated) changes tend to present with choreoathetosis, a negative CSF HSV PCR, and the absence of new hemorrhagic/necrotic lesions on imaging, whereas reinfection presents as fever with new neurologic symptoms, a positive CSF HSV PCR, and the absence of extrapyramidal movements. The authors additionally distinguish between early and late relapse, associating the former with reinfection and ineffective or inadequate acyclovir treatment and the latter with innate, likely inherited, HSV-specific immune susceptibility. Of note, they reiterate that structural neuroimaging has failed to show lesions of the basal ganglia and thalamus, which would help localize the involved anatomic structures.3
The distinction between active reinfection and postinfectious, inflammatory encephalopathy is unquestionably crucial, because the former would be managed with a repeat course of acyclovir, and the latter with corticosteroids and, possibly, intravenous immunoglobulin or even plasmapheresis.3 Given these parameters, our patient presents a management conundrum. The patient presented with a negative CSF HSV PCR and choreoathetosis, which would suggest a postinfectious etiology. However, she had striking new lesions on MRI and presented within 1 month of initial disease onset, which suggested possible reinfection. As would be expected with postinfectious inflammation, the patient did not improve with a 10-day repeat course of acyclovir, despite the dramatic improvement after her initial 21-day course.
HSE is a morbid disease, with a 70% mortality rate in the absence of treatment and 10% with current antiviral therapy.5 Approximately 25% of children are observed to have a clinical relapse in the setting of HSE.3 Presentations associated with movement disorders have an estimated mortality rate of 20%; additionally, 50% of survivors with HSE-associated movement disorders have a poor neurodevelopmental outcome. There is a slowly accumulating body of literature on these rare movement disorders that are associated with HSE. One obstacle to understanding the pathologic basis of these disorders has been the absence of involvement of brain structures governing movement on neuroimaging studies. Our patient presented with choreoathetosis after HSE, with lesions in the thalamus, which could not be seen on MRI after initial infection. This finding suggests a clear association between the development of thalamic lesions and a movement disorder in our patient. The diffusion-weighted MRI sequence additionally helped distinguish the thalamic lesions from other areas of brain involvement, because it did not show the same signal changes and, thus, suggested inflammation rather than infarction.
This patient creates an opportunity to review current understanding of the pathogenesis of post-HSE movement disorders. Clinical relapses have been organized into an early, often reinfectious process versus a late, postinfectious inflammatory process. A clear-cut dichotomy is difficult, given the overlap in timing and in symptoms at presentation. Indeed, without a brain biopsy to confirm active viral replication in neuronal cells, it would be difficult to definitively rule out residual active HSV infection in any given case. This makes treatment with an antiviral agent, at least initially, necessary.4 However, mounting evidence seems to favor an immune-mediated, noninfectious process in the overwhelming majority of children who present with post-HSE movement disorders. This pathophysiology also fits with the emerging understanding of other postinfectious antibody-mediated movement disorders such as those than may occur in Sydenham's chorea, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection, and paraneoplastic syndromes.
The literature on HSE and movement disorders is limited by the rarity of this condition. Future studies are needed to document patient presentation, abnormal findings on imaging, treatments, and outcomes. It is the hope that retrospective analyses of larger patient populations may provide additional insight into disease pathogenesis and guide appropriate management.
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Marschitz, I, Rödl, S, Gruber-Sedlmayr U, et al. Severe chorea with positive anti-basal ganglia antibodies after herpes simplex encephalitis.J Neurol Neurosurg Psychiatry. 2007;78(1):105–107
Shanks DE, Blasco PA, Chason DP. Movement disorder following herpes simplex encephalitis.Dev Med Child Neurol. 1991;33(4):348–352
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