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Epileptic Disorders

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Benzodiazepine receptor imaging in an adult with Rasmussen's encephalitis and epilepsia partialis continua Volume 13, numéro 2, Juin 2011

epd.2011.0427

Auteur(s) : Hiroshi Kataoka1 hk55@naramed-u.ac.jp, Takayuki Shinkai2, Takao Kiriyama1, Yasuyo Tonomura1, Satoshi Ueno1

1 Department of Neurology

2 Radiation Oncology, Nara Medical University, Kashihara, Nara, Japan

Correspondence: H. Kataoka Department of Neurology, Nara Medical University 840 Shijo-cho, Kashihara, Nara 634-8522, Japan

Rasmussen's encephalitis (RE) is a rare immuno-mediated disorder with onset usually in childhood; some cases in adults have been reported. Clinically, RE is characterised by intractable focal epilepsy and progressive hemispheric dysfunction. Progressive cerebral hemiatrophy on computed tomography and magnetic resonance imaging is a characteristic finding of RE which has contributed greatly to establishing a clinical diagnosis (Bien et al., 2005). Brain fluorine-18 fluorodeoxyglucose (FDG)-positron emission tomography (PET) or single-photon emission computed tomography (SPECT) using Tc-99m hexamethyl-propylamine-oxime (HMPAO) or technetium-99m-ethyl cysteinate dimer (Tc-ECD) tracers also show large areas of severe hypometabolism or hypoperfusion from the fronto-temporal to the posterior cortical regions, related to progressive atrophy (Bien et al., 2005; Villani et al., 2006).

Here, we describe an adult with RE since childhood, associated with widespread decreased accumulation of tracer on 123-I iomazenil (IMZ) SPECT.

Case study

A 38-year-old, right-handed man with no family history of convulsive disorders first manifested partial motor seizures involving the right limbs at five years of age. Birth was uneventful and his subsequent development was normal. When he was 11 years old, partial motor seizures and secondary generalised seizures developed. Electroencephalography (EEG) showed asymmetric slow background rhythms with left dominance and some sharp waves in the left hemisphere. He received oral anticonvulsant drugs and the frequency of seizures decreased. However, partial motor seizures in the orolingual region persisted.

At 28 years of age, he had difficulty in walking and had partial motor seizures in the orolingual region and right limbs, with no impairment of consciousness. Mild weakness of the right limbs was present. Cranial MRI showed mild cerebral atrophy in the left frontal and temporal lobes, without abnormal intensity. Increased doses of anticonvulsant drugs such as phenytoin (250 mg/day), carbamazepine (800 mg/day), phenobarbital (170 mg/day), and clonazepam (1.0 mg/day) reduced the frequency or duration of partial motor seizures, but motor weakness persisted.

When he was 34 years old, episodes of right hemiclonic seizures and secondary generalized seizures with impaired consciousness and vocalization increased in frequency. EEG showed frequent epileptic discharges and diffuse delta waves confined to the left hemisphere. Hemiatrophy in the left frontal, parietal, and temporal lobes on cranial MRI developed. Cerebrospinal fluid showed no pleocytosis, and the results of viral studies were negative, showing low serum titres of antibodies to a variety of viruses, including measles. Autoantibodies (IgG and IgM) against the N-methyl-d-aspartate glutamate receptor (NMDA-type GluR) epsilon2 subunit and its epitopes were detected in serum and cerebrospinal fluid. Tc-ECD and IMZ SPECT studies were performed using a three-headed γ-camera (Multi-SPECT3, Siemens, United States of America) at 34 years of age. Tc-ECD SPECT imaging with a fan-beam collimator was started 10 minutes after an intravenous bolus injection of 600 MBq Tc-99m ECD. Tomographic data with a slice thickness of 5.78 mm were obtained continuously for 20 minutes. Static data were acquired in 128×128 matrices. The data were prefiltered using a Ramp filter with a high cut-off value. IMZ SPECT imaging with a parallel-hole collimator was performed 20 (early image) and 180 minutes (delayed image) after an intravenous bolus injection of 167 MBq [123I]iomazenil. Tomographic data with a slice thickness of 4.92 mm were obtained continuously for 20 minutes. The data were recorded in 128×128 matrices. A Butterworth and Ramp filter was used for image reconstruction. Attenuation correction of both Tc-ECD and IMZ SPECT was performed by Chang's method. Tc-ECD showed mildly decreased accumulation in the left temporal region (figure 1B). During the SPECT study, the patient did not have a seizure. Delayed IMZ SPECT showed widespread decreased accumulation of tracer in the left temporal and frontal regions and the cerebellum (figure 1D and 1d). An early scan also showed decreased accumulation in the same regions, but the decreases in the frontal and temporal regions were narrower than those on the delayed images (figure 1C and 1c). Switching from carbamazepine to zonisamide (300 mg/day) resolved the generalized seizures, but partial motor seizures of the right side of the face and orolingual region persisted. He required assistance in daily living.

At 37 years of age, episodes of partial clonic seizures involving the face and right limbs with generalized seizures occurred frequently. Serial cranial MRI confirmed the development of progressive left hemiatrophy over the course of 12 years (figure 1A). Since we considered surgical intervention to prevent frequent seizures, we repeated IMZ SPECT to detect the seizure focus. Three-dimensional stereotactic surface projection (3D-SSP) analysis showed that the decreased regions on delayed IMZ images were slightly larger as compared with the previous IMZ study performed at 34 years of age (figure 1b and 1d), but the decreased frontal and temporal regions on early IMZ images had apparently not increased (figure 1a and c). The generalized seizures and partial clonic seizures were resolved by modifying the doses of anticonvulsant drugs such as phenytoin (190 mg/day), zonisamide (460 mg/day), phenobarbital (110 mg/day), and clonazepam (1.5 mg/day). The frequency and magnitude of partial motor seizures in the orolingual region were reduced to approximately 40% and 70%, respectively. At follow-up after 15 months, partial seizures in the face and orolingual region persisted and generalized seizures occurred occasionally.

All SPECT images were assessed by visual inspection and performed independently by two experienced reviewers who were blinded to clinical data. In the event of disagreement, a decision was reached by consensus.

Discussion

The patient had a form of epilepsia partialis continua and neurological deterioration associated with hemiatrophy. The presence of unilateral progressive brain atrophy is a cardinal feature of RE (Bien et al., 2005). Brain biopsy, which we did not perform, is not required in all cases of RE because abnormal and normal tissue elements are located in very close apposition, which may lead to non-specific results (Bien et al., 2005; Pardo et al., 2004). The European consensus statement has proposed diagnostic criteria focusing on clinical, electroencephalographic, and neuroimaging features (Bien et al., 2005), which strongly support the diagnosis of RE in the patient.

In our patient, 123-I IMZ showed large areas of decreased accumulation ipsilaterally to brain atrophy. This tracer is a central benzodiazepine receptor ligand with a high affinity for the A subtype of the gamma aminobutyric acid (GABA) receptor (Innis et al., 1991). This receptor is expressed on virtually all cortical and striatal neurons (Olsen, 1981). Delayed images on IMZ SPECT are considered to represent benzodiazepine receptor density (neuronal density) (Onishi et al., 1995). Histopathological examination in RE reveals chronic progressive encephalitis, showing neuronal loss and gliosis (Bien et al., 2005). IMZ SPECT can provide direct information on the extent of neuronal loss in RE. Flumazenil PET of specific and high affinity GABAA receptor images has suggested that receptor concentration may sometimes decrease independently of neuronal density (Hammers et al., 2001). If the decrease of IMZ on delayed images is related to the decreased benzodiazepine receptor concentration, this could contribute to epileptogenicity.

In our patient, some regions without decreased accumulation of Tc-ECD showed a decrease in 123-I IMZ. Decreased accumulation of Tc-ECD tracer in late-stage encephalitis is caused by severe neuronal damage, leading to decreased metabolism and hence reduced regional cerebral blood flow (Launes et al., 1988). Launes et al. proposed that regions with decreased IMZ uptake and increased HMPAO uptake in a patient with herpes simplex encephalitis were signs of inflammation-induced early neuronal loss (Launes et al., 1995). Early IMZ images are considered to represent blood flow, and the regions without decreased accumulation on the early images showed a decrease on the delayed images, as shown in figure 1 (white arrow). These regions also newly showed decreased accumulation on a second series of delayed images. Moreover, the mismatched regions did not show abnormal intensity on conventional MRI. [11C](R)-PK11195 PET imaging of activated microglia/brain macrophages detects a range of neuroinflammation of which conventional MRI does not unequivocally indicate an inflammatory tissue reaction (Banati et al., 1999). We speculate that the difference in uptake between Tc-ECD or early IMZ images and delayed IMZ images might reflect early neuronal loss or neuroinflammation. However, the differences may suggest not only a decrease in IMZ, but also a partial volume effect or the effects of long-term treatment with antiepileptic medications.

The cerebellum of our patient showed mild atrophy and decreased IMZ accumulation. Previously, hemisphere atrophy associated with contralateral cerebellar atrophy or alternated accumulation on SPECT has been reported in patients with RE (Tessonnier et al., 2009).

This crossed phenomenon was attributed to damage of the corticopontocerebellar pathway (Tessonnier et al., 2009). RE is associated with a greater tendency to bilateral disease, and our cerebellar phenomenon can be explained by bilateral damage of the pathway. However, we ascribe the phenomenon to long-term treatment with phenytoin, causing cerebellar degeneration or atrophy (McLain et al., 1980).

Conclusion

This case study suggests that benzodiazepine receptors may be reduced in the affected hemisphere of patients with RE. Benzodiazepine receptor imaging may be useful for monitoring disease progression in RE.

Disclosure

None of the authors has any conflict of interest or financial support to disclose.