The potential for vigabatrin-induced intramyelinic edema in humans.

PURPOSE: Vigabatrin (Sabril, Hoechst Marion Roussel) is an antiepilepsy drug (AED) presently marketed in 64 countries for the treatment of partial and secondarily generalized seizures. Vigabatrin (VGB) is marketed in a subset of these countries for the treatment of infantile spasms. Clinical experience in humans has shown that VGB provides effective seizure control with a wide margin of safety. However, animal toxicity studies raised concern when prolonged administration of VGB was shown to induce intramyelinic edema (IME) in some laboratory animal species. METHODS: Animal and human data were reviewed with respect to the potential for VGB-induced IME. Surveillance of patients receiving VGB in clinical trials or by prescription has been conducted for >15 years to identify patients developing clinical abnormalities that might be IME related. RESULTS: The histologic lesions of VGB-induced IME in animals are reliably reproduced and correlate with changes in multimodality evoked potentials (EPs) and magnetic resonance imaging (MRI). Numerous studies of the effects of VGB on EP and MRI in epilepsy patients have demonstrated no clear-cut IME-related changes in these modalities. Additionally, autopsy and surgical brain samples from VGB-treated patients have been scrutinized for potential IME histopathology. In an estimated 350,000 patient-years of VGB exposure (approximately 175,000 patients exposed for 2 years at an average dose of 2 g/day), no definite case of VGB-induced IME has been identified. CONCLUSIONS: Comprehensive review of a variety of sources of data failed to identify any definite case of IME in humans treated with VGB.

Use of ex vivo magnetic resonance imaging to detect onset of vigabatrin-induced intramyelinic edema in canine brain.

Vigabatrin (VGB) causes intramyelinic edema (microvacuolation) in brain of dogs and rodent, which has encouraged development of noninvasive methods to monitor for this effect during clinical trials. We report the qualitative ex vivo magnetic resonance imaging (MRI) changes observed in a neuropathology study in dogs to detect time of onset and regression of VGB-induced intramyelinic edema. Beagles were randomly assigned to 18 groups of 6 dogs per group and administered vigabatrin orally (p.o.) at a dose of 300 mg/kg/day (2 males, 2 females) or placebo (1 male, 1 female). Animals were killed and examined at weekly intervals during the 12 weeks of treatment and at 1, 2, 4, 8, 12, and 16 weeks after discontinuation of drug treatment. Myelin microvacuolation in thalamus, hypothalamus, and fornix were noted histologically after 4-5 weeks of treatment. Increases in MRI T2 intensity were observed in hypothalamus after 4 weeks and in thalamus and columns of the fornix after 7 weeks. Both MRI T2 intensity and microvacuolation continued to increase during 12-week VGB treatment. When VGB treatment was discontinued after 12 weeks, both MRI T2 intensity and microvacuolation began to decrease. Sixteen weeks after VGB discontinuation, histopathology had returned to normal and MRI examination demonstrated a marked trend toward reversal of the increased T2 signal intensity. MRI thus has potential as a noninvasive surveillance technique in certain experimental and clinical conditions associated with intramyelinic edema.

Abnormal corpus callosum: a sensitive and specific indicator of multiple sclerosis.

The authors investigated whether identification of corpus callosal (CC) involvement might increase the specificity of magnetic resonance (MR) imaging in differentiating multiple sclerosis (MS) from other periventricular white matter diseases (PWDs). They prospectively evaluated 42 patients with MS and 127 control patients with other PWDs. Ninety-three percent of the MS patients demonstrated confluent and/or focal lesions involving the callosal-septal interface (CSI). These lesions characteristically involved the inferior aspect of the callosum and radiated from the ventricular surface into the overlying callosum. CSI lesions were optimally demonstrated on sagittal long repetition time (TR)/short echo time (TE) images and frequently (45% of cases) went undetected on axial images. Only 2.4% of the control patients had lesions of the CC. The authors conclude that midsagittal long TR/short TE images are highly sensitive and specific for MS and that callosal involvement in MS is more common than previously reported.

Iodine125 labeled anti-epidermal growth factor receptor-425 in the treatment of malignant astrocytomas. A pilot study.

In 1986, a pilot Phase I/II project was initiated using Iodine-125 labeled anti-epidermal growth factor receptor-425 in the treatment of patients with recurrent glioblastoma multiforme of the brain. The monoclonal antibody was administered intra-arterially by the internal carotid arterial system or the vertebral arterial system depending upon the blood supply to the tumor. The treatment program was repeated at intervals for two or three times. Demonstrated was the intense localization of the monoclonal antibody in the brain tumor prior to therapy using Indium-111 labeled anti-epidermal growth factor receptor-425. This localization was demonstrated prior to any therapy as well as after failure from primary radiation therapy with or without concomitant chemotherapy. To date, 15 patients have been treated following recurrence of their glioma (1/15 metastatic adenocarcinoma) with the monoclonal antibody labeled with Iodine-125. Of the 15 patients, there has been one surgically documented complete response, two partial responders, and five patients with stable disease. The results indicate the potential activity of this radiolabeled monoclonal antibody and have prompted continued accession of patients into a Phase II study as a part of the primary treatment regimen (surgery, radiation therapy with or without chemotherapy) followed by administration of the Iodine-125 labeled anti-epidermal growth factor receptor-425.

Intraocular tumors: evaluation with MR imaging.

Sixty-seven ocular tumors were studied with magnetic resonance (MR) imaging and computed tomography (CT). These tumors included primary uveal melanoma (n = 55), circumscribed choroidal hemangioma (n = 3), diffuse choroidal hemangioma (n = 1), retinal capillary hemangioma (n = 1), medulloepithelioma (n = 1), choroidal nevus (n = 1), retinoblastoma (n = 1), and choroidal metastases (n = 4). MR imaging demonstrated all these lesions, while CT demonstrated 88%. Associated retinal detachment was more easily distinguished from the neoplasms with MR imaging. Extrascleral extension of melanoma and hemorrhagic cystic necrosis within the melanoma were clearly demonstrated with MR imaging, but not with CT. Ninety-three percent of melanomas were markedly hyperintense, compared with the intensity of the vitreous body, on T1-weighted images and hypointense on T2-weighted images. All metastatic lesions were isointense on T1-weighted images and hypointense on T2-weighted images. The circumscribed choroidal hemangiomas were hyperintense on T1-weighted images and isointense on T2-weighted images. MR imaging is superior to CT in detection of intraocular tumors and may be more specific in diagnosis.

Infrasellar craniopharyngioma: CT and MR studies.

A rare case of an infrasellar craniopharyngioma is reported. Pathological proof and CT and magnetic resonance (MR) images of the tumor are presented. This case is thought to demonstrate the first example of MR images of an infrasellar craniopharyngioma. Evidence suggesting that the tumor originated from an infrasellar location is presented.

Sixth nerve schwannoma: MR and CT demonstration.

A sixth nerve schwannoma arising in the region of the pons and midbrain is reported. The magnetic resonance and CT characteristics are discussed.

CT demonstration of extraocular muscle atrophy.

Two cases of CT-documented extraocular muscle atrophy are presented. Unilateral atrophy was observed in a patient with a lesion of the cavernous sinus. Atrophic extraocular muscles were noted bilaterally in a young woman with "ophthalmoplegia plus" (probable Kearns-Sayre syndrome).

Computed tomography of posterior uveal melanomas.

Computed tomographic (CT) scans were obtained from 48 patients with posterior uveal melanoma. The CT measurements of maximal and minimal basal diameters and thickness of each tumor were compared with the assessments of these tumor dimensions obtained by ophthalmoscopic estimation (basal diameters only) and standardized A-scan ultrasonography (thickness only) and with the gross pathologic measurements of these tumors. The correlation between measurements of tumor thickness by CT scanning, standardized A-scan ultrasonography, and gross pathologic analysis was substantially better than that between the CT, ophthalmoscopic, and gross pathologic measurements of tumor basal diameters. Computed tomographic scanning appears to be a good method for determining the in vivo size of choroidal and ciliary body melanomas.

Orbital metastasis from a carcinoid tumor. Computed tomography, magnetic resonance imaging, and electron microscopic findings.

An otherwise asymptomatic 63-year-old woman with a history of a carcinoid tumor of the ileum and a cutaneous melanoma of the shoulder developed unilateral proptosis. Orbital ultrasonography, computed tomography, and magnetic resonance imaging revealed a large, well-circumscribed orbital mass involving the superior rectus muscle. The surgically excised tumor was studied by light microscopy, histochemistry, and transmission electron microscopy. These studies confirmed the diagnosis of carcinoid tumor. The clinical and pathologic features of this rare type of orbital metastasis are discussed.

Orbital metastasis: role of magnetic resonance imaging and computed tomography.

Imaging of ocular and oral metastasis with CT and MRI is discussed. The relative advantages and disadvantages of the two techniques are presented. MRI seems to be particularly useful in discriminating intraocular tumor from retinal detachment. Both techniques depict orbital lesions well.

Isolation of the right subclavian artery with subclavian steal in a child with Klippel-Feil anomaly: an example of the subclavian artery supply disruption sequence.

We studied a patient with Klippel-Feil anomaly and subclavian steal due to isolation of the right subclavian artery. Other anomalies included hypoplasia of the right clavicle and right vertebral artery, low bifurcation of the left common carotid artery and left choanal atresia. The patient was mentally retarded with corticospinal, cerebellar, and brain stem signs. The entire brain and cervical spinal cord were small; there was no central nervous system malformation, hydrocephalus, or bony impingement on neural structures. Embryologic vascular disorders have been found to be responsible for various congenital systemic and neurologic anomalies such as intestinal atresia and hydranencephaly. Subclavian artery supply disruption sequence has been hypothesized to result in Klippel-Feil, Poland, and Möbius anomalies. In this case the vertebral and facial abnormalities may well be related to anomalous subclavian and carotid supply. An embryonic vascular "steal" has been thought to cause the sirenomelia anomaly. We postulate that the subclavian steal, during the embryonic period, may have been responsible for the small size of this patient's cerebral hemispheres, brain stem, cerebellum, and cervical spinal cord.

CT of cerebral venous sinus thrombosis in a child with homocystinuria.

We describe a case of cerebral venous sinus thrombosis in a child with homocystinuria. We present both the classic CT findings of cerebral sinus thrombosis, and also the first report of the CT visualization of transdural venous collateral circulation.

Sixth nerve neuroma in the cavernous sinus: CT features.

A sixth nerve neuroma arising within the cavernous sinus is reported. This is the third sixth nerve neuroma cited in the world literature and the first to have CT demonstration. The unusual CT enhancement characteristics excluded the more common cavernous sinus masses and suggested the correct diagnosis preoperatively.

Exophthalmos caused by excessive fat: CT volumetric analysis and differential diagnosis.

CT has proven to be excellent in identifying orbital pathology responsible for proptosis. Occasionally, no discrete mass or extraocular muscle enlargement to explain the exophthalmos is found, only an appearance suggestive of an abnormal increase in orbital fat volume. Fifteen patients were studied with proptosis apparently resulting from increased orbital fat. Clinical follow-up revealed that four of them had Graves orbitopathy, unilateral in one; two had Cushing disease/syndrome; and nine were obese without endocrinopathy. The orbital volume and percentage orbital fat volume were measured by CT software analysis in these patients and in a control group of 16 patients without proptosis. Measurements of proptosis and thickness of the scalp fat pad at the inion level were also performed. Significantly greater values for orbital fat volume, percentage fat volume, and proptosis were found in the proptosis group compared with the control group. There was excellent correlation between proptosis and percentage fat volume, supporting the contention that increased orbital fat is responsible for the proptosis. The thickness of the scalp fat pad at the inion level was significantly greater in obese and Cushing patients than in control subjects, but the thickness was not significantly greater in Graves patients than in controls. Proptosis and inion fat were well correlated (r = 0.74) in the control and obese patients, which suggests a relation between general body fat and orbital fat volume.

CT of the normal pituitary gland.

Retrospective evaluation of the pituitary gland on coronal post-contrast CT scan in 251 patients demonstrated that the pituitary gland is somewhat larger in females than in males. In males, glands measuring greater than 7.7 mm should be considered abnormal; in females, a statistically significant decline of gland height occurs with increasing age, the upper limit of normal for female gland height decreasing from 9.2 cm for a 20-year-old to 6.0 cm for a 90-year-old. Focal low densities greater than 3 mm are rare in males and probably should be considered abnormal.

CT visualization of ruptured berry aneurysm within hematoma: the flip-flop sign.

Postcontrast CT of the head may be a useful screening technique for identifying an aneurysm within an intracerebral hematoma. This could avoid unnecessary angiography with its attendant morbidity in inoperable situations and obviate initial arteriography in patients whose surgery is to be delayed.