Hamartia in hippocampal sclerosis-associated mesial temporal lobe epilepsy.

Hamartia are small collections of rounded glioneuronal cells that are thought to be due to aberrant cell migration. Their presence has been recognized in association with mesial temporal lobe epilepsy; their prevalence among cases of hippocampal sclerosis (HS) and any potential association with patient demographics and outcomes is unknown. This study examines hamartia in a series of 292 patients with pathologically confirmed HS. Medical records were reviewed for pertinent patient clinical information (follow-up mean 5years). Hamartia were identified in 96 cases (33%) and were seen primarily in the amygdala (n=88) and less commonly in the hippocampus (n=10) and temporal lobe (n=4). A statistically significant relationship was found between the presence of hamartia and male gender, younger age of seizure onset, and history of childhood febrile seizures and developmental delay. It is unclear if these associations represent a real association or are a result of the underlying pathologies related to chronic epilepsy. At follow-up, there were no significant differences between patients who had hamartia and those who lacked this finding. Hamartia were observed in all subtypes of HS and there was a significant difference found in subtype distribution as well as proportion of cases between subtypes, but no association with any specific subtype overall. The presence of hamartia was not associated with the coexistence of focal cortical dysplasia or any specific histologic pattern of dysplasia. Hamartia are a common concomitant finding in HS and indicates evidence of aberrant cell migration in the hippocampal and parahippocampal regions in these patients.

Re-review of MRI with post-processing in nonlesional patients in whom epilepsy surgery has failed.

Management of MRI-negative patients with intractable focal epilepsy after failed surgery is particularly challenging. In this study, we aim to investigate whether MRI post-processing could identify relevant targets for the re-evaluation of MRI-negative patients who failed the initial resective surgery. We examined a consecutive series of 56 MRI-negative patients who underwent resective surgery and had recurring seizures at 1-year follow-up. T1-weighted volumetric sequence from the pre-surgical MRI was used for voxel-based MRI post-processing which was implemented in a morphometric analysis program (MAP). MAP was positive in 15 of the 56 patients included in this study. In 5 patients, the MAP+ regions were fully resected. In 10 patients, the MAP+ regions were not or partially resected: two out of the 10 patients had a second surgery including the unresected MAP+ region, and both became seizure-free; the remaining 8 patients did not undergo further surgery, but the unresected MAP+ regions were concordant with more than one noninvasive modality in 7. In the 8 patients who had unresected MAP+ regions and intracranial-EEG before the previous surgery, the unresected MAP+ regions were concordant with ictal onset in 6. Our data suggest that scrutiny of the presurgical MRI guided by MRI post-processing may reveal relevant targets for reoperation in nonlesional epilepsies. MAP findings, when concordant with the patient's other noninvasive data, should be considered when planning invasive evaluation/reoperation for this most challenging group of patients.

Effects of dual pathology on cognitive outcome following left anterior temporal lobectomy for treatment of epilepsy.

The objective of this retrospective study was to determine if dual pathology [DUAL - focal cortical dysplasia (FCD) and mesial temporal sclerosis (MTS)] in patients with left temporal lobe epilepsy is associated with greater risk for cognitive decline following temporal lobectomy than single pathology (MTS only). Sixty-three adults (Mage=36.5years, female: 52.4%) who underwent left anterior temporal lobectomy for treatment of epilepsy (MTS=28; DUAL=35) completed preoperative and postoperative neuropsychological evaluations. The base rate of dual pathology was 55.5%. Repeated measures ANOVAs yielded significant 2-way interactions (group×time) on most measures of language and memory with generally moderate effect sizes. Specifically, patients with MTS only demonstrated postoperative declines, while those with dual pathology remained unchanged or improved. Results suggest that dual pathology may be associated with better cognitive outcome following epilepsy surgery than MTS alone, possibly reflecting limited functionality of the resected tissue or intrahemispheric reorganization of function in the context of a developmental lesion.

Arteriovenous malformation of the brain mimicking primary central nervous system vasculitis.

In the diagnosis of primary central nervous system (CNS) vasculitis, it is crucial to rule out clinical, angiographic, and pathological mimics. We report a case of arteriovenous malformation (AVM) mimicking primary CNS vasculitis. A young male presented with intracerebral haemorrhage and no other clinical, laboratory, or angiographic features suggesting vasculitis. Cerebral biopsy showed perivascular inflammation and slight infiltration of the muscular layer of cerebral vessels by chronic inflammatory cells close to the haemorrhagic areas. These findings led to a diagnosis of CNS vasculitis. The patient was initially treated with corticosteroids, but 10 months after the discovery and surgical repair of the AVM, the patient is not receiving any immunosuppressant and has not developed any features of cerebral or systemic vasculitis.

ApoE-epsilon4 is associated with reduced memory in long-standing intractable temporal lobe epilepsy.

OBJECTIVE: To investigate the relationship between the apolipoprotein (ApoE) epsilon4 allele and memory performance (verbal and nonverbal) in patients with medically intractable temporal lobe epilepsy (TLE) who underwent temporal lobectomy. METHODS: Presurgical and postsurgical memory performance was examined in 87 adult patients with TLE (epsilon4 = 22; non-epsilon4 = 65) to determine whether the expression of ApoE-epsilon4 may be associated with memory performance in this population and to examine how this relationship may be affected by duration of epilepsy. RESULTS: There was a significant interaction between ApoE-epsilon4 status and duration of epilepsy such that epsilon4 carriers with a long duration of epilepsy demonstrated the poorest memory performance on both verbal and nonverbal measures. This relationship was observed both before and after temporal lobectomy, with little change in test performance over time. CONCLUSIONS: The ApoE-epsilon4 allele interacts with longstanding seizures to affect memory performance, both verbal and nonverbal, in patients with medically intractable temporal lobe epilepsy.

The value of interictal diffusion-weighted imaging in lateralizing temporal lobe epilepsy.

BACKGROUND: A subgroup of patients with nonlesional temporal lobe epilepsy (TLE) has no evidence of hippocampal sclerosis on standard temporal lobe protocol MRI. OBJECTIVE: To investigate whether interictal diffusion-weighted imaging adds lateralizing information in patients with TLE with and without lateralizing conventional MRI. METHODS: We studied 22 patients (9 right, 13 left TLE) who had undergone temporal lobectomy and 18 control subjects. We measured hippocampal volumes on high- resolution coronal magnetization-prepared rapid gradient echo scans. Apparent diffusion coefficients (ADCs) for the entire hippocampus and three arbitrarily defined areas of interest within the hippocampal head, body, and tail were measured from the coregistered ADC map. Pathology was reviewed and correlated with imaging findings. RESULTS: Fourteen of 22 patients had hippocampal atrophy on MRI (defined as volume asymmetry greater than 2 SDs compared with asymmetry in the control group). Overall, resected hippocampi (n = 22) were significantly smaller than contralateral hippocampi as well as ipsilateral hippocampi in controls. ADCs were significantly higher in resected hippocampi than contralateral hippocampi as well as ipsilateral hippocampi in controls. These differences were also observed within the three areas of interest. ADCs in the hippocampi contralateral to the epileptogenic zone (n = 22) were also higher than in ipsilateral hippocampi in controls. In the subgroup of eight patients with nonlateralizing conventional MRIs, ADCs of resected hippocampi were not significantly different compared with the contralateral side. Pathology in these patients revealed gliosis only without apparent neuron loss. CONCLUSION: Interictal apparent diffusion coefficients confirm lateralization in patients with hippocampal atrophy on standard temporal lobe protocol MRI. However, they do not provide lateralizing information in patients with nonlateralizing conventional MRI.

Predictors of outcome after temporal lobectomy for the treatment of intractable epilepsy.

To assess short- and long-term seizure freedom, the authors reviewed 371 patients who underwent anterior temporal lobectomy to treat pharmacoresistant epilepsy. The mean follow-up duration was 5.5 years (range 1 to 14.1 years). Fifty-three percent of patients were seizure free at 10 years. The authors identified multiple predictors of recurrence. Results of EEG performed 6 months postoperatively correlated with occurrence and severity of seizure recurrence, in addition to breakthrough seizures with discontinuation of antiepileptic drugs.

Branch retinal artery occlusions as the presenting feature of primary central nervous system vasculitis.

A 39-year-old woman presented with multiple branch retinal artery occlusions almost three years before developing a mass lesion containing calcium in the left frontal lobe. Brain biopsy revealed a small vessel vasculitis and ischemic necrosis of brain with dystrophic calcification. We believe this to be the first case of primary CNS vasculitis with branch retinal artery occlusions and brain calcification.

West Nile virus infection: a new acute paralytic illness.

OBJECTIVE: To determine the clinical, laboratory, electrodiagnostic, radiologic, and pathologic characteristics that define the spectrum of CNS disease caused by West Nile virus (WNV) infection. METHODS: The records of all patients hospitalized at the Cleveland Clinic from August 2002 to September 2002 with WNV infection were reviewed. RESULTS: Of 23 cases, the median age was 74 years old, and 74% were men. Symptoms included fever (100%), altered mental status (74%), gastrointestinal complaints (43%), back pain (35%), and rash (26%). In half, meningitis or encephalitis overlapped with flaccid weakness that progressed over 3 to 8 days, with a tendency to be proximal and asymmetric. Laboratory abnormalities included hyponatremia (30%) and initial CSF neutrophilic pleocytosis. Electrodiagnostic studies in two patients showed reduced motor amplitudes with normal conduction velocities and active denervation. In two other patients, reduced sensory amplitudes were also seen. MRI changes included cauda equina enhancement and parenchymal spinal cord signal abnormalities and parenchymal or leptomeningeal signal changes in the brain. Autopsy in three cases showed chronic perivascular inflammation in the brain and inflammatory changes with anterior horn cell loss in the spinal cord. CONCLUSION: An overlapping spectrum of meningitis, encephalitis, and myeloradiculitis occurs in CNS WNV infection. Fever, rash, abdominal and back pain, preceding a proximal, asymmetric flaccid weakness, with CSF pleocytosis help distinguish the motor syndrome from Guillain-Barré syndrome. Pathologic changes in the CNS resembled poliomyelitis.

Shah-Waardenburg syndrome and Dandy-Walker malformation: an autopsy report.

Autopsy reports of individuals with Shah-Waardenburg syndrome are rare, and to the best of our knowledge, have never been reported in association with Dandy-Walker malformation. This report documents the autopsy findings of a 2.5-year-old boy with Shah-Waardenburg syndrome (Type IV Waardenburg syndrome) and a Dandy-Walker malformation. The patient had a past medical history of congenital deafness, skin and hair pigmentary disturbances, Hirschsprun disease and hydrocephalus. At autopsy, multiple patches of dermal and hair hypopigmentation were observed over the face, trunk, eyelashes and eyebrows. The brain had a small, underdeveloped anterior cerebellar vermis, bilateral atrophic cerebelli, a markedly dilated ventricular system and a large incomplete midline cerebellar cyst. The entire colon and much of the small bowel had been previously excised secondary to the Hirschsprung disease. This case expands the spectrum of pathologic findings in Shah-Waardenburg syndrome to include the Dandy-Walker malformation.

Mycobacterium avium intracellulare otitis media.

Atypical mycobacterial infections of the middle ear are extremely rare. To our knowledge, only eight cases have been reported in the literature, five of which involve Mycobacterium avium intracellulare. We present a case of culture-proven, M. avium intracellulare otomastoiditis in an 8-year-old boy with common variable immunodeficiency syndrome. The patient clinically presented with pain and otorrhea. The histopathology was marked by acid-fast bacilli-laden histiocytes. Consideration of this entity in the differential diagnosis of chronic, recalcitrant otorrhea can lead to timely diagnosis, treatment, an decreased morbidity.

Metastatic adenocarcinoma to a pituitary adenoma.

Metastatic tumor to a pituitary adenoma has rarely been documented in the literature. We report a case of a 60-year-old man who presented with a history of progressive blurred vision and an incomplete homonymous hemianopsia. Magnetic resonance imaging showed a 5 cm heterogeneous mass which focally was contrast enhancing, involving the sella turcica and extending into the right cavernous sinus region. After worsening symptoms, repeat magnetic resonance imaging showed an increase in size of the lesion. Histologically, the mass consisted of a metastatic adenocarcinoma to a nonsecreting pituitary adenoma. The carcinoma stained focally positive with antibodies to carcinoembryonic antigen, cytokeratin 20, and p53 (60% of tumor cells), and did not stain with antibody to cytokeratin 7. The histologic appearance and immunohistochemical profile of the metastasis suggests a colorectal primary.

In situ expression of interleukin-4 (IL-4) receptors in human brain tumors and cytotoxicity of a recombinant IL-4 cytotoxin in primary glioblastoma cell cultures.

We have reported that human malignant glioma cell lines express high levels of plasma membrane interleukin-4 receptors (IL-4R). We have also reported that biopsy/surgical samples or primary explant cell cultures from brain tumors express mRNA and protein for the IL-4Ralpha chain, a primary IL-4-binding protein. However, whether IL-4R are expressed in brain tumors in situ has not been resolved. In addition, expression of IL-4R on the cell surface of various normal brain tissues is not known. We examined the expression of IL-4R by using a monoclonal antibody to the IL-4Ralpha chain (also known as IL-4R beta) in surgical/biopsy samples of brain tumor tissues by immunohistochemistry. Our data indicate that 15 of 18 glioblastoma multiforme (GBMs) tumors obtained from two different institutions and 12 other brain tumor samples are moderately to intensely positive for IL-4Ralpha. In contrast, although IL-4Ralpha mRNA was expressed, no IL-4R protein was detectable in two adult and one pediatric brain tissue specimens. In addition, a commercially available human neural tissue grid containing fixed tissues from various areas of brain showed no positive staining for the IL-4Ralpha chain. IL-4Ralpha expression was also demonstrated on astrocytoma grades I, II, and III. Because IL-4 cytotoxin comprised of a circularly permutated IL-4 and a mutated form of Pseudomonas exotoxin [IL4(38-37)-PE38KDEL] is cytotoxic to IL-4R-expressing cells, we tested whether primary GBM explant cell cultures are sensitive to IL-4 cytotoxin. Our data indicate that 13 of 15 GBM cell cultures were 25-74 times more sensitive to IL-4 cytotoxin compared with normal human astrocytes or the NT2 neuronal cell line. These observations indicate that human brain tumors in situ overexpress IL-4R compared with normal brain tissues, thus confirming our previous conclusions that IL-4R in brain tumors may serve as an attractive target for anticancer therapy.

Bcl-2, Bcl-x, and Bax expression by immunohistochemistry in inclusion body myositis: a study of 27 cases.

CONTEXT: Bcl-2, Bcl-x, and Bax are among the variety of proteins that have been described as being involved in the regulation of apoptotic cell death. Bcl-2 and Bcl-x(L) inhibit apoptosis, and Bax is proapoptotic. OBJECTIVE: To evaluate the expression of Bcl-2, Bcl-x, and Bax in inclusion body myositis (IBM).Design.-We examined muscle specimens from 27 patients (17 men, 10 women) with IBM to evaluate Bcl-2, Bcl-x, and Bax expression by immunohistochemistry. RESULTS: Patient ages ranged from 29 to 80 years (mean 62.2 years). All biopsies were marked by endomysial chronic inflammation, muscle fiber necrosis, and regeneration. Rimmed (autophagic) vacuoles were present in all cases. Ragged red fibers were noted in 4 biopsies (15%), and cytochrome oxidase-deficient fibers were found in 10 biopsies (37%). Ultrastructural evidence of intranuclear or cytoplasmic tubulofilamentous inclusions, confirming the diagnosis of IBM, were noted in all cases. Paracrystalline mitochondrial inclusions were seen in 5 biopsies (18.5%). Inflammatory cells stained positively with Bcl-2 in all biopsies, Bax in 26 biopsies (96%), and Bcl-x in 8 biopsies (30%). Degenerating muscle fibers were highlighted with Bax in 24 biopsies (89%), Bcl-2 in 2 biopsies (7%), and Bcl-x in 3 biopsies (11%). Regenerative muscle fibers were noted to stain with Bax in 24 muscles (89%), Bcl-2 in 21 muscles (78%), and Bcl-x in 4 muscles (15%). Rimmed vacuoles were highlighted by Bax in 24 biopsies (89%) and only rarely by Bcl-2 (n = 2, 7%) and Bcl-x (n = 3, 11%). A subsarcolemmal staining pattern was observed in 21 biopsies (78%) with Bax, 6 biopsies (22%) with Bcl-2, and only 1 biopsy (4%) with Bcl-x. CONCLUSIONS: (1) Bax (proapoptotic) immunostaining highlighted most autophagic vacuoles; (2) subsarcolemmal Bax and Bcl-2 immunoreactivity may be associated with mitochondrial defects that are commonly noted in IBM; (3) Bcl-2 and Bax immunoreactivity were not confined to degenerating muscle fibers and in fact appeared to be expressed more commonly in regenerating fibers, suggesting that their expression may be independent of apoptosis in the setting of IBM.

Diagnostic yield muscle biopsy in patients with clinical evidence of mitochondrial cytopathy.

We retrospectively reviewed 118 muscle biopsy specimens from 113 patients with clinical and/or biochemical evidence of mitochondrial cytopathy. Light microscopic evaluation revealed histologic abnormalities in 65 specimens. The most common histologic findings included angular atrophic esterase-positive muscle fibers, type II muscle atrophy, regenerating muscle fibers, and scattered cytochrome-oxidase deficient fibers. Ragged red fibers were noted in 3 specimens on a Gomori trichrome stain. Electron microscopic evaluation was performed in 113 muscle specimens, and in 34, no abnormalities were identified. Increased numbers of mitochondria, particularly in the subsarcolemmal region, were identified in 54 specimens. Increased mitochondrial size was seen in 8 specimens and paracrystalline mitochondrial inclusions in 3. Other ultrastructural findings included focally increased glycogen deposition, focal Z-band streaming, and focally increased lipid accumulation. For 39 cases, concomitant skin biopsy specimens were available; abnormalities were identified by electron microscopy in 12. The majority of biopsy specimens demonstrated some light or electron microscopic abnormality. Specific histologic findings suggestive of mitochondrial abnormalities (partial cytochrome oxidase deficiency, ragged red fibers) were noted in a minority of cases. Ultrastructural evidence of mitochondrial abnormalities was noted in the majority of cases.

Clinicopathologic study of retinoblastoma including MIB-1, p53, and CD99 immunohistochemistry.

UNLABELLED: Retinoblastoma is the most common intraocular tumor of childhood and has served as a model for the understanding or tumorigenesis. This study retrospectively examines the clinicopathologic features of 19 retinoblastomas and defines the MIB-1 (cell proliferation marker), p53 (tumor suppression gene), and CD99 (HBA71 or MIC2 antibody) immunoreactivity in 10 selected cases. Nineteen patients (11 boys), ranging in age from 6 to 47 months (mean, 20 months), were included for study. Clinical presentations included: leukocoria (n = 12), strabismus (n = 6), apparent decreased visual acuity (n = 5), and proptosis (n = 1). Five patients had bilateral tumors and one neoplasm arose in a patient with a known family history of retinoblastoma. All tumors were histologically characterized by a proliferation of small cells with high nuclear-to-cytoplasmic ratios. Commonly encountered histologic features included necrosis (n = 17, 89%), calcification (n = 16, 84%), fleurettes (n = 14, 74%), and Flexner-Wintersteiner rosettes (n = 11, 58%). Retinal involvement was noted in 18 tumors (95%) and optic nerve invasion in six cases (32%). The surgical optic nerve margin was positive in one case. Mitosis counts were evaluable in 18 cases and ranged from 1 to 42 mitotic figures/10 high power field (mean, 13 mitotic figures/10 high power field). Ten tumors were evaluated with MIB-1, p53, and CD99 antibodies by paraffin immunohistochemistry. MIB-1 labeling indices ranged from 31.4 to 77.1 (mean, 49.4). p53 immunostaining was observed in six tumors; less than 10% of tumor cells were noted to be p53 positive in each case. CD99 positivity was demonstrable focally in three tumors. Adjuvant chemotherapy and/or radiation therapy was administered in six patients. Tumor recurrence was not observed in any of the patients with a mean follow-up of 8.9 years. Only one patient died (20 years after enucleation) because of metastatic osteosarcoma. IN CONCLUSION: (1) Fleurettes and Flexner-Wintersteiner rosettes are variable findings in retinoblastoma. (2) Retinoblastomas are characterized by marked cell proliferation as evidenced by generally high mitosis counts and extremely high MIB-1 labeling indices, but this does not appear to adversely impact on prognosis. (3) Unlike peripheral primitive neuroectodermal tumors, most retinoblastomas do not stain positively with antibody to CD99. (4) Limited p53 immunostaining was present in 60% of tumors studied. (5) Enucleation with negative optic nerve margin is potentially curative in patients with retinoblastoma.

Desmoplastic infantile ganglioglioma (DIG): cranial ultrasound findings.

Desmoplastic infantile ganglioglioma (DIG) is a rare brain tumor encountered in infants. In spite of its large size at presentation and occasional high mitotic activity on histopathology, the tumor has a good prognosis. A 7-month-old baby girl developed increasing head circumference. On ultrasound, a large multicystic mass was seen. We report the cranial ultrasound findings for the first time. Correlative imaging of this recently recognized entity is shown.

Ultrastructural examination of the axillary skin biopsy in the diagnosis of metabolic diseases.

There is little information in the literature regarding the usefulness of ultrastructural examination of axillary skin biopsies in the evaluation of metabolic diseases. This is a retrospective clinicopathologic review of 143 patients who underwent axillary skin biopsies as part of evaluations for metabolic disease. Twenty-three (16%) had abnormalities, classified as follows: mitochondrial (n = 12), lysosomal (n = 6), increased glycogen (n = 3), nonspecific cytoplasmic inclusions (n = 2), ceroid lipofuscinosis (n = 1), and intradermal giant cells containing vacuoles and tubular inclusions (n = 1). Muscle biopsies were performed in 13 of the 23 patients; 11 showed abnormalities, including those related to mitochondria (n = 4) and other nonspecific changes (n = 7). Two patients underwent postmortem examination. Follow-up was available in 21 patients. A clinical or biochemical diagnosis was reached in 11 patients: metachromatic leukodystrophy (n = 2), electron transport chain abnormalities (n = 2), glutaric aciduria type II (n = 1), Unverricht disease (n = 1), Lennox-Gastaut syndrome (n = 1), ketotic hypoglycemia of childhood (n = 1), probable Leigh disease (n = 1), 5-methyl tetrahydrofolate homocystine methyltransferase deficiency (n = 1), and pyruvate dehydrogenase deficiency (n = 1). Of the 120 patients with negative skin biopsy results, 29 had abnormal findings on muscle (n = 27), nerve (n = 7), or brain (n = 3) biopsies. One patient had an abnormal heart biopsy result, and 3 patients underwent postmortem examinations. Follow-up was obtained in 27 of 29 patients. Diagnoses were achieved in 15 patients: electron transport chain abnormalities (n = 5), cortical dysplasia (n = 3), myoclonic epilepsy (n = 1), leukodystrophy (n = 2), Pallister-Killian mosaic syndrome (n = 1), Rett syndrome (n = 1), Landau-Kleffner syndrome (n = 1), and mitochondrial cardiomyopathy (n = 1). In conclusion, axillary skin biopsy is helpful in the evaluation of some causes of metabolic disease, but often the findings are nonspecific. A negative biopsy result does not rule out the possibility of metabolic disease, but a positive result may provide direction for further evaluation.

Dura mater involvement in ochronosis (alkaptonuria).

Clinical manifestations of alkaptonuria have been well described and are most commonly characterized by ochronosis or pigmentation of connective tissue. Sites most commonly involved in ochronosis include joints, heart, skin, and kidney. We describe a 66-year-old woman with a history of alkaptonuria who had widespread ochronosis. The dura mater showed extensive pigment deposition, which was evident both grossly and microscopically at autopsy. To our knowledge, description of dura mater involvement by ochronosis has not been previously reported in the literature.