F. Curtis Dohan

Autoimmunity due to molecular mimicry as a cause of neurological disease

One hypothesis that couples infection with autoimmune disease is molecular mimicry. Molecular mimicry is characterized by an immune response to an environmental agent that cross-reacts with a host antigen, resulting in disease. This hypothesis has been implicated in the pathogenesis of diabetes, lupus and multiple sclerosis (MS). There is limited direct evidence linking causative agents with pathogenic immune reactions in these diseases. Our study establishes a clear link between viral infection, autoimmunity and neurological disease in humans. As a model for molecular mimicry, we studied patients with human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a disease that can be indistinguishable from MS (refs. 5,6,7). HAM/TSP patients develop antibodies to neurons. We hypothesized these antibodies would identify a central nervous system (CNS) autoantigen. Immunoglobulin G isolated from HAM/TSP patients identified heterogeneous nuclear ribonuclear protein-A1 (hnRNP-A1) as the autoantigen. Antibodies to hnRNP-A1 cross-reacted with HTLV-1-tax, the immune response to which is associated with HAM/TSP (refs. 5,9). Immunoglobulin G specifically stained human Betz cells, whose axons are preferentially damaged. Infusion of autoantibodies in brain sections inhibited neuronal firing, indicative of their pathogenic nature. These data demonstrate the importance of molecular mimicry between an infecting agent and hnRNP-A1 in autoimmune disease of the CNS.

A grading system for mesial temporal pathology (hippocampal sclerosis) from anterior temporal lobectomy

A practical grading system based on routine light microscopic examination that quantifies histopathlogy of mesial temporal damage in temporal obectomy specimens is proposed. The aim of this grading system is to standardize the terminology used in reporting mesial temporal pathology that will help provide a means of comparing patient populations in research reports. This proposed system has five tiers that range from no hippocampal pathology present to Grade IV (marked hippocampal sclerosis) with three intermediate grades. Our internal blinded testing shows this grading system to be reliable and reproducible when used independently among individual pathologists.

Pathological status of the mesial temporal lobe predicts memory outcome from left anterior temporal lobectomy.

This investigation tested the hypothesis that the degree of impairment to memory function caused by an anterior temporal lobectomy (ATL) is inversely related to the pathological status of the resected hippocampus. Specifically, the greatest risk to postoperative memory function should be to patients with no or minimal hippocampal sclerosis, i.e., those with a functional hippocampus. Forty patients who underwent a partial resection of the left (n = 21) or right (n = 19) anterior temporal lobe were administered tests of immediate and delayed verbal and figural memory, both preoperatively and 6 months postoperatively. The degree of postoperative impairment in memory function was then investigated as a function of the degree of hippocampal sclerosis, as determined by a standardized procedure. For a left ATL, an absence or mild degree of hippocampal sclerosis was associated with significantly greater postoperative impairment of both verbal and figural memory, compared with patients with moderate or marked sclerosis. No statistically significant relationship was noted for patients who underwent a right ATL, but the findings were in the same direction for five of six memory measures. It may be possible to predict and avoid surgically induced impairment of memory function among patients who undergo left ATL through the use of preoperative hippocampal volumetric magnetic resonance imaging. Better clinical tests of right hippocampal function are needed to predict the outcome for patients who undergo a right ATL.

Relationship of hippocampal sclerosis to duration and age of onset of epilepsy, and childhood febrile seizures in temporal lobectomy patients

Controversy exists as to whether hippocampal sclerosis (HS) is a preexisting cause or a consequence of seizures. We investigated 122 consecutive patients who underwent anterior temporal lobectomy for intractable epilepsy between 1989 and 1992. MRI scans were normal apart from evidence of HS in 5 cases. The degree of HS was graded from 0 to 4. There was a significant inverse correlation between age of seizure onset and grade of HS (P < 0.0001), and a positive correlation between duration of epilepsy and grade of HS (P < 0.001). Using a dichotomous grouping of HS (HPSC - for grades 0 and 1 [no/mild HS], and HPSC + for grades 3 and 4 [moderate/marked HS]), there was a positive correlation between HPSC + and a history of childhood febrile seizures (CFS) (P = 0.003), earlier age of onset of epilepsy (P < 0.001) and longer duration of epilepsy (P < 0.001). There was no correlation with history of particularly prolonged individual seizures. Partial correlations after controlling for age at onset of epilepsy showed that there was no longer a significant relationship between HPSC + and duration of epilepsy. After controlling for duration of epilepsy, the relationship between HPSC + and age of onset remained significant (P < 0.001). The correlation between HPSC + and CFS, controlling for age at onset, was not significant. A series of logistic regression analyses showed age at onset to be the only predictor of HPSC +. It is concluded that this is supportive evidence for preexisting HS being a cause of temporal lobe epilepsy and not a consequence of seizures.

Naming Decline After Left Anterior Temporal Lobectomy Correlates with Pathological Status of Resected Hippocampus

Summary: Purpose: To evaluate the determinants of postoperative change in visual confrontation naming ability and the differential sensitivity of two common tests of confrontation naming.

Neuropsychological outcome following anterior temporal lobectomy in patients with and without the syndrome of mesial temporal lobe epilepsy.

The nature, pattern, and degree of neuropsychological change following anterior temporal lobectomy (ATL) were examined as a function of the presence or absence of the syndrome of mesial temporal lobe epilepsy (MTLE). Fifty-four patients exhibited the syndrome of MTLE, while 34 patients were without the syndrome (non-MTLE). The test-retest performance of a group of 40 epilepsy patients who did not undergo surgery was used to derive regression-based estimates of test-retest change. Overall, the MTLE group did not show significant cognitive decline following ATL. In contrast, the left non-MTLE group showed significant declines on verbal memory, confrontation naming, and verbal conceptual ability. Further, verbal memory was the most substantial area of decline, and was independent of seizure outcome. Clinical and theoretical implications of these findings are discussed.

Reports by Patients and Their Families of Memory Change after Left Anterior Temporal Lobectomy: Relationship to Degree of Hippocampal Sclerosis

ABSTRACT: MEMORY DECLINE REPRESENTS the primary neuropsychological morbidity of anterior temporal lobectomy. Recent investigations using laboratory tests of memory have reported an association between the neuropathological status of the resected left mesial temporal region and memory outcome, with adverse memory outcome associated with a lack of significant left hippocampal pathology. The purpose of this investigation was to examine the relationship between the reports by the patients and their families of observed postoperative changes in day‐to‐day memory function and the degree of hippocampal sclerosis in resected left mesial temporal lobes. Twenty patients and a close family member (parent or spouse) of each of the patients completed standardized questionnaires assessing pre‐ to postoperative changes in verbal and spatial memory; these were related to the neuropathological findings. The results indicated that patients without left hippocampal sclerosis reported significantly worse memory outcome than those with hippocampal sclerosis. The ratings provided by the relatives of the patients yielded a comparable effect, and objective memory tests supported the reports by the patients and their families. The neuropsychological findings associated with left hippocampal pathology are of clinical significance and should be considered in surgical evaluation and in the counseling process.

Reorganization of verbal memory function in early onset left temporal lobe epilepsy.

The purpose of this investigation was to examine the issue of reorganization of verbal memory function following early insult to the left mesial temporal region. It was hypothesized that reorganization of memory function was most likely to occur in those patients with an early age of seizure onset who have a more limited degree of extra-hippocampal neuropathology. Fifty-four patients with epilepsy of unequivocal left temporal lobe origin were classified into four groups on the basis of the presence/absence of hippocampal sclerosis and degree of postoperative seizure relief. Measures of verbal learning and memory as well as nonmemory measures were administered both before and 6 to 8 months after anterior temporal lobectomy. Findings were consistent with the reorganization proposal. The clinical and theoretical significance of the findings are discussed.

Gliomas of the Tectum and Periaqueductal Region of the Mesencephalon

Gliomas that arise in the tectal and periaqueductal region of the mesencephalon usually present with hydrocephalus secondary to occlusion of the aqueduct of Sylvius. A review of 486 brain tumors in children treated during a 5-year period revealed 6 children with gliomas of the tectal plate. The 6 children were shunted for hydrocephalus, presumed secondary to aqueductal stenosis, prior to establishing the diagnosis of tectal plate glioma. No abnormalities were noted on the initial, uncontrasted computed tomography (CT) scans. The tumors are isodense without contrast enhancement which makes the CT diagnosis difficult. Magnetic resonance imaging (MRI) is diagnostic and demonstrates the characteristic enlargement of the tectum with increased density on T2 images. T1 density and gadolinium enhancement are variable. Pathological confirmation was obtained by open biopsy in 2 patients, a stereotaxic biopsy was performed on 2 children; 2 children were not biopsied. The tumor histology obtained was that of pilocytic astrocytoma. Two patients were treated with radiation therapy at the time of diagnosis. One child was followed closely and subsequently irradiated after tumor progression. All patients in this series are alive and functioning adequately 2-10 years after the onset of symptoms.

Hippocampal sclerosis and verbal encoding ability following anterior temporal lobectomy

Previous research has shown that the degree of verbal memory decline following left anterior temporal lobectomy (ATL) is inversely related to the extent of neuronal dropout in resected left hippocampus. The goal of this investigation was to clarify further the nature of the free recall impairment and to determine the relative contribution of verbal retrieval and encoding processes. Seventy-six patients who underwent left (n = 46) or right (n = 30) ATL were classified according to the presence or absence of hippocampal sclerosis and pre- to postoperative changes in free recall, cued recall and recognition memory for verbal material were examined. Surgically induced free recall impairments were selectively associated with resection of nonsclerotic left hippocampus and represented a 29-35% decline in verbal learning ability. These free recall deficits were due to postoperative impairment in verbal encoding efficiency, not retrieval difficulties. Assessment of false positive recognition errors indicated that resection of nonsclerotic left hippocampus selectively impaired the ability to encode stimulus uniqueness within correct semantic fields. The clinical and theoretical significance of these results are discussed.