Unilateral hippocampal mossy fiber sprouting and bilateral asymmetric neuron loss with episodic postictal psychosis

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✓ Rarely are both sides of the hippocampus available for pathological study in a patient with intractable temporal lobe epilepsy (TLE). The authors report a patient with TLE investigated with bilateral depth electrodes who had an episode of postictal psychosis. The patient died 4 weeks after temporal lobectomy of unknown reasons, despite complete postmortem examination and clinical evidence of postsurgery seizure control. Pathological examination of surgical and autopsy hippocampal specimens found bilateral asymmetric neuron losses. However, only the resected epileptogenic hippocampus showed the profile of neuron loss typical of mesial temporal sclerosis (MTS) and abnormal mossy fiber synaptic reorganization. Quantitative depth electroencephalographic (EEG) analysis of the postictal psychotic event showed that it was not associated with a cluster of seizures, increased postictal depth EEG spike activity, or insufficient antiepileptic medication. These results support the hypothesis that ipsilateral hippocampal epileptogenesis is associated with MTS and mossy fiber sprouting. The results also suggest that the etiology of postictal psychosis in this patient was initiated by an ictal event and the behavior apparently depended on seizure propagation outside the hippocampus. The relevance of these two findings to the literature is discussed.

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Address reprint requests to: Gary W. Mathern, M.D., Division of Neurosurgery, Reed Neurological Research Center, Room 2144, University of California at Los Angeles Center for Health Sciences, Los Angeles, California 90024–1769.

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    Scalp ictal electroencephalographic (EEG) recording of a typical complex partial seizure from this case study, presented as a bipolar montage using the international 10–20 system. At the onset of the seizure (left side of panel) a diffuse change in background EEG activity was seen. The first lateralized features were observed in the right temporal and frontal electrodes (Channels 1–4 and 9–11). Within 3 to 4 seconds a phase reversal was seen at the left sphenoidal electrode (S1, Channels 14–15). However, several seconds later the phase reversal shifted to the right sphenoidal electrode (S2, Channels 13–14). This was typical of all this patient's ictal scalp EEG recordings and was interpreted as a “non-lateralized ictal EEG” recording. Calibration bar = 1 second in the horizontal direction; in the vertical direction the bar equals 100 µV before the sensitivity change and 150 µV after the change (see line in middle of figure).

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    Preoperative neuroimaging studies. Left: Representative T2-weighted magnetic resonance image oriented perpendicular to the hippocampal axis, showing that the left hippocampus (arrow) was smaller than the right. Right: Representative positron emission tomography scan, enhanced axial view, showing a mild amount of decreased interictal utilization in the left mesial temporal structures (arrow).

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    Depth electrode ictal recording. Multicontact electrodes were placed orthogonally through both temporal lobes with the most mesial contacts (numbered 1 and 2) in the hippocampal complex and the lateral contacts (numbered 7 and 8) in the lateral temporal neocortex. There were four electrodes in the right (R) temporal lobe and five electrodes in the left (L) temporal lobe (A = amygdala; AP = anterior pes hippocampus; PG = posterior hippocampal gyrus; MP = middle pes hippocampus; AG = anterior hippocampal gyrus). The ictal onset of all of this patient's typical seizures began diffusely throughout the left mesial electrode contacts (LAP 1–2, LMP 1–2, LAG 1–2, and LPG 1–2; channels 6–9). The left amygdala (LA 1–2, channel 5) was not initially involved in the seizure, nor were the other depth EEG contacts. Calibration bars = 1 second horizontally and 300 µV vertically.

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    Photomicrographs (A and B) and graph (C) illustrating bilateral hippocampal pathology. Timm's-stained high-magnification sections from the fascia dentata of the surgically removed left (A) and the right (B) hippocampus that underwent autopsy are oriented with the inner molecular layer (IML) at the top, followed by the stratum granulosum (SG), and the hilus (H) at the bottom. Note the significant aberrant mossy fiber sprouting into the IML of the surgically removed left hippocampus (A) compared to no sprouting on the opposite side (B). Bar = 50 µm. C: The hippocampus showed bilateral loss of principal neurons in most subfields compared to control tissue. The surgically removed left hippocampus (solid boxes and line) showed an average neuron loss of 56% and a profile of damage typical of mesial temporal sclerosis (MTS). There was an 18% decline in neurons in CA-2, while the CA-1 (80% loss) and prosubiculum (PRO; 85% loss) showed much greater damage. The autopsied right hippocampus (circles and dashed line) also showed neuron loss that averaged 30%. However, the profile was diffuse and not specific for MTS.

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    Graph illustrating the mean time course, after bilateral depth electrode recording, of interictal spike frequency (bars ± standard error of the mean), seizures (solid arrows), carbamazepine (CBZ) levels, and episode of postictal psychosis. The frequency of the interictal hippocampal spiking was determined as the number of spikes over 10 minutes in the mesial temporal depth electrode contacts. Several epochs were counted and the mean and standard error determined. There were a large number of interictal spikes in the immediate postimplant period, which is not unusual in depth recordings. The patient was not psychotic during this period but did often complain that she felt as if a seizure were about to begin. Over the next several days the frequency of interictal spiking decreased, as did the auras. With her second typical seizure on Day 13 she became transiently psychotic during the postictal period, at which time the amount of spike activity increased slightly compared to the previous day but not significantly compared to the immediate postimplant period. The psychotic episode cleared within a few hours. Following two more seizures on Days 14 and 16 the interictal activity was greater on Day 17 compared to the postictal psychotic episode, and she was not clinically psychotic. Note that the carbamazepine level was in the therapeutic range before and after the psychotic episode. Finally, inspection of the depth recording for several hours prior to the psychotic episode did not disclose any subclinical seizures, and there were interictal spikes at regular intervals every few seconds.

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