Isolated seizures are a common early feature of paraneoplastic anti-GABAB receptor encephalitis.

OBJECTIVE: To report the clinical features and long-term outcome of 22 newly diagnosed paraneoplastic patients with GABAB receptor antibodies (GABABR-Abs). METHODS: Retrospective clinical study of CSF-confirmed cases of GABABR-Abs encephalitis. RESULTS: We identified 22 patients (4 female) with GABABR-Abs, with a median age of 64 years (range 55-85). All were paraneoplastic: 20 small-cell lung cancer, one malignant thymoma, and one uncharacterized lung mass. The most frequent first symptom was the isolated recurrent seizures without cognitive inter-ictal impairment in 17 patients (77%). In the other, three presented the first behavioral disorders and two presented de novo status epilepticus (SE). After a median delay of 10 days (range 1-30), the recurrent seizures' phase was followed by an encephalitic phase characterized by confusion in 100% of cases and SE in 81% (n = 17), with 53% (n = 9) non-convulsive SE. Dysautonomic episodes were frequent (36%, n = 8, bradycardia and central apnea) and killed three patients. CSF study was abnormal in 95% of the cases (n = 21). At the encephalitic phase, MRI showed a temporal FLAIR hypersignal in 73% (n = 16) of the cases. First-line immunotherapy was initiated after a median delay of 26 days (range 6-65) from disease onset, and a partial response was observed in 10 out of 20 patients (50%). There was no complete response. Two years after onset, a massive anterograde amnesia affected all still alive patients. Nine patients died from cancer progression (median survival: 1.2 years). CONCLUSION: Paraneoplastic GABABR-Abs encephalitis is characterized by a stereotype presentation with an epilepsy phase before an encephalitic phase with dysautonomia. The functional prognosis is poor.

Temporal lobectomy with delayed amnesia following a new lesion on the other side.

PURPOSE: To describe a delayed severe complication of temporal lobectomy for intractable epilepsy. METHOD: A case of amnesia occurring 24 years after surgery is described and five similar cases from the literature reviewed. RESULTS: Mean age at surgery (5 right) was 40 years (19-62 years), 3 female. Four of five tested had impaired visual and verbal memory preoperatively but not sufficient to contraindicate surgery. Pathology was mesial temporal sclerosis in 3, 1 cavernoma, 1 dysembryoplastic neuroepithelial tumor (DNET) and 1 normal. Postoperatively, four were seizure free 3-12 years off medication and two continued with seizures. There was no unexpected postoperative memory change until incapacitating anterograde amnesia developed 1-24 years after surgery. In five patients, including ours, this followed definite or possible status epilepticus with new mesial temporal sclerosis on the opposite side in the four that were investigated by MRI. One patient developed a glioblastoma in the opposite temporal lobe. CONCLUSION: Continuing or late recurrence of seizures from the remaining temporal lobe after temporal lobectomy can result in incapacitating amnesia if status epilepticus occurs. Other new lesions on the opposite side to surgery can have the same effect.

Prevalence and clinical characteristics of unremembered nocturnal eating in diabetic subjects: Kurume sleep trouble in obesity and metabolic disorders (KUSTOMED) study.

Nighttime food intake is associated with weight gain and higher HbA1c levels. We experienced night eaters who have no memory of their nocturnal eating in the morning. In this study, the curious night eating behavior was designated as "unremembered nocturnal eating syndrome (UNES)". We screened 1,169 patients with diabetes for sleep quality and abnormal eating behavior at night using the Pittsburgh Sleep Quality Index questionnaire with an additional question regarding UNES. When abnormal nocturnal eating behavior was noted, detailed clinical information was extracted from interviews with the patients. We identified 9 patients who experienced UNES. They had a higher BMI compared with subjects who reported no such episodes. Among them, 6 patients who consumed food at night without memory 2-5 times per month or more had significantly higher HbA1c levels. Continuous glucose monitoring in a patient with type 1 diabetes revealed an abrupt elevation of glucose levels from midnight when some foods were consumed. Eight of the 9 patients were taking benzodiazepine and/or non-benzodiazepine hypnotic agents when they experienced the episodes. The prevalence of UNES was 0.8% in all subjects and 4% in those taking hypnotic drugs. The ratio of hypnotic drug use in subjects with UNES was significantly higher than for individuals without UNES (89% vs. 17%, p<0.0001). Although UNES seems to be etiologically heterogeneous, hypnotics-induced parasomnia and/or anterograde amnesia may be associated with the behavior. UNES is not rare in diabetic patients on hypnotic medicine and may be a hidden cause of unexpected morning hyperglycemia.

Hypoxia/reoxygenation impairs memory formation via adenosine-dependent activation of caspase 1.

After hypoxia, a critical adverse outcome is the inability to create new memories. How anterograde amnesia develops or resolves remains elusive, but a link to brain-based IL-1 is suggested due to the vital role of IL-1 in both learning and brain injury. We examined memory formation in mice exposed to acute hypoxia. After reoxygenation, memory recall recovered faster than memory formation, impacting novel object recognition and cued fear conditioning but not spatially cued Y-maze performance. The ability of mice to form new memories after hypoxia/reoxygenation was accelerated in IL-1 receptor 1 knockout (IL-1R1 KO) mice, in mice receiving IL-1 receptor antagonist (IL-1RA), and in mice given the caspase 1 inhibitor Ac-YVAD-CMK. Mechanistically, hypoxia/reoxygenation more than doubled caspase 1 activity in the brain, which was localized to the amygdala compared to the hippocampus. This reoxygenation-dependent activation of caspase 1 was prevented by broad-spectrum adenosine receptor (AR) antagonism with caffeine and by targeted A1/A2A AR antagonism with 8-cyclopentyl-1,3-dipropylxanthine plus 3,7-dimethyl-1-propargylxanthine. Additionally, perfusion of adenosine activated caspase 1 in the brain, while caffeine blocked this action by adenosine. Finally, resolution of anterograde amnesia was improved by both caffeine and by targeted A1/A2A AR antagonism. These findings indicate that amygdala-based anterograde amnesia after hypoxia/reoxygenation is sustained by IL-1ß generated through adenosine-dependent activation of caspase 1 after reoxygenation.

Dissociable anterograde amnesic effects of retrosplenial cortex and hippocampal lesions on spontaneous object recognition memory in rats.

The amnesic effects of excitotoxic lesions of the rat retrosplenial cortex (RS) and hippocampus (HPC) in the spontaneous object recognition (SOR) performance were investigated. The SOR test consisted of the sample-exposure session(s) and a test session. First, to test retrograde amnesia, rats received four sample-exposure sessions within a day at 4 weeks and 1 day before the surgery, respectively. In the test sessions conducted 1 week after the surgery, both lesion groups showed a temporally ungraded retrograde amnesia. Second, to test anterograde amnesia, 1- and 4-week retention intervals were inserted between the four sample-exposure sessions and the test session. The RS-lesioned rats showed a retention interval-dependent impairment in the test sessions, while the HPC-lesioned rats showed an impairment regardless of the retention interval. Finally, to test short-term recognition memory, 5- or 30-min delay was interposed between the single sample-exposure session and the test session. Both lesion groups performed normally irrespective of the delay length. These results suggest that both the RS and HPC are important for long-term object recognition memory, but these areas have different roles in it.

EPS Mid-Career Award 2006. Understanding anterograde amnesia: disconnections and hidden lesions.

Three emerging strands of evidence are helping to resolve the causes of the anterograde amnesia associated with damage to the diencephalon. First, new anatomical studies have refined our understanding of the links between diencephalic and temporal brain regions associated with amnesia. These studies direct attention to the limited numbers of routes linking the two regions. Second, neuropsychological studies of patients with colloid cysts confirm the importance of at least one of these routes, the fornix, for episodic memory. By combining these anatomical and neuropsychological data strong evidence emerges for the view that damage to hippocampal-mammillary body-anterior thalamic interactions is sufficient to induce amnesia. A third development is the possibility that the retrosplenial cortex provides an integrating link in this functional system. Furthermore, recent evidence indicates that the retrosplenial cortex may suffer "covert" pathology (i.e., it is functionally lesioned) following damage to the anterior thalamic nuclei or hippocampus. This shared indirect "lesion" effect on the retrosplenial cortex not only broadens our concept of the neural basis of amnesia but may also help to explain the many similarities between temporal lobe and diencephalic amnesia.

Anterograde and retrograde amnesia of place discrimination in retrosplenial cortex and hippocampal lesioned rats.

Retrograde and anterograde amnesic effects of excitotoxic lesions of the rat retrosplenial cortex (RS) and hippocampus (HPC) were investigated. To test retrograde amnesia, rats were trained with two-arm place discrimination in a radial maze 4 wk and 1 d before surgery with a different arm pair, respectively. In the retention test 1 wk after surgery, both lesion groups showed temporally ungraded retrograde amnesia. To test anterograde amnesia, animals were trained after surgery to discriminate three arm pairs successively within a day, and then after interposition of 1- to 4-wk intervals, one of these pairs, respectively, was tested for retention. RS-lesioned rats could acquire these pairs of place discriminations rapidly but showed a retention interval-dependent impairment in the retention test. Conversely, HPC-lesioned rats took more sessions to acquire these pairs than did the control group, and their retention was approximately 70% of correct performance regardless of retention interval. Results suggest that RS and HPC have different roles in spatial memory and that RS is important for remote memory process.

Aprendizaje de nombres en una paciente con amnesia anterógrada / Names learning in an anterograde amnesic patient

En este trabajo se describe la aplicación de algunas técnicas empleadas para la rehabilitación de la memoria en personas con daño cerebral, con el fin de facilitar el aprendizaje de nombres de personas cercanas y conocidas en una paciente de 55 años, universitaria, diestra y quien como secuela de una encefalitis herpética presentó lesión isquémica en territorio frontotemporal izquierdo y severas alteraciones cognoscitivas y funcionales. Aunque la aplicación combinada de técnicas favorece los procesos de aprendizaje, éstos suelen ser lentos y desgastantes en personas con amnesia severa. No obstante, los resultados apoyan la propuesta de la conservación de la memoria implícita en esta población y favorecen el planteamiento de perspectivas de intervención.

In this work, we describe the application of some techniques used for the memory rehabilitation in people with brain damage, in order to facilitate learning the names of close and known persons in a 55 year old patient, college graduate, right handed, with herpetic encephalitis who presented injury in left frontotemporal region and severe cognitive and functional alterations. As show in the results, of the six names selected for the intervention, it was possible to work with three of them and to obtain significant results in two. Although the mix of techniques favors the learning processes, this process is usually slow in people with severe amnesia. However, these results support the proposal of the implicit memory conservation and favor the intervention from this perspective.

Cerebellar lesions: is there a lateralisation effect on memory deficits?

BACKGROUND: Until recently, neurosurgeons eagerly removed cerebellar lesions without consideration of future cognitive impairment that might be caused by the resection. In children, transient cerebellar mutism after resection has lead to a diminished use of midline approaches and vermis transection, as well as reduced retraction of the cerebellar hemispheres. The role of the cerebellum in higher cognitive functions beyond coordination and motor control has recently attracted significant interest in the scientific community, and might change the neurosurgical approach to these lesions. The aim of this study was to investigate the specific effects of cerebellar lesions on memory, and to assess a possible lateralisation effect. METHODS: We studied 16 patients diagnosed with a cerebellar lesion, from January 1997 to April 2005, in the "Centre Hospitalier Universitaire Vaudois (CHUV)", Lausanne, Switzerland. Different neuropsychological tests assessing short term and anterograde memory, verbal and visuo-spatial modalities were performed pre-operatively. RESULTS: Severe memory deficits in at least one modality were identified in a majority (81%) of patients with cerebellar lesions. Only 1 patient (6%) had no memory deficit. In our series lateralisation of the lesion did not lead to a significant difference in verbal or visuo-spatial memory deficits. FINDINGS: These findings are consistent with findings in the literature concerning memory deficits in isolated cerebellar lesions. These can be explained by anatomical pathways. However, the cross-lateralisation theory cannot be demonstrated in our series. The high percentage of patients with a cerebellar lesion who demonstrate memory deficits should lead us to assess memory in all patients with cerebellar lesions.

Limbic encephalitis - a review.

The clinical features of limbic encephalitis are diverse and early diagnosis of the disorder is frequently difficult. Four patients with limbic encephalitis are described. An antineuronal antibody was identified in three of these patients. Antibodies directed against voltage-gated potassium channels, the N-methyl-D-aspartate receptor and an unidentified neuropil antigen were each found in one patient. The fourth patient had multifocal paraneoplastic encephalitis associated with small cell lung cancer. The clinical and imaging findings associated with these antibodies and the other antineuronal antibodies described in patients with limbic encephalitis are reviewed. An approach to the diagnosis and management of limbic encephalitis is presented.

Post-transplant acute limbic encephalitis: clinical features and relationship to HHV6.

BACKGROUND: Acute limbic encephalitis has been reported in the setting of treatment-related immunosuppression and attributed to human herpesvirus-6 (HHV6) infection. Clinical and laboratory features of the syndrome, however, have not been well characterized. METHODS: We describe the clinical, EEG, MRI, and laboratory features of nine patients with acute limbic encephalitis after allogeneic hematopoietic stem cell transplantation (HSCT). To explore the relationship between HHV6 and this syndrome, we reviewed available CSF HHV6 PCR results from all HSCT patients seen at our center from March 17, 2003, through March 31, 2005. RESULTS: Patients displayed a consistent and distinctive clinical syndrome featuring anterograde amnesia, the syndrome of inappropriate antidiuretic hormone secretion, mild CSF pleocytosis, and temporal EEG abnormalities, often reflecting clinical or subclinical seizures. MRI showed hyperintensities within the uncus, amygdala, entorhinal area, and hippocampus on T2, fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging (DWI) sequences. CSF PCR assays for HHV6 were positive in six of nine patients on initial lumbar puncture. All patients were treated with foscarnet or ganciclovir. Cognitive recovery varied among long-term survivors. The one brain autopsy showed limbic gliosis and profound neuronal loss in amygdala and hippocampus. Among 27 HSCT patients with CSF tested for HHV6 over a 2-year period, positive results occurred only in patients with clinical limbic encephalitis. CONCLUSIONS: Patients undergoing allogeneic hematopoietic stem cell transplantation are at risk for post-transplant acute limbic encephalitis (PALE), a distinct neurologic syndrome. Treatment considerations should include aggressive seizure control and, possibly, antiviral therapy. PALE can be associated with the CSF presence of human herpesvirus-6, but the pathogenic role of the virus requires further exploration.

Acquired amnesia in childhood: a single case study.

We report the case of C.L., an 8-year-old child who, following the surgical removal of an ependymoma from the left cerebral ventricle at the age of 4 years, developed significant difficulties in retaining day-to-day events and information. A thorough neuropsychological analysis documented in C.L. a severe anterograde amnesic syndrome, characterised by normal short-term memory, but poor performance on episodic long-term memory tests. In particular, C.L. demonstrated virtually no ability to recollect new verbal information several minutes after the presentation. As for semantic memory, C.L. demonstrated general semantic competencies, which, depending on the test, ranged from the level of a 6-year-old girl to a level corresponding to her actual chronological age. Finding a patient who, despite being severely impaired in the ability to recollect new episodic memories, still demonstrates at least partially preserved abilities to acquire new semantic knowledge suggests that neural circuits implicated in the memorisation of autobiographical events and factual information do not overlap completely. This case is examined in the light of growing literature concerned with the dissociation between episodic and semantic memory in childhood amnesia.

[Tumour of the corpus callosum: the association between interhemispheric disconnection and an anterograde amnesia syndrome]. / Tumor del cuerpo calloso: asociación de la desconexión interhemisférica con un síndrome de amnesia anterógrada.

INTRODUCTION: Sperry, or interhemispheric disconnection, syndrome was reported in patients who had undergone surgical section of the corpus callosum carried out in an attempt to control medication-resistant epilepsy. It has occasionally been linked to tumours of the corpus callosum and, although even more rarely, it has also been associated to an amnesic syndrome. In this paper we report the anatomical and neuropsychological findings in a patient with interhemispheric disconnection syndrome associated to a hippocampal-type amnesic syndrome, caused by a tumour in the splenius of the corpus callosum that extended into the fornix. CASE REPORT: A 52-year-old white male who visited because of loss of memory; on admission to hospital the physical examination revealed a certain degree of asomatognosia with regard to the left-hand side of the body. An axial tomography brain scan showed a dense central lesion in the brain that extended laterally and occluded the body of both lateral ventricles. A biopsy study revealed an undifferentiated astrocytoma that affected the corpus callosum and the fornix. CONCLUSIONS: Sperry, or interhemispheric disconnection, syndrome produced by a tumour in the splenius of the corpus callosum is very likely to course with an amnesic syndrome due to disconnection caused by destruction of the fornix. This association, which characterised our patient's clinical picture, has only previously been described in three cases.

Anterograde and retrograde amnesia in a person with bilateral fornix lesions following removal of a colloid cyst.

AD, a 45-year-old man, presented with a severe and global anterograde amnesia following surgery for removal of a colloid cyst. Structural neuroimaging confirmed bilateral lesions to the fornix and a small lesion in the basal forebrain. Testing for remote episodic memory of autobiographical events, and for remote semantic memory of personal and public events, and of famous people, revealed that AD had a severe retrograde amnesia for autobiographical episodes that covered his entire lifetime, and a time-limited retrograde amnesia for semantic memory. Because the fornix and basal forebrain lesions disrupted major afferent and efferent pathways of the hippocampus, it was concluded that the integrity of the hippocampus and its projections are needed to retain and/or recover autobiographical memories no matter how old they are. By contrast, hippocampal contribution to semantic memory is time-limited. These findings were interpreted as consistent with Multiple Trace Theory, which holds that the hippocampal system is essential for recovering contextually rich memories no matter how old they are, but is not needed for recovering semantic memories.

Interactions between anandamide-induced anterograde amnesia and post-training memory modulatory systems.

Rats were bilaterally implanted with indwelling cannulae in the CA1 region of the dorsal hippocampus. After recovery from surgery, they were trained in a one-trial, step-down inhibitory avoidance task using a 0.5 mA foot shock. The animals received intrahippocampal infusions of either vehicle or anandamide (100 microM, 0.5 microl/side) 30 min before training. Then, either immediately post-training or 3 h later, they received infusions of saline, noradrenaline (0.5 microg/side), SKF 38393 (1.5 microg/side), oxotremorine (0.6 microg/side) or Sp-cAMPs (0.5 microg/side) also in the hippocampus. All animals were tested for retention 24-h post-training. Anandamide produced anterograde amnesia. Immediate, but not delayed, post-training treatment with Sp-cAMPs and noradrenaline reversed this effect. SKF 38393 and oxotremorine had no influence on the amnesia caused by anandamide either when given immediately or 3 h after training. The results suggest that the amnesic effect of anandamide is related to the known noradrenergic regulation of cAMP-dependent protein kinase (PKA) activity previously described in the hippocampus immediately after avoidance training, which is crucial to long-term memory (LTM) formation.

Preserved anterograde and retrograde memory of rapidly acquired olfactory discrminations after neurotoxic hippocampal lesions.

A forced-choice discrimination paradigm was used in two experiments, to evaluate retrograde and anterograde amnesia in rats after hippocampal ablation. In a within-subjects design (Experiment 1), rats were trained on a set of 10 olfactory discriminations 4 weeks before surgery and on a separate set of 10 discriminations 1 week before surgery. In a mixed design (Experiment 2), rats were trained on olfactory discriminations in one of three conditions: condition 1 (10 discriminations at 4 weeks before surgery); condition 2 (10 discriminations at 1 week before surgery); or condition 3 (10 discriminations at 4 weeks before surgery and 10 discriminations at 1 week before surgery). Discriminations in both experiments were rapidly learned, requiring 7-10 trials to reach criterion. After training, half of the rats in each condition received bilateral neurotoxic lesions of the hippocampus, and the other half received sham surgery. One week after surgery, all rats were given a retention test, consisting of a single critical trial for each discrimination. In both experiments, rats with selective hippocampal lesions exhibited preserved retention of these olfactory discriminations with no observable retention gradient. A postoperative acquisition test for two new discriminations indicated that anterograde memory was also preserved, while a postoperative test of spatial learning in the Morris water maze confirmed that the hippocampal lesions impaired spatial learning. Together, these experiments refute the contention that the hippocampus is requisite for (non-spatial) olfactory memory consolidation, storage, or access, despite the condition that the information be rapidly acquired.

Role of platelet activating factor in triazolobenzodiazepines-induced retrograde amnesia.

Benzodiazepine (diazepam), triazolobenzodiazepines (brotizolam, triazolam) and platelet activating factor (PAF) antagonist (BN 52021) are administered to mice before acquisition and retrieval trials conducted using Morris water maze. Benzodiazepine has produced only anterograde amnesia and it has not produced retrograde amnesia. Triazolobenzodiazepines have produced both anterograde and retrograde amnesia. PAF antagonist (BN 52021) has only produced retrograde amnesia and it has not produced anterograde amnesia. The anterograde amnesia produced by benzodiazepine and triazolobenzodiazepines, has been prevented by benzodiazepine receptor antagonist (flumazenil). It suggests that benzodiazepine- and triazolobenzodiazepines-induced anterograde amnesia may be mediated through benzodiazepine receptors. On the other hand, retrograde amnesia produced by PAF antagonist (BN 52021) and triazolobenzodiazepines has been attenuated by PAF and PAF acetyl hydrolase inhibitors such as cigarette smoke extract (CSE) and phenylmethanesulfonylflouride. It suggests that triazolobenzodiazepine-induced retrograde amnesia may be mediated through blockade of PAF receptors.

Retrograde and anterograde object recognition in rats with hippocampal lesions.

Retrograde and anterograde object-recognition memory was assessed in rats with cytotoxic lesions of the hippocampal formation (HPC), using a paradigm based on the natural tendency of rats to spend more time exploring novel objects than familiar objects. The rats were allowed to explore a sample object for 5 min/day on 5 consecutive days, either 5 weeks or 1 week before surgery. After surgery, retrograde recognition was assessed by comparing the amount of time spent exploring the sample versus a novel object in a free-choice situation. Control rats spent more time exploring the novel object than the sample objects from both presurgery time periods, whereas rats with HPC lesions did not discriminate between the novel objects and sample objects from either presurgery time period. Despite their deficits on the retrograde recognition test, the rats with HPC lesions performed like control rats on anterograde recognition tests, displaying a strong exploratory preference for novel objects over sample objects, with retention delays of either 15 min or 24 h. The findings suggest that extrahippocampal circuitry is capable of supporting object recognition, but only if the HPC does not participate in encoding the original encounter with the object.

Selective lesions of basal forebrain cholinergic neurons produce anterograde and retrograde deficits in a social transmission of food preference task in rats.

We examined the performance of Long-Evans rats with 192 IgG-saporin lesions of the medial septum/vertical limb of the diagonal band (MS/VDB) or nucleus basalis magnocellularis/substantia innominata (NBM/SI), which removed cholinergic projections mainly to hippocampus or neocortex, respectively. We studied the effects of these lesions on anterograde and retrograde memory for a natural form of hippocampal-dependent associative memory, the social transmission of food preference. In a study of anterograde memory, MS/VDB lesions did not affect the immediate, 24-h or 3-week retention of the task. In contrast, NBM/SI lesions severely impaired immediate and 24-h retention. In a study of retrograde memory in which rats acquired the food preference 5 days or 1 day before surgery and they were tested 10-11 days after surgery, MS/VDB-lesioned rats showed striking memory deficits for the preference acquired at a long delay (5 days) before surgery, although all lesioned rats exhibited poorer retention on both retest sessions than on their pretest performance. Subsequent testing of new anterograde learning in these rats revealed no disrupting effects of lesions on a standard two-choice test. When rats were administered a three-choice test, in which the target food was presented along with two more options, NBM/SI-lesioned rats were somewhat impaired on a 24-h retention test. These results provide evidence that NBM/SI and MS/VDB cholinergic neurons are differentially involved in a social memory task that uses olfactory cues, suggesting a role for these neurons in acquisition and consolidation/retrieval of nonspatial declarative memory.