Hippocampal sclerosis | |
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Mesial temporal sclerosis (MTS) | |
Specialty | Neurology |
Hippocampal sclerosis (HS) or mesial temporal sclerosis (MTS) is a neuropathological condition with severe neuronal cell loss and gliosis in the hippocampus. [1] Neuroimaging tests such as magnetic resonance imaging (MRI) and positron emission tomography (PET) may identify individuals with hippocampal sclerosis. [2] Hippocampal sclerosis occurs in 3 distinct settings: mesial temporal lobe epilepsy, adult neurodegenerative disease and acute brain injury. [2] [3] : 1503
In 1825, Bouchet and Cazauvieilh described palpable firmness and atrophy of the uncus and medial temporal lobe of brains from epileptic and non-epileptic individuals. [4] : 565 In 1880, Wilhelm Sommer investigated 90 brains and described the classical Ammon's horn sclerosis pattern, severe neuronal cell loss in hippocampal subfield cornum Ammonis 1 (CA1) and some neuronal cell loss in hippocampal subfield CA4. a finding later confirmed by Bratz. [4] : 565 [5] In 1927, Spielmeyer described cell loss of all hippocampal subfields, the total Ammon's horn sclerosis pattern, and in 1966, Margerison and Corsellis described cell loss primarily involving the CA4 subfield, the end folium sclerosis pattern. [4] : 566 In 1935. Stauder linked mesial temporal lobe seizures to hippocampal sclerosis. [4] : 566
Hippocampal sclerosis was later found to occur in older adults with neurodegenerative diseases such as frontotemporal lobar degeneration and amyotrophic lateral sclerosis. [6] [3] : 1505 In 2006, researchers determined that amyotrophic lateral sclerosis and frontotemporal lobar degeneration are often TAR DNA-binding protein 43 (TDP-43) proteinopathies. [3] : 1506 In 2009, researchers recognized that about 10-20% of individuals with frontotemporal lobar degeneration not caused by tau proteinopathy occurred because of a RNA-binding protein FUS (FUS) proteinopathy; hippocampal sclerosis often accompanied the FUS proteinopathy. [7]
In 1994, Dickson et al. described hippocampal sclerosis occurring in elderly demented individuals > 80 years old with disproportionately greater impaired memory. [8] [9] In 2007, researchers determined that this neurodegenerative disease, Limbic-predominant age-related TDP-43 encephalopathy (LATE), is a TDP-43 proteinopathy. [3] : 1505
The typical brain sample is a surgical specimen , a brain sample obtained during epilepsy surgery. [1] The International League Against Epilepsy (ILAE) defines 3 hippocampal sclerosis (HS) types: predominant neuronal cell loss in subfields CA1 and CA4 (HS ILAE type 1), subfield CA1 (HS ILAE type 2) or subfield CA4 (HS ILAE type 3). [1] : 1315 The classic and total Ammon's horn sclerosis pattern correspond to HS ILAE type 1. [1] : 1318 Among brain samples with hippocampal sclerosis, HS ILAE type 1 is the most prevalent, HS ILAE type 2 has a 5-10% prevalence, and HS ILAE type 3 has a 4-7.4% prevalence. [1] : 1318–1319 Mossy fiber sprouting is common. [10] : 697
Dentate gyrus granule cell dispersion refers to a granule cell layer that is widened, poorly demarcated, or accompanied by granule cells outside the layer (ectopic granule cells). [1] : 1318 Although this pattern was thought to be linked to hippocampal sclerosis, a comparative study has shown this association is not correct as the same pattern occurs in brains without hippocampal sclerosis. [11]
A dual pathology is a temporal lobe abnormality that accompanying hippocampal sclerosis. [12] : 126 This occurs in about 15% of those with hippocampal sclerosis who completed epilepsy surgery. [12] : 126 The dual pathologies include cavernous hemangioma, heterotopia, cortical dysplasia, arteriovenous malformation, dysembryoplastic neuroepithelial tumor, cerebral infarction and cerebral contusion. [12] : 129 The common association is dual pathology with HS ILAE type 3. [1] : 1319
The typical brain sample is an autopsy specimen, a brain sample obtained during an autopsy. [3] : 1503
For elderly adults with suspected LATE, TDP-43 immunochemistry will determine if TDP-43 proteinopathy caused hippocampal sclerosis. [13] : 8–9 Pyramidal cell loss and gliosis occurs in the CA1 sector, subiculum, entorhinal cortex, and the amygdala. [3] The hippocampal neuronal cell loss and gliosis are disproportionate to the Alzheimer's disease "neuropathological change in the same section." [13] One sided hippocampal sclerosis has a 40-50% prevalence even when the TDP-43 inclusions involve both sides of the brain. [3] : 1508 TDP-43 immunochemistry does not identify TDP-43 proteinopathy if hippocampal sclerosis arises from hypoxia or mesial temporal lobe epilepsy. [3] : 1506 Mossy fiber sprouting is uncommon. [10] : 697
The LATE consensus working group report proposed a LATE staging system based on the anatomic location of TPD-43 proteinopathy: amygdala alone (stage1), amygdala and hippocampus (stage 2), and amygdala, hippocampus, and middle frontal gyrus (stage 3); hippocampal sclerosis is not sufficient or necessary for staging. [3] : 1505
Immunochemistry may identify RNA-binding protein FUS, phosphorylated tau protein or ubiquitin if frontotemporal lobar degeneration is not caused by TGP-43 proteinopathy. [13] : 9
On an MRI T2-weighted or T2–fluid‐attenuated inversion recovery (FLAIR) scan, hippocampal sclerosis appears as an increased signal, smaller sized (atrophic) hippocampus with a less well-defined internal structure. [2] Increased signal means that hippocampal sclerosis will appear brighter on the MRI image. Less well-defined internal structure means the expected sharp boundaries between hippocampal gray and white matter structures are absent. [2] The total volume of the hippocampus is also reduced. [2] The reduced volume arises from neuronal cell loss, and increased signal arises from gliosis. [2]
The 18F-fluorodeoxyglucose PET (18F-FDG) scan may show decreased glucose metabolism in the temporal lobe with hippocampal atrophy. [2] This region of decreased glucose metabolism may extend beyond the hippocampus and involve the medial and lateral temporal lobe. [2]
In LATE, MRI often shows asymmetrical hippocampal atrophy that progresses in a rostral-caudal gradient. [3] : 1509 Inferior frontal, anterior temporal, and insular cortex atrophy often accompanies LATE hippocampal atrophy, the same anatomical pattern of TDP-43 proteinopathy at autopsy. [3] : 1509 Reduced subiculum and CA1 volumes identified by MRI correspond to hippocampal sclerosis later identified at autopsy. [14]
The 18F-FDG PET scans of those with LATE show reduced glucose metabolism in the medial temporal lobe including the hippocampus. [15] : 8S
Hippocampal sclerosis is the most common brain abnormality in those with temporal lobe epilepsy. [16] Hippocampal sclerosis may occur in children under 2 years of age with 1 instance seen as early as 6 months. [17] About 70% of those evaluated for temporal lobe epilepsy surgery have hippocampal sclerosis. [1] : 1316 About 7% of those with temporal lobe epilepsy have familial mesial temporal lobe epilepsy, and 57% of those with familial mesial temporal lobe epilepsy have MRI evidence of hippocampal sclerosis. [18]
Electroencephalographic and surgical studies show that temporal lobe seizures arise from hippocampal regions with severe neuronal cell loss. [19] : 9 Intracranial electroencephalogram records anterior hippocampal seizure onset in those with severe anterior hippocampal neuronal loss and combined anterior and posterior hippocampal seizure onset in those with severe combined anterior and posterior neuronal cell loss. [19] : 9 Surgical removal of the hippocampus that spares neighboring structures leads to improved seizure control in many instances of mesial temporal lobe epilepsy. [19] : 9 The absence of hippocampal sclerosis in some with temporal lobe epilepsy suggests that uncontrolled seizures do not invariably lead to hippocampal sclerosis. [19] : 9
There is no clear relationship between febrile seizures and development of mesial temporal sclerosis. [20] Investigators found that hippocampal sclerosis and greater than 10-year epilepsy duration leads to parasympathetic dysfunction, refractory epilepsy leads to sympathetic dysfunction, and left hippocampal sclerosis leads to relatively greater parasympathetic dysfunction. [21] Hippocampal sclerosis may influence how the thalamus modulates the seizures of mesial temporal lobe epilepsy. [22]
The morbidity and mortality of refractory epilepsy and the adverse effects of medication treatment have a severe impact on life. [17] Those with an early age of epilepsy onset and hippocampal sclerosis have a poorer prognosis for becoming seizure-free. [16] Among those with intractable mesial temporal lobe epilepsy and hippocampal sclerosis, about 70% become seizure-free after epilepsy surgery. [23] : 751
In LATE, TDP-43, a normally non-phosphorylated protein residing in the nucleus, is phosphorylated and mislocalized in the cytoplasm and neurites. [3] : 1506 The inclusions occur in the amygdala, hippocampus, entorhinal cortex, or dentate gyrus. [3] : 1511 LATE occurs in about 20-50% of elderly individuals' brains. [3] : 1505 About 5-40% of those with LATE occur without hippocampal sclerosis. [3] : 1506 LATE appears as amnestic dementia similar to Alzheimer's disease in elderly adults > 80 years of age. [3] : 1503
Hippocampal sclerosis occurs in other neurodegenerative diseases. Hippocampal sclerosis occurs in about 66% of those with frontotemporal lobar degeneration arising from TDP-43 or FUS proteinopathy. [24] [7] Hippocampal sclerosis occurs in about 60% of those with progressive supranuclear palsy TDP-43 proteinopathy (PSP-TDP) and in about 5% of those with Lewy body dementia. [6] [25] Hippocampal sclerosis occurs in about 23% of those with chronic traumatic encephalopathy; TP-43 proteinopathy accompanied 96% of those with hippocampal sclerosis. [26]
Hippocampal sclerosis may occur with hypoxic-ischemic injury, hypoglycemia, toxins (kainic acid, domoic acid), and viral human herpesvirus 6 limbic encephalitis. [3] : 1506 [27] [28] [29] [30] [31] [32] [33]
The hippocampus is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, and plays important roles in the consolidation of information from short-term memory to long-term memory, and in spatial memory that enables navigation. The hippocampus is located in the allocortex, with neural projections into the neocortex, in humans as well as other primates. The hippocampus, as the medial pallium, is a structure found in all vertebrates. In humans, it contains two main interlocking parts: the hippocampus proper, and the dentate gyrus.
The temporal lobe is one of the four major lobes of the cerebral cortex in the brain of mammals. The temporal lobe is located beneath the lateral fissure on both cerebral hemispheres of the mammalian brain.
Hypergraphia is a behavioral condition characterized by the intense desire to write or draw. Forms of hypergraphia can vary in writing style and content. It is a symptom associated with temporal lobe changes in epilepsy and in Geschwind syndrome. Structures that may have an effect on hypergraphia when damaged due to temporal lobe epilepsy are the hippocampus and Wernicke's area. Aside from temporal lobe epilepsy, chemical causes may be responsible for inducing hypergraphia.
Frontotemporal dementia (FTD), frontotemporal degeneration disease, or frontotemporal neurocognitive disorder encompasses several types of dementia involving the progressive degeneration of the brain's frontal and temporal lobes. FTDs broadly present as behavioral or language disorders with gradual onsets.
Focal cortical dysplasia (FCD) is a congenital abnormality of brain development where the neurons in an area of the brain failed to migrate in the proper formation in utero. Focal means that it is limited to a focal zone in any lobe. Focal cortical dysplasia is a common cause of intractable epilepsy in children and is a frequent cause of epilepsy in adults. There are three types of FCD with subtypes, including type 1a, 1b, 1c, 2a, 2b, 3a, 3b, 3c, and 3d, each with distinct histopathological features. All forms of focal cortical dysplasia lead to disorganization of the normal structure of the cerebral cortex :
Frontotemporal lobar degeneration (FTLD) is a pathological process that occurs in frontotemporal dementia. It is characterized by atrophy in the frontal lobe and temporal lobe of the brain, with sparing of the parietal and occipital lobes.
The subiculum is the most inferior component of the hippocampal formation. It lies between the entorhinal cortex and the CA1 subfield of the hippocampus proper.
Kainic acid, or kainate, is an acid that naturally occurs in some seaweed. Kainic acid is a potent neuroexcitatory amino acid agonist that acts by activating receptors for glutamate, the principal excitatory neurotransmitter in the central nervous system. Glutamate is produced by the cell's metabolic processes and there are four major classifications of glutamate receptors: NMDA receptors, AMPA receptors, kainate receptors, and the metabotropic glutamate receptors. Kainic acid is an agonist for kainate receptors, a type of ionotropic glutamate receptor. Kainate receptors likely control a sodium channel that produces excitatory postsynaptic potentials (EPSPs) when glutamate binds.
Focal seizures are seizures which affect initially only one hemisphere of the brain. The brain is divided into two hemispheres, each consisting of four lobes – the frontal, temporal, parietal and occipital lobes. A focal seizure is generated in and affects just one part of the brain – a whole hemisphere or part of a lobe. Symptoms will vary according to where the seizure occurs. When seizures occur in the frontal lobe the patient may experience a wave-like sensation in the head. When seizures occur in the temporal lobe, a feeling of déjà vu may be experienced. When seizures are localized to the parietal lobe, a numbness or tingling may occur. With seizures occurring in the occipital lobe, visual disturbances or hallucinations have been reported.
In the field of neurology, temporal lobe epilepsy is an enduring brain disorder that causes unprovoked seizures from the temporal lobe. Temporal lobe epilepsy is the most common type of focal onset epilepsy among adults. Seizure symptoms and behavior distinguish seizures arising from the medial temporal lobe from seizures arising from the lateral (neocortical) temporal lobe. Memory and psychiatric comorbidities may occur. Diagnosis relies on electroencephalographic (EEG) and neuroimaging studies. Anticonvulsant medications, epilepsy surgery and dietary treatments may improve seizure control.
Anterior temporal lobectomy (ATL) is the complete or partial removal of the anterior portion of the temporal lobe of the brain. The exact boundaries for removal can vary slightly in practice and between neurosurgeons. It is a treatment option for temporal lobe epilepsy for those in whom anticonvulsant medications do not control epileptic seizures, and who have frequent seizures, and who additionally qualify based on a WADA test to localize the dominant hemisphere for language module.
In the field of neurology, seizure types are categories of seizures defined by seizure behavior, symptoms, and diagnostic tests. The International League Against Epilepsy (ILAE) 2017 classification of seizures is the internationally recognized standard for identifying seizure types. The ILAE 2017 classification of seizures is a revision of the prior ILAE 1981 classification of seizures. Distinguishing between seizure types is important since different types of seizures may have different causes, outcomes, and treatments.
Granulin is a protein that in humans is encoded by the GRN gene. Each granulin protein is cleaved from the precursor progranulin, a 593 amino-acid-long and 68.5 kDa protein. While the function of progranulin and granulin have yet to be determined, both forms of the protein have been implicated in development, inflammation, cell proliferation and protein homeostasis. The 2006 discovery of the GRN mutation in a population of patients with frontotemporal dementia has spurred much research in uncovering the function and involvement in disease of progranulin in the body. While there is a growing body of research on progranulin's role in the body, studies on specific granulin residues are still limited.
TAR DNA-binding protein 43 is a protein that in humans is encoded by the TARDBP gene.
Transmembrane protein 106B is a protein that is encoded by the TMEM106B gene. It is found primarily within neurons and oligodendrocytes in the central nervous system with its subcellular location being in lysosomal membranes. TMEM106B helps facilitate important functions for maintaining a healthy lysosome, and therefore certain mutations and polymorphisms can lead to issues with proper lysosomal function. Lysosomes are in charge of clearing out mis-folded proteins and other debris, and thus, play an important role in neurodegenerative diseases that are driven by the accumulation of various mis-folded proteins and aggregates. Due to its impact on lysosomal function, TMEM106B has been investigated and found to be associated to multiple neurodegenerative diseases.
An epilepsy syndrome is defined as "a characteristic cluster of clinical and EEG features, often supported by specific etiological findings ."
The hippocampus participates in the encoding, consolidation, and retrieval of memories. The hippocampus is located in the medial temporal lobe (subcortical), and is an infolding of the medial temporal cortex. The hippocampus plays an important role in the transfer of information from short-term memory to long-term memory during encoding and retrieval stages. These stages do not need to occur successively, but are, as studies seem to indicate, and they are broadly divided in the neuronal mechanisms that they require or even in the hippocampal areas that they seem to activate. According to Gazzaniga, "encoding is the processing of incoming information that creates memory traces to be stored." There are two steps to the encoding process: "acquisition" and "consolidation". During the acquisition process, stimuli are committed to short term memory. Then, consolidation is where the hippocampus along with other cortical structures stabilize an object within long term memory, which strengthens over time, and is a process for which a number of theories have arisen to explain the underlying mechanism. After encoding, the hippocampus is capable of going through the retrieval process. The retrieval process consists of accessing stored information; this allows learned behaviors to experience conscious depiction and execution. Encoding and retrieval are both affected by neurodegenerative and anxiety disorders and epilepsy.
Hyperreligiosity is a psychiatric disturbance in which a person experiences intense religious beliefs or episodes that interfere with normal functioning. Hyperreligiosity generally includes abnormal beliefs and a focus on religious content or even atheistic content, which interferes with work and social functioning. Hyperreligiosity may occur in a variety of disorders including epilepsy, psychotic disorders and frontotemporal lobar degeneration. Hyperreligiosity is a symptom of Geschwind syndrome, which is associated with temporal lobe epilepsy.
LATE is a term that describes a prevalent condition with impaired memory and thinking in advanced age, often culminating in the dementia clinical syndrome. In other words, the symptoms of LATE are similar to those of Alzheimer's disease.
Christine Kilpatrick is an Australian neurologist and the chief executive of Royal Melbourne Health. She has held this position since 2017. Previously, she was the chief executive of the Royal Children's Hospital from 2008 to 2017 and the executive director of Medical Services, Melbourne Health and executive director of the Royal Melbourne Hospital from 2004 to 2008. Before she held these positions, she worked as a neurologist at Royal Melbourne Health and engaged in extensive neurological research, especially epilepsy.
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