Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a progressive disorder of the nervous system that is characterized by a loss of intellectual functioning (dementia) and seizures. At first, affected individuals may have difficulty sustaining attention and concentrating. Their judgment, insight, and memory become impaired as the condition progresses. Over time, they lose the ability to perform the activities of daily living, and most people with this condition eventually require comprehensive care.

The signs and symptoms of familial encephalopathy with neuroserpin inclusion bodies vary in their severity and age of onset. In severe cases, the condition causes seizures and episodes of sudden, involuntary muscle jerking or twitching (myoclonus) in addition to dementia. These signs can appear as early as a person's teens. Less severe cases are characterized by a progressive decline in intellectual functioning beginning in a person's forties or fifties.

Mutations in the "SERPINI1" gene cause familial encephalopathy with neuroserpin inclusion bodies. The "SERPINI1" gene provides instructions for making a protein called neuroserpin. This protein is found in nerve cells, where it plays a role in the development and function of the nervous system. Neuroserpin helps control the growth of nerve cells and their connections with one another, which suggests that this protein may be important for learning and memory. Mutations in the gene result in the production of an abnormally shaped, unstable version of neuroserpin. Abnormal neuroserpin proteins can attach to one another and form clumps (called neuroserpin inclusion bodies or Collins bodies) within nerve cells. These clumps disrupt the cells' normal functioning and ultimately lead to cell death. Progressive dementia results from this gradual loss of nerve cells in certain parts of the brain. Researchers believe that a buildup of related, potentially toxic substances in nerve cells may also contribute to the signs and symptoms of this condition.

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In many cases, an affected person has a parent with the condition.

Depending on the location of the brain lesion different symptoms are more frequent:

- Brainstem tegmentum. - Ocular: pupillary changes. Extraocular muscle palsy; gaze palsy: nystagmus.

- Hypothalamus. Medulla: dorsal nuc. of vagus. - Autonomic dysfunct.: temperature; cardiocirculatory; respiratory.

- Medulla: vestibular region. Cerebellum. - Ataxia.

- Dorsomedial nuc. of thalamus. Mammillary bodies. - Amnestic syndrome for recent memory.

Mamillary lesion are characteristic-small petechial hemorrhages are found.

- Diffuse cerebral dysfunction.- Altered cognition: global confusional state.

- Brainstem: periaqueductal gray.- Reduction of consciousness

- Hypothalamic lesions may also affect the immune system, which is known in alcohol abusers, causing dysplasias and infections.

The classic triad of symptoms found in Wernicke's encephalopathy is:

- ophthalmoplegia (later expanded to other eye movement abnormalities, most commonly affecting the lateral rectus or any eye sign. Lateral nystagmus is most commonly seen although lateral rectus palsy, usually bilateral, may be seen).

- ataxia (later expanded to imbalance or any cerebellar signs)

- confusion (later expanded to other mental changes. Has 82% incidence in diagnosis cases)

However, in actuality, only a small percentage of patients experience all three symptoms, and the full triad occurs more frequently among those who have overused alcohol.

Also a much more diverse range of symptoms has been found in patients with this condition, including:

- pupillary changes, retinal hemorrhage, papilledema, impaired vision and hearing, vision loss

- hearing loss,

- fatigability, apathy, irritability, drowsiness, psycho and/or motor slowing

- dysphagia, blush, sleep apnea, epilepsy and stupor

- lactic acidosis

- memory impairment, amnesia, depression, psychosis

- hypothermia, polyneuropathy, hyperhidrosis.

Although hypothermia is usually diagnosed with a body temperature of 35 °C / 95° Fahrenheit, or less, incipient cooling caused by deregulation in the CNS needs to be monitored because it can promote the development of an infection. The patient may report feeling cold, followed by mild chills, cold skin, moderate pallor, tachycardia, hypertension, tremor or piloerection. External warming techniques are advised to prevent hypothermia.

Among the frequently altered functions are the cardio circulatory. There may be tachycardia, dyspnea, chest pain, orthostatic hypotension, changes in heart rate and blood pressure. The lack of thiamine sometimes affects other major energy consumers, the myocardium, and also patients may have developed cardiomegaly. Heart failure with lactic acidosis syndrome has been observed. Cardiac abnormalities are an aspect of the WE, which was not included in the traditional approach, and are not classified as a separate disease.

Infections have been pointed out as one of the most frequent triggers of death in WE. Furthermore, infections are usually present in pediatric cases.

In the last stage others symptoms may occur: hyperthermia, increased muscle tone, spastic paralysis, choreic dyskinesias and coma.

Because of the frequent involvement of heart, eyes and peripheral nervous system, several authors prefer to call it Wernicke disease rather than simply encephalopathy.

Early symptoms are nonspecific, and it has been stated that WE may present nonspecific findings. In Wernicke Korsakoff’s syndrome some single symptoms are present in about one-third.

The hallmark of encephalopathy is an altered mental state. Characteristic of the altered mental state is impairment of the cognition, attention, orientation, sleep–wake cycle and consciousness. An altered state of consciousness may range from failure of selective attention to drowsiness. Hypervigilance may be present; with or without: congnitive deficits, headache, epileptic seizures, myoclonus (involuntary twitching of a muscle or group of muscles) or asterixis ("flapping tremor" of the hand when wrist is extended).

Depending on the type and severity of encephalopathy, common neurological symptoms are loss of cognitive function, subtle personality changes, inability to concentrate. Other neurological signs may include dysarthria, hypomimia, problems with movements (they can be clumsy or slow), ataxia, tremor. Another neurological signs may include involuntary grasping and sucking motions, nystagmus (rapid, involuntary eye movement), jactitation (restless picking at things characteristic of severe infection), and respiratory abnormalities such as Cheyne-Stokes respiration (cyclic waxing and waning of tidal volume), apneustic respirations and post-hypercapnic apnea. Focal neurological deficits are less common.

Encephalopathies exhibits both neurologic and psychopathologic symptoms.

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.

Common proteinopathies that are found in FTLD include the accumulation of Tau proteins and TARDBPs. Mutations in the C9orf72 gene have been established as a major genetic contribution of FTLD, although defects in the GRN and MAPT genes are also associated with it.

There are 3 main histological subtypes found at post-mortem:

- FTLD-tau is characterised by tau positive inclusions often referred to as Pick-bodies. Examples of FTLD-tau include; Pick's disease, corticobasal degeneration, progressive supranuclear palsy.

- FTLD-TDP (or FTLD-U ) is characterised by ubiquitin and TDP-43 positive, tau negative, FUS negative inclusions. The pathological histology of this subtype is so diverse it is subdivided into four subtypes based on the detailed histological findings:

Two physicians independently categorized the various forms of TDP-43 associated disorders. Both classifications were considered equally valid by the medical community, but the physicians in question have jointly proposed a compromise classification to avoid confusion.

- FTLD-FUS; which is characterised by FUS positive cytoplasmic inclusions, intra nuclear inclusions, and neuritic threads. All of which are present in the cortex, medulla, hippocampus, and motor cells of the spinal cord and XIIth cranial nerve.

Dementia lacking distinctive histology (DLDH) is a rare and controversial entity. New analyses have allowed many cases previously described as DLDH to be reclassified into one of the positively defined subgroups.

Encephalopathy is a difficult term because it can be used to denote either a disease or finding (i.e., an observable sign in a patient).

When referring to a finding, encephalopathy refers to permanent (or degenerative) brain injury, or a reversible one. It can be due to direct injury to the brain, or illness remote from the brain. The individual findings that cause a clinician to refer to a patient as having encephalopathy include intellectual disability, irritability, agitation, delirium, confusion, somnolence, stupor, coma and psychosis. As such, describing a patient as having a clinical picture of encephalopathy is not a very specific description.

When referring to a disease, encephalopathy refers to a wide variety of brain disorders with very different etiologies, prognoses and implications. For example, prion diseases, all of which cause transmissible spongiform encephalopathies, are invariably fatal, but other encephalopathies are reversible and can have a number of causes including nutritional deficiencies and toxins.

Neurodegeneration is the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases – including amyotrophic lateral sclerosis, Parkinson's, Alzheimer's, and Huntington's – occur as a result of neurodegenerative processes. Such diseases are incurable, resulting in progressive degeneration and/or death of neuron cells. As research progresses, many similarities appear that relate these diseases to one another on a sub-cellular level. Discovering these similarities offers hope for therapeutic advances that could ameliorate many diseases simultaneously. There are many parallels between different neurodegenerative disorders including atypical protein assemblies as well as induced cell death. Neurodegeneration can be found in many different levels of neuronal circuitry ranging from molecular to systemic.

Movement Disorder

- Dystonia

- Parkinsonism

- Chorea

- Ocular flutter

- Motor tics

Psychiatric Symptoms

- Agitation

- Emotional lability

- Psychosis

- Depression

Associated symptoms

- Encephalopathy

- Sleep disorder

- Reduced consciousness

- Mutism

It typically presents as a severe encephalopathy with myoclonic seizures, is rapidly progressive and eventually results in respiratory arrest.Standard evaluation for inborn errors of metabolism and other causes of this presentation does not reveal any abnormality (no acidosis, no hypoglycaemia, or hyperammonaemia and no other organ affected). Pronounced and sustained hiccups in an encephalopathic infant have been described as a typical observation in non-ketotic hyperglycinaemia.

Progressive myoclonus epilepsy (PME) is a rare epilepsy syndrome caused by a variety of genetic disorders. The syndrome includes myoclonic seizures and tonic-clonic seizures together with progressive neurological decline.

Based on syndrome with focal or diffuse neurological dysfunction associated with fever. Inflammatory lesion in MRI and CSF pleocytosis. EEG signs of encephalitis.

Typical symptoms of PRES, listed according to prevalence, include: altered mental status (encephalopathy), seizure, and headache. Less commonly there may be visual disturbances, focal neurologic signs, and status epilepticus.

Tauopathy belongs to a class of neurodegenerative diseases associated with the pathological aggregation of tau protein in neurofibrillary or gliofibrillary tangles in the human brain. Tangles are formed by hyperphosphorylation of a microtubule-associated protein known as tau, causing it to aggregate in an insoluble form. (These aggregations of hyperphosphorylated tau protein are also referred to as paired helical filaments). The precise mechanism of tangle formation is not completely understood, and it is still controversial as to whether tangles are a primary causative factor in the disease or play a more peripheral role. Primary tauopathies, i.e., conditions in which neurofibrillary tangles (NFT) are predominantly observed, include:

- Primary age-related tauopathy (PART)/Neurofibrillary tangle-predominant senile dementia, with NFTs similar to AD, but without plaques.

- Chronic traumatic encephalopathy, including dementia pugilistica

- Progressive supranuclear palsy

- Corticobasal degeneration

- Frontotemporal dementia and parkinsonism linked to chromosome 17

- Lytico-Bodig disease (Parkinson-dementia complex of Guam)

- Ganglioglioma and gangliocytoma

- Meningioangiomatosis

- Postencephalitic parkinsonism

- Subacute sclerosing panencephalitis

- As well as lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, and lipofuscinosis

Neurofibrillary tangles were first described by Alois Alzheimer in one of his patients suffering from Alzheimer's disease (AD), which is considered a secondary tauopathy. AD is also classified as an amyloidosis because of the presence of senile plaques.

The degree of NFT involvement in AD is defined by Braak stages. Braak stages I and II are used when NFT involvement is confined mainly to the transentorhinal region of the brain, stages III and IV when there's also involvement of limbic regions such as the hippocampus, and V and VI when there's extensive neocortical involvement. This should not be confused with the degree of senile plaque involvement, which progresses differently.

In both Pick's disease and corticobasal degeneration, tau proteins are deposited as inclusion bodies within swollen or "ballooned" neurons.

Argyrophilic grain disease (AGD), another type of dementia, is marked by an abundance of argyrophilic grains and coiled bodies upon microscopic examination of brain tissue. Some consider it to be a type of Alzheimer's disease. It may co-exist with other tauopathies such as progressive supranuclear palsy and corticobasal degeneration, and also Pick's disease.

Huntington's disease (HD): a neurodegenerative disease caused by a CAG tripled expansion in the Huntington gene is the most recently described tauopathy (Fernandez-Nogales et al. Nat Med 2014). JJ Lucas and co-workers demonstrate that, in brains with HD, tau levels are increased and the 4R/3R balance is altered. In addition, the Lucas study shows intranuclear insoluble deposits of tau; these "Lucas' rods" were also found in brains with Alzheimer's disease.

Tauopathies are often overlapped with synucleinopathies, possibly due to interaction between the synuclein and tau proteins.

The non-Alzheimer's tauopathies are sometimes grouped together as "Pick's complex" due to their association with frontotemporal dementia, or frontotemporal lobar degeneration.

In the early stages, it can be difficult to distinguish progressive myoclonic epilepsy from benign idiopathic generalised epilepsies, such as juvenile myoclonic epilepsy. With PME, the initial effectiveness of anticonvulsant treatment diminishes as seizures become more frequent and neurological decline progresses. However, these can also be signs of anticonvulsant intoxication. The myoclonus in PME is usually severe and is the prominent seizure type.

There are several different forms of glycine encephalopathy, which can be distinguished by the age of onset, as well as the types and severity of symptoms. All forms of glycine encephalopathy present with only neurological symptoms, including mental retardation (IQ scores below 20 are common), hypotonia, apneic seizures, and brain malformations.

With the classical, or neonatal presentation of glycine encephalopathy, the infant is born after an unremarkable pregnancy, but presents with lethargy, hypotonia, apneic seizures and myoclonic jerks, which can progress to apnea requiring artificial ventilation, and often death. Apneic patients can regain spontaneous respiration in their second to third week of life. After recovery from the initial episode, patients have intractable seizures and profound mental retardation, remaining developmentally delayed. Some mothers comment retrospectively that they noticed fetal rhythmic "hiccuping" episodes during pregnancy, most likely reflecting seizure episodes in utero. Patients with the infantile form of glycine encephalopathy do not show lethargy and coma in the neonatal period, but often have a history of hypotonia. They often have seizures, which can range in severity and responsiveness to treatment, and they are typically developmentally delayed. Glycine encephalopathy can also present as a milder form with episodic seizures, ataxia, movement disorders, and gaze palsy during febrile illness. These patients are also developmentally delayed, to varying degrees. In the later onset form, patients typically have normal intellectual function, but present with spastic diplegia and optic atrophy.

Transient neonatal hyperglycinemia has been described in a very small number of cases. Initially, these patients present with the same symptoms and laboratory results that are seen in the classical presentation. However, levels of glycine in plasma and cerebrospinal fluid typically normalize within eight weeks, and in five of six cases there were no neurological issues detected at follow-up times up to thirteen years. A single patient was severely retarded at nine months. The suspected cause of transient neonatal hyperglicinemia is attributed to low activity of the glycine cleavage system in the immature brain and liver of the neonate.

Corticobasal degeneration is a rare form of dementia that is characterized by many different types of neurological problems that get progressively worse over time. This is because the disorder affects the brain in many different places, but at different rates. One common sign is difficulty with using only one limb. One symptom that is extremely rare in any condition other than corticobasal degeneration is the "alien limb." The alien limb is a limb of the person that seems to have a mind of its own, it moves without control of the person's brain. Other common symptoms include jerky movements of one or more limbs (myoclonus), symptoms that are different in different limbs (asymmetric), difficulty with speech that is due to not being able to move the mouth muscles in a coordinated way, numbness and tingling of the limbs and neglecting one side of the person's vision or senses. In neglect, a person ignores the opposite side of the body from the one that has the problem. For example, a person may not feel pain on one side, or may only draw half of a picture when asked. In addition, the person's affected limbs may be rigid or have muscle contractions causing strange repetitive movements (dystonia).

The area of the brain most often affected in corticobasal degeneration is the posterior frontal lobe and parietal lobe. Still, many other part of the brain can be affected.

Progressive supranuclear palsy (PSP) is a form of dementia that is characterized by problems with eye movements. Generally the problems begin with difficulty moving the eyes up and/or down (vertical gaze palsy). Since difficulty moving the eyes upward can sometimes happen in normal aging, problems with downward eye movements are the key in PSP. Other key symptoms of PSP include falls backwards, balance problems, slow movements, rigid muscles, irritability, apathy, social withdrawal, and depression. The person may also have certain "frontal lobe signs" such as perseveration, a grasp reflex and utilization behavior (the need to use an object once you see it). People with PSP often have progressive difficulty eating and swallowing, and eventually with talking as well. Because of the rigidity and slow movements, PSP is sometimes misdiagnosed as Parkinson's disease.

On scans of the brain, the midbrain of people with PSP is generally shrunken (atrophied), but there are no other common brain abnormalities visible on images of the person's brain.

The syndrome is a combined manifestation of two namesake disorders, Wernicke's encephalopathy and Korsakoff's psychosis. It involves an acute Wernicke-encephalopathy phase, followed by the development of a chronic Korsakoff's syndrome phase.

WE is characterized by the presence of a triad of symptoms;

1. Ocular disturbances (ophthalmoplegia)

2. Changes in mental state (confusion)

3. Unsteady stance and gait (ataxia)

This triad of symptoms results from a deficiency in vitamin B which is an essential coenzyme. The aforementioned changes in mental state occur in approximately 82% of patients' symptoms of which range from confusion, apathy, inability to concentrate, and a decrease in awareness of the immediate situation they are in. If left untreated, WE can lead to coma or death. In about 29% of patients, ocular disturbances consist of nystagmus and paralysis of the lateral rectus muscles or other muscles in the eye. A smaller percentage of patients experience a decrease in reaction time of the pupils to light stimuli and swelling of the optic disc which may be accompanied by retinal hemorrhage. Finally, the symptoms involving stance and gait occur in about 23% of patients and result from dysfunction in the cerebellum and vestibular system. Other symptoms that have been present in cases of WE are stupor, low blood pressure (hypotension), elevated heart rate (tachycardia), as well as hypothermia, epileptic seizures and a progressive loss of hearing.

Interestingly, about 19% of patients have none of the symptoms in the classic triad at first diagnosis of WE; however, usually one or more of the symptoms develops later as the disease progresses.

Posterior reversible encephalopathy syndrome (PRES), also known as reversible posterior leukoencephalopathy syndrome (RPLS), is a syndrome characterized by headache, confusion, seizures and visual loss. It may occur due to a number of causes, predominantly malignant hypertension, eclampsia and some medical treatments. On magnetic resonance imaging (MRI) of the brain, areas of edema (swelling) are seen. The symptoms tend to resolve after a period of time, although visual changes sometimes remain. It was first described in 1996.

Symptoms of CTE, which occur in four stages, generally appear 8 to 10 years after an athlete experiences repetitive mild traumatic brain injury.

First-stage symptoms include attention deficit hyperactivity disorder as well as confusion, disorientation, dizziness, and headaches. Second-stage symptoms include memory loss, social instability, impulsive behavior, and poor judgment. Third and fourth stages include progressive dementia, movement disorders, hypomimia, speech impediments, sensory processing disorder, tremors, vertigo, deafness, depression and suicidality.

Additional symptoms include dysarthria, dysphagia, cognitive disorder such as amnesia, and ocular abnormalities, such as ptosis.

The condition manifests as dementia, or declining mental ability, problems with memory, dizzy spells or lack of balance to the point of not being able to walk under one's own power for a short time and/or Parkinsonism, or tremors and lack of coordination. It can also cause speech problems and an unsteady gait. Patients with DP may be prone to inappropriate or explosive behavior and may display pathological jealousy or paranoia.

Ohtahara syndrome (OS), also known as early infantile epileptic encephalopathy with burst-suppression (EIEE), is a progressive epileptic encephalopathy. The syndrome is outwardly characterized by tonic spasms and partial seizures, and receives its more elaborate name from the pattern of burst activity on an electroencephalogram (EEG). It is an extremely debilitating progressive neurological disorder, involving intractable seizures and severe mental retardation. No single cause has been identified, although in many cases structural brain damage is present.

The first symptom of CJD is usually rapidly progressive dementia, leading to memory loss, personality changes, and hallucinations. Myoclonus (jerky movements) typically occurs in 90% of cases, but may be absent at initial onset. Other frequently occurring features include anxiety, depression, paranoia, obsessive-compulsive symptoms, and psychosis. This is accompanied by physical problems such as speech impairment, balance and coordination dysfunction (ataxia), changes in gait, rigid posture, and seizures. In most patients, these symptoms are accompanied by involuntary movements and the appearance of an atypical, diagnostic electroencephalogram tracing. The duration of the disease varies greatly, but sporadic (non-inherited) CJD can be fatal within months or even weeks. Most victims die six months after initial symptoms appear, often of pneumonia due to impaired coughing reflexes. About 15% of patients survive for two or more years.

The symptoms of CJD are caused by the progressive death of the brain's nerve cells, which is associated with the build-up of abnormal prion protein molecules forming amyloids. When brain tissue from a CJD patient is examined under a microscope, many tiny holes can be seen where whole areas of nerve cells have died. The word "spongiform" in "transmissible spongiform encephalopathies" refers to the sponge-like appearance of the brain tissue.

Ohtahara syndrome is rare and the earliest-appearing age-related epileptic encephalopathy, with seizure onset occurring within the first three months of life, and often in the first ten days. Many, but not all, cases of OS evolve into other seizure disorders, namely West syndrome and Lennox-Gastaut syndrome.

The primary outward manifestation of OS is seizures, usually presenting as tonic seizures (a generalized seizure involving a sudden stiffening of the limbs). Other seizure types that may occur include partial seizures, clusters of infantile spasms, and, rarely, myoclonic seizures. In addition to seizures, children with OS exhibit profound mental and physical retardation.

Clinically, OS is characterized by a "burst suppression" pattern on an EEG. This pattern involves high voltage spike wave discharge followed by little brain wave activity.

It is named for the Japanese neurologist Shunsuke Ohtahara (1930–2013), who identified it in 1976.