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John Libbey Eurotext - Epileptic Disorders - Testing blood and CSF in people with epilepsy: a practical guide

John Libbey Eurotext - Epileptic Disorders - Testing blood and CSF in people with epilepsy: a practical guide | AntiNMDA | Scoop.it
From www.jle.com - September 12, 2020 6:13 PM
Figures Tables Table 1 Table 2 The diagnosis and management of epilepsy, including first seizures and status epilepticus, depends largely on thorough history taking, including a forensic approach to obtaining witness accounts and information about the background and circumstances affecting an individual. Investigations, such as EEG and MRI, as will be covered in separate articles in this series, and are of particular value in identifying the type of epilepsy and underlying cause, and contributing to predicting risk of recurrence after a first unprovoked seizure. However, at least 55% of new-onset seizures (Beghi et al., 2010), including around 50% of status epilepticus cases, are provoked (acute symptomatic seizures). In patients with known epilepsy, systemic illnesses may also contribute to deterioration in seizure control. It is in this context that laboratory (blood, urine, cerebrospinal fluid) investigations are especially important. This review summarises the role of laboratory investigations in the diagnosis and management of people presenting with seizures, to provide an educational resource to help the managing clinician decide which patients should receive laboratory tests and which types of tests should be ordered. This is a core competency (Level 1) defined in the ILAE Epileptology Curriculum (Blümcke et al., 2019), which is relevant for all health professionals involved in the diagnosis and management of people with epilepsy. FIRST SEIZURE Although not key to the diagnosis of a first seizure, or new-onset seizures, some laboratory investigations performed as soon as possible after the seizure onset can be key to identifying the cause, specifically with respect to determining if the event is provoked (acute symptomatic) or unprovoked. Acute symptomatic seizures occur at the time of, or in close association with, a documented brain insult (Thurman et al., 2011), which likely account for over 50% of all first seizures (Hauser and Beghi, 2008). Importantly, with an acute symptomatic seizure, the key priority in management is addressing the cause. Some untreated are rapidly fatal, but if successfully managed, are associated with full recovery and a recurrence risk of less than 3% (Pohlmann-Eden et al., 2006). In contrast, the five-year risk of recurrence is at least 10-fold higher following a first unprovoked seizure (Marson et al., 2005). Thus, correctly distinguishing between provoked and unprovoked at the outset has important implications for the individual both in the first few hours and also with respect to longer-term management and safety advice including driving. Almost any acute brain insult, including stroke and trauma, can result in an acute symptomatic seizure, but in the context of this article, the most important triggers are metabolic, toxic, infectious and inflammatory. Metabolic: Metabolic derangements causing seizures can be extremely dangerous and need to be treated urgently, therefore checking (capillary and then serum) glucose, sodium, calcium and magnesium and renal and liver function should be done as soon as possible. These, and other essential initial tests, are summarized in table 1. The only exception is children with simple febrile seizures, for which there is consensus that additional investigations are not required unless there are other clinical markers of concern (American Academy of Pediatrics, 2011; Wilmshurst et al., 2015). Glucose: In patients of any age, including neonates for whom it is especially important (Gataullina et al., 2015), checking that the blood glucose is within normal range should be of the utmost priority, as untreated hypoglycaemia can rapidly lead to irreversible neurological damage and death. In adults, a glucose level below 2 mM/L or above 25 mM/L is usually required to produce seizures, the latter most commonly in older patients with type II diabetes, whereas hyperglycaemia accompanied by ketosis is not usually epileptogenic (Nass et al., 2017; Ohara et al., 2017). Additionally, diabetes mellitus is an independent risk factor for seizures in the elderly, therefore HbA1c (glycosylated haemoglobin) testing should be performed in older patients as a measure of longer-term blood glucose (Baviera et al., 2017). Sodium: Hyponatraemia is the commonest electrolyte disturbance to provoke seizures in adults. The mechanism for this is cerebral oedema, which is due to the osmotic gradient between the plasma and the brain. The more rapid the fall in sodium, the fewer adaptive responses the brain can produce to protect itself and more severe the resulting cerebral oedema will be. Whilst less common, children are particularly vulnerable to the effects of cerebral oedema as they have relatively large brains compared to their scull size (Nardone et al., 2016). Correction of low sodium must be carefully monitored to avoid the potentially devastating complication of pontine myelinolysis. Hypernatraemia is a much less common cause of seizures but may produce them due to brain shrinkage (Castilla-Guerra et al., 2006). Calcium and magnesium: Hypocalcaemia, and less frequently hypercalcaemia, can provoke seizures. When this is identified, further investigations as to the cause, usually in consultation with an endocrinologist, may also be required, which is beyond the scope of this article. Hypomagnesaemia is much less common but can cause seizures in any age group. Potassium: Derangements in serum potassium are clearly very dangerous from a cardiovascular and neuromuscular perspective, and so important to identify, but do not cause central nervous system (CNS) symptoms or seizures (Riggs, 2002; Castilla-Guerra et al., 2006). Urea, nitrogen and creatinine: Seizures are common in patients with renal failure due to elevated urea. It should be noted that non-convulsive status and status epilepticus may mimic uremic encephalopathy, therefore it is particularly important to consider these as possible diagnoses in renal patients (Titoff et al., 2019). Infective and inflammatory disease: Infective or inflammatory causes should be considered in any one with a history of fever or recent malaise, and untreated can prove fatal. Febrile seizures are particularly common in children up to school age, but seizures can be the presenting feature of infection or inflammatory conditions at any age. All patients should have a full blood count (FBC) and test for C-reactive protein (CRP) as a minimum. Mild leucocytosis and raised CRP are commonly found postictally due to a generalised inflammatory response, with a lack of evidence to define clear levels above which a more aggressive search for infection should follow. Further investigations will depend on the clinical history, examination, observations and sometimes repeated laboratory tests to look for trends. If there are clinical reasons to suspect a central nervous system infection or sepsis (which can itself be associated with an encephalopathy), blood and urine cultures, and cerebrospinal fluid (CSF) samples should be obtained. In any patient with focal signs or who has not completely recovered, brain imaging (typically brain CT) will be needed before CSF can be collected (indications for brain imaging in epilepsy are covered in a separate article). CSF opening pressure should be recorded (for example, venous sinus thrombosis can present with seizures and a high opening pressure), and CSF sent for routine tests including cell count, protein, sugar (with matched blood sugar), bacterial culture and viral PCR. Depending on the clinical history and examination, additional tests for fungal or mycobacterial infections, and oligoclonal bands, might also be appropriate. It is sensible to take more than required for initial tests, with a saved sample for additional tests, should they be required based on initial results, or other information that emerges later. In persons presenting with behavioural changes, memory problems, a high frequency of new-onset seizures or (as will be covered later) status epilepticus, if other tests have been non-contributory, the possibility of an autoimmune encephalitis needs to be considered. This should be investigated alongside specific serum and CSF antigens (Dalmau and Graus, 2018). If there is any suspicion of multiple sclerosis, then oligoclonal bands may also be important. Clinical treatment decisions usually have to be made before the results of these additional investigations are available (this can take 2-3 weeks, even in well-resourced settings), further discussion of which is beyond the scope of this article, but decision-making algorithms have been created to aid this (Graus et al., 2016; Wagner et al., 2018). Intoxication: In parallel with assessing for metabolic and infectious causes of a first seizure, one should consider whether recreational drugs, alcohol or medications may have been precipitants. It is not possible to provide absolute cut-off thresholds for these, as inter-individual differences in seizure susceptibility play a substantial role (Brathen et al., 2005), but the detection of substances at all in the appropriate time window may be highly relevant. Importantly, when drug or alcohol-provoked seizures are identified, co-morbid epilepsy, sometimes as yet undiagnosed, is not uncommon and the recurrence risk (due to recurrent ingestion or epilepsy) is also higher, therefore additional investigations as for any first unprovoked seizure (EEG and MRI) should still be undertaken at a later date. Alcohol: Alcohol withdrawal, particularly in combination with sleep deprivation, is a very common cause of seizures. Seizures usually occur 6-48 hours after cessation of drinking (Leach et al., 2012). As markers of chronic alcohol consumption, mean corpuscular volume (MCV) and serum gamma glutamyl transferase (GGT) may be useful, although the latter may be elevated due the ingestion of certain drugs, including many antiepileptic drugs (AEDs). Benzodiazepines and recreational drugs: A broad range of widely available, though mostly illegal, stimulant drugs can cause seizures even at low levels of consumption. Cocaine, crack, normeperidine, meperidine, methaqualone, glutarimide, ethylenedioxymethamphetamine and a range of other synthetic stimulants are considered high risk, along with phencyclidine and quatadine (Beghi et al., 2010). Other drugs with narcotic effects, such as benzodiazepines, synthetic cannabinoids, gamma-hydroxybutyrate and opiates including heroin, may trigger seizures during their withdrawal (Leach et al., 2012). The use of multiple intoxicants is common, so rather than testing for individual agents, urinary drug screening for metabolites is recommended in the first instance. Prescription medications: Drugs such as antibiotics, antidepressants and antipsychotics in routine use rarely induce seizures, even in people with epilepsy other than in the context of significant overdoses. Usually patient history is sufficient, but to identify intoxication or slow metabolizers, serum drug monitoring may be useful. Was it a seizure? Diagnostic uncertainty. A number of laboratory investigations have also been proposed as potentially useful where there is diagnostic uncertainty as to the nature of an event, specifically to discriminate between epileptic seizures, psychogenic non-epileptic seizures (PNES) and syncope. However, whilst of academic interest, none should be considered diagnostic and, in most instances, will not be useful. Many of these markers are only raised in tonic-clonic seizures, and even then, they are not wholly reliable as summarized below. Clinical history and witness accounts remain the mainstay in the diagnosis of epileptic seizures. Prolactin is the most widely suggested but has substantial limitations: It is only useful when there is a known (pre-event) baseline and taken 20 minutes post-event, which is rarely achievable. It does not always rise after an epileptic seizure; it may rise due to other events such as syncope and its levels depend on many other variables including age, gender, circadian rhythm, medications, pregnancy and even psychological stress. In status epilepticus, prolactin levels may normalise after an initial rise (Abubakr and Wambacq, 2016; Nass et al., 2017). Creatinine kinase (CK): A transitory (sometimes very substantial) increase in creatinine kinase, 24-72 hours after a tonic-clonic seizure (TCS), is a relatively specific but not sensitive marker (i.e. raised CK points towards a TCS, but a normal CK does not rule it out). However, it should be noted that CK may be elevated due to other conditions such as a post-syncopal long lie. Nevertheless, a raised CK is important to help identify patients who will be at higher risk of developing acute kidney injury as a result of muscle breakdown due to seizures, and these patients will need careful monitoring and treatment if this develops (Nass et al., 2017). Ammonia: A transitory increase in ammonia, lasting 3-8 hours after an event, is a relatively specific but not sensitive marker of a convulsion. Patients with cirrhosis and no history of convulsions will have persistently elevated ammonia. Valproic acid may also cause elevations in serum ammonia (Nass et al., 2017). Lactate: A raised lactate level above 2.45 mmol/L, taken within two hours of the event, has been postulated to be a useful indicator of a likely TCS. However, this is not very sensitive (Matz et al., 2016). Furthermore, simulated seizures can also produce markedly raised lactate levels (Lou Isenberg et al., 2020). There are also numerous other causes of a raised lactate level, such as sepsis, tumour or liver disease, therefore this cannot be considered diagnostic in isolation. Other parameters in infants: In infants (under one year) with new-onset seizures (also covered below), ideally, the genetic syndrome of pyridoxine-deficiency epilepsy should be excluded (van Karnebeek et al., 2016) based on determination of alpha-aminoadipic semialdehyde/pyrroline 6’ carboxylate (in urine, plasma or cerebrospinal fluid) and ALDH7A1 molecular analysis. STATUS EPILEPTICUS In the previous sections we discuss what to test the first time someone presents with seizures, and the limited utility of laboratory testing in the case of diagnostic uncertainty. In this section, we discuss what laboratory tests to perform in the patient who does not stop seizing, i.e. presents with status epilepticus (SE). As with any seizure, the diagnosis of status epilepticus is primarily a clinical one, supported, when possible, by neurophysiological (EEG) data (Trinka et al., 2015). The role of laboratory testing is, as with first seizures, to identify the cause but also, particularly in convulsive SE, to evaluate the possible consequences of what is a life-threatening medical emergency, to inform on ongoing management. A suggested approach to laboratory testing for SE is summarized in figure 1. For all patients: All patients in SE should have the mandatory blood tests described in table 1. In addition, coagulation studies and creatine kinase, an arterial blood gas and toxicology screening should be performed. This is to establish a baseline, as part of investigating the cause, and to identify those who might be at particularly high risk of complications, such as those with acute kidney injury (from rhabdomyolysis) or a coagulopathy. Patients with known epilepsy: An antiepileptic drug (AED) level must be checked as low AED levels are the most common cause of SE in this group of patients (Trinka et al., 2012). Ideally, AED levels should be tested on a sample taken prior to any AED administration. In practice, as relevant background information may not be available at the point of presentation, it is sensible to take an additional 5 mL of serum saved for future testing at the outset, before AEDs given as part of treating the episode confound interpretation. Specific AED levels can then be requested for the original sample at a later date when prescribed drugs are known. AED levels are most useful/reliable if a prescribed drug is not-detected, indicating poor adherence, though beyond that the results should be interpreted with caution, ideally compared to the individual's own therapeutic concentration as this may vary from the standard reference ranges (Lunardi et al., 2019). Therapeutic drug monitoring is not routinely recommended during SE treatment as AED concentrations may actually exceed the published target concentrations (NICE, 2012 [Update 2019]), other than in refractory or super-refractory cases in which confirming at least adequate levels before an agent is considered ineffective can be useful. Infectious disease: Lumbar puncture should be performed in any patient with a suspicion of CNS infection or inflammation or in any patient without another clear cause of SE. A CSF pleocytosis of greater than 5 × 106/L is not usually caused by SE alone, and so this should prompt careful investigation of any infectious or inflammatory cause (Frank et al., 2012; Scramstad and Jackson, 2017; Johnson et al., 2014). Testing for HIV is also important to consider if not already known. Common infectious causes of SE are bacterial (e.g. meningococcus, pneumococcus and haemophilus), viral (e.g. herpes simplex 1 and enteroviruses) or protozoal (Lowenstein et al., 2014; He et al., 2016). There is considerable regional variation in likely infectious causes of SE, for example Japanese encephalitis is endemic in South-East Asia, malaria in sub-Saharan Africa and Asia, and neurocystericosis in Latin America, India and Africa, therefore the country of origin and travel history will impact on choice of laboratory investigations. HIV-positive patients will need a more comprehensive workup to exclude opportunistic infections (Solomon et al., 2012). Immunological & inflammatory disease: Autoimmune encephalitis (AE) is an uncommon but potentially treatable cause of SE. Identifying it is of vital importance because it may be associated with AED-refractory seizures that will only improve with immunotherapy or, in the case of paraneoplastic encephalitis, with treatment of the underlying cancer. Our knowledge of the autoimmune encephalitides and the antibodies associated with them is relatively recent and continues to evolve (Dalmau and Graus, 2018). Multiple anti-neuronal antibodies may be implicated, including, likely, some yet to be discovered, with a range of presentations. Those most frequently associated with seizures and status epilepticus include: antibodies against the GluN1 subunit of the NMDA (N-methyl-D-aspartate) receptor and anti-GAD, anti-GABA (gammaaminobutyric acid) type A and B receptor, anti-LGI1 receptor (leucine-rich glioma inactivated 1), and anti-Hu antibodies (Jacobs et al., 2003; Johnson et al., 2010; Lancaster et al., 2010; Illingworth et al., 2011; Suleiman et al., 2011; Bien, 2013; Petit-Pedrol et al., 2014). Any patient with a history of new-onset cognitive or memory deficits, speech problems, movement disorder or behavioural changes leading up to the SE, when no other obvious cause is identified, should be investigated for autoimmune encephalitis. In practice, rather than requesting full panels for all patients, discussion with the local laboratory, to agree priorities and understand local techniques and their sensitivity and specificity which can vary, is recommended. Anti-GAD (glutamic acid decarboxylase) antibodies are also not uncommonly identified, but also found in a range of other disorders including diabetes, and of uncertain pathogenicity (Alexopoulos and Dalakas, 2013). CSF will usually show a mild pleocytosis, but it may be normal. Both serum and CSF should be tested for antibodies (Graus et al., 2016). For further guidance on when to investigate for AE, see figure 1. A diagnosis of Hashimoto's encephalopathy may be considered in patients who have no anti-neuronal antibodies in serum and CSF. These patients should be investigated with thyroid function tests, and serum thyroid peroxidase and thyroglobulin antibodies, in order to assess if they meet the diagnostic criteria. In patients who are negative for anti-neuronal antibodies, and do not meet the criteria for Hashimoto's encephalopathy, further antibody testing in research laboratories for new antibodies may be considered, and the patient may be evaluated for the diagnosis of auto-antibody-negative but probable autoimmune encephalitis (Graus et al., 2016). Systemic autoimmune conditions may also cause SE, including Sjogren's and systemic lupus erythematosus, and serum autoantibody testing may be useful in these cases. SE can also occur in the context of multiple sclerosis and Rasmussen's encephalitis, but almost never as the presenting symptom. If there is clinical suspicion of either of these inflammatory conditions, then testing of serum and CSF oligoclonal bands may be supportive in diagnosis. Cryptogenic new-onset refractory status epilepticus (NORSE) and what may be a subtype of the same condition, febrile infection-related epilepsy syndrome (FIRES), are characterised by the rapidly progressive onset of seizures and encephalopathy that evolve into prolonged super-refractory SE over a few days. In the case of FIRES, this is preceded by a minor febrile infection (Gaspard et al., 2018). Both are thought to have an inflammatory/autoimmune basis, possibly involving a post-infection cytokine-medicated mechanism. There are currently no diagnostic laboratory tests for these conditions. Genetic, mitochondrial and other disorders: There are a number of mitochondrial diseases which, though rare, have SE as a prominent feature. These include: Alpers disease; mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS); Leigh syndrome; and myoclonic encephalopathy with ragged red fibres (MERRF) (Trinka et al., 2012; Myers et al., 2019). For these patients’ serum and CSF, testing for lactate is recommended, though alone, this neither proves nor excludes a mitochondrial disorder, and where there is a strong clinical suspicion, specialist advice should be sought. Inborn errors of metabolism, such as porphyria, Wilson's disease and Alexander's disease, as well as chromosomal aberrations such as Angelman syndrome, may be investigated with specific genetic and/or laboratory testing. A comprehensive list of all the genetic and mitochondrial disorders which may cause SE is beyond the scope of this article, but covered in Myers et al (2019). ROLE OF BLOOD TESTS IN LONG-TERM MONITORING Some authorities suggest laboratory tests should ideally be performed prior to initiation of, and during treatment with, almost any AED (Patsalos and St. Louis, 2018). In most instances, some baseline parameters will nevertheless be available as part of an initial investigation of the presenting seizure or associated illness. Beyond that, the only other recommended pre-treatment test (table 2) is when treatment with carbamazepine, oxcarbazepine or eslicarbazepine is considered in individuals of Southeast Asian descent. The human leucocyte antigen (HLA) allele, HLA-B*1502, is highly prevalent in this population (up to 15% in Hong Kong, Thailand and the Philippines), and strongly associated with severe cutaneous hypersensitivity reactions (Stevens Johnson syndrome, toxic epidermal necrolysis). For carbamazepine, hetero- or homozygosity is estimated to show 98.3% sensitivity and 97% specificity for the development of SJS/TEN, with a 100% negative predictive value. Guidelines for screening prior to treatment are now in place in several developed countries (Fowler et al., 2019), though simply avoiding these drugs when alternatives are readily available is also of course entirely appropriate. A number of other alleles have also been identified, but none with such a strong association. According to most practitioners and guidelines, regular (e.g. annually or more) blood test monitoring of children or adults with epilepsy is not recommended as routine and should only be performed if clinically indicated (NICE, 2012 [Update 2019]). Infrequent monitoring, e.g. at 2-5-year intervals, is almost certainly sufficient. That said, awareness of the more common potential laboratory abnormalities associated with AED use is important. Patients need to be advised to seek medical advice if indicative symptoms occur, and non-specialists need to know which specific abnormalities to test for depending on the AED in question, and the clinical situation. It is similarly just as important to know what minor derangements can be safely attributed to AED use, without needing any change in treatment or further investigation. Broad recommendations by drug are summarized in table 2. Haematologic reactions: Many AEDs are associated with a spectrum of haematological side effects. These include aplastic anaemia (carbamazepine, valproate and phenytoin), megaloblastic anaemia (phenytoin, phenobarbital and primidone) and thrombocytopaenia (carbamazepine and valproate). Transient leukopaenia and neutropaenia may also occur, especially in patients with low pre-treatment levels. Clinical indications to test include the development of a sore throat/bacterial infection within a few weeks of starting or a dose increase, new bleeding or bruising, or excessive fatigue. Second and third-generation AEDs tend to be associated with fewer haematological side effects, but for newer drugs, it must not be forgotten that rare but potentially dangerous effects can sometimes only become apparent some years after licensing. For all AED therapy, discontinuation is usually not indicated, unless symptoms are severe. In general, withdrawal should be considered if cell count falls below: 2,000/mL for white blood cells, 1,000/mL for neutrophils, 3.5 × 106/mL for red blood cells (11 g/dL for haemoglobin concentration) and 80,000/mL for platelets (Verrotti et al., 2014). Overwhelmingly, haematological reactions are reversible after withdrawal and do not need any special treatment (Callaghan et al., 1985). Electrolytes and pH changes: Hyponatremia is a common finding with carbamazepine, oxcarbazepine and eslicarbazepine treatment, most likely due to antidiuretic effects. It is usually mild (>130 mmol/L) and asymptomatic, though often causes undue concern if picked up incidentally. Concurrent use of other agents, such as antihypertensives and serotonin re-uptake inhibitors, increases the risk. Levels between 125 and 130 nmol/L (moderate), particularly when chronic, may also appear to be asymptomatic, though can also be associated with subtle symptoms and increased morbidity and mortality in some contexts. Symptoms, when present, range from minor unsteadiness, falls, and reduced concentration through to confusion, nausea, and in severe cases, life-threatening cardiorespiratory distress or coma (Williams et al., 2016). Thorough clinical assessment is essential, with management of symptoms (or lack of) being a more important factor than absolute sodium. Additional investigations (including plasma and urine osmolality) are indicated in all but the mildest cases to exclude and address other contributors and inform decisions about the suspect AED. Asymptomatic metabolic (renal tubular) acidosis is common during topiramate treatment (Garris and Oles, 2005), and also seen with other carbonic anhydrase inhibitors, zonisamide (Baulac et al., 2014) and acetazolamide (Hamed, 2017). In some, this is likely associated with an increased the risk of nephrolithiasis (Kuo et al., 2002; Hamed, 2017) and a crystalline nephropathy, although not all studies support this (Shen et al., 2015). Hepatotoxicity: Use of many AEDs, especially older drugs such as phenytoin, carbamazepine and valproate (Bjornsson, 2008; Hamed, 2017), as well as some of the newer agents including cannabidiol, is associated with abnormalities of liver function. Mild derangements based on liver function tests (<double the normal upper limit of normal) are usually not of concern unless symptomatic or deteriorating on repeat testing. Valproate use also causes raised ammonia levels, sometimes causing a reversible encephalopathy (Chopra et al., 2012), though, of note, a non-hyperammonaemic valproate encephalopathy is also recognized. Testing should be considered in any patient presenting with confusion, lethargy or drowsiness after initiation or a dose increase. Bone health: An increased risk of fracture related to AED use is now well established (Theochari and Cock, 2018). Whilst a broad range of parameters such as markers of bone turnover have been evaluated in research studies, the only laboratory measure independently associated with fracture risk is vitamin D. AED use and epilepsy are both risk factors for hypovitaminosis D, with likely pharmacological and other contributors (e.g. reduced sunlight exposure, lower physical activity). Current evidence supports testing serum vitamin D, calcium, albumin and alkaline phosphatase (“bone profile”), 2-5 times yearly in adults and children on AEDs (NICE, 2012 [Update 2019]), with vitamin D supplementation as required, aiming for a yearly average serum level of >50nmol/L (Dobson et al., 2018). Most of the evidence relates to enzymes inducing older AEDs, specifically carbamazepine, phenytoin and barbiturates, in whom more frequent monitoring (e.g. annually) may be justified (Arora et al., 2016). However, there is no doubt that valproate (and enzyme inhibitor) is also implicated (MHRA, 2009), and the paucity of evidence against newer AEDs may just reflect less cumulative exposure and should not be considered to indicate a lack of risk. It is reasonable to assume, unless proven otherwise, that other enzyme inducers carry at least similar risks, and other AEDs may carry some risk, though some reassuring data with respect to lamotrigine and levetiracetam is emerging (Theochari and Cock, 2018). Cardiovascular risk factors; Obesity, diabetes and hypercholesterolaemia are all independently associated with cardiovascular disease and premature mortality. These risks apply as much to people with epilepsy as to others in the population. Several antiepileptic drugs can be associated with weight gain, in particular, valproate, pregabalin, gabapentin, and vigabatrin, in whom monitoring of lipid profile and glucose may be appropriate and inform lifestyle change, or in some instances, a change in AED. In recent years, interest in the potential for AEDs to influence other circulatory markers of vascular risk, such as homocysteine, folate, C-reactive protein, and more recently, homoarginine and asymmetric dimethylarginine, has also emerged (Kim et al., 2013; Sarecka-Hujar et al., 2019). However, the clinical implications of this in practice remain uncertain, with insufficient evidence as yet to guide a monitoring or intervention strategy. Therapeutic drug monitoring: Therapeutic drug monitoring (TDM) is a tool which, correctly utilized, can be extremely helpful in optimizing treatment for some individuals. Certainly for many drugs, there is a better correlation between serum levels and efficacy than with the oral dose (Patsalos et al., 2018). However, for the vast majority of patients, if they are free of seizures and side effects, Class I evidence now supports that knowing the serum level is of little, if any, benefit in routine practice (Aícua-Rapún et al., 2020). Thus, taking costs into account, routine monitoring is generally not recommended (NICE, 2012 [Update 2019]). TDM can, however, be critical to support (or refute) a suspicion of non-adherence or for suspected toxicity or seizure persistence despite prescribing of an adequate dose (to identify fast metabolisers or non-compliance), when a formulation change is to occur and when pharmacokinetic variability is expected (e.g. in children or the elderly, pregnancy, or for hepatic or renal disease), or drug interactions are anticipated (Patsalos et al., 2018). This is particularly so with phenytoin (which exhibits saturation kinetics, meaning even a small change in dose or metabolism can result in substantial changes in level), and in situations where reliance on clinical judgement alone is felt to be insufficient, for example, when even a single, potentially preventable seizure, after a period of remission, might have significant consequences. In this situation, if available, the best comparator is the “individual therapeutic concentration”, i.e. a plasma AED concentration trough level taken during a time of optimum therapeutic response on an established dose. Individualized therapeutic AED monitoring is accepted as much more meaningful than a comparison to fixed reference ranges (Patsalos et al., 2018). Strictly speaking, predicting drug adherence or non-adherence based on AED plasma levels is only possible when the level is compared to that individual's therapeutic concentration (Lunardi et al., 2019), though in practice reasonable inferences can be drawn from big fluctuations or undetectable levels despite stable prescribed doses. KNOWN EPILEPSY WITH DETERIORATION OF CONTROL A frequent clinical challenge is represented by people with established epilepsy presenting to acute medical services, reporting a deterioration in seizure control. This might be a single unprovoked seizure after a period of remission, a reported increase in seizure frequency, or seizure clusters sometimes escalating and leading to concern about imminent status epilepticus. In this situation, it is important to remember that all the factors discussed earlier that can trigger acute symptomatic seizures, or status epilepticus, can similarly influence seizure frequency in individuals with established epilepsy, therefore a similar approach to laboratory testing is recommended. Excluding intercurrent infection, as well as checking AED levels and alcohol and toxicology screens can be key, yet the latter in our experience are often overlooked in favour of CT or even EEG, which are rarely informative or indicated in this context. PREGNANCY IN WOMEN WITH EPILEPSY Specific issues pertain to women with epilepsy who might become or who are pregnant: Some AEDs are known to have teratogenic effects and so choice and optimization of drug treatment in advance of any potential pregnancy in women of childbearing age is particularly important (Tomson et al., 2019). Non-adherence rates are increased during pregnancy (likely due to concerns over teratogenicity as well as other factors such as vomiting) (Schmidt et al., 1983). Therefore, pre-pregnancy counselling regarding the importance of treatment continuation, because of the maternal and foetal risks of uncontrolled seizures, is extremely important (Pennell, 2003). Serum levels of most AEDs fall during pregnancy due to haemodilution, changes in absorption and metabolism and increased excretion. Whilst the seizure frequency of most women will remain unchanged or fall during pregnancy, a significant number of them will experience an increase in seizures, likely due to medication non-compliance and reduced serum levels (Harden et al., 2009; Pennell, 2003). In light of the above issues, the question arises as to the utility of therapeutic drug monitoring (TDM) during pregnancy, and to some, identifying a pre-pregnancy individual therapeutic concentration and then monitoring and adjusting the dose during pregnancy may seem like an obvious strategy. However, in the only study to date to formally address this in a prospective and blinded manner, there was no evidence to support “treating the level” over and above standard practice (increasing the dose in response to changes in seizure frequency) (Thangaratinam et al., 2018). An exception to this might be lamotrigine which exhibits markedly increased clearance during pregnancy, resulting in a reduction of plasma levels of around 65% in the second and third trimester (Petrenaite et al., 2005). There is some evidence that TDM of lamotrigine during pregnancy may be superior to clinical monitoring alone in reducing seizure deterioration (Pennell, 2003; Pirie et al., 2014). Both the ILAE and the American Academy of Neurology currently recommend TDM during pregnancy in women on an AED known to undergo substantial clearance changes, including lamotrigine, levetiracetam, oxcarbazepine and phenytoin. When a pre-pregnancy level is unknown, increasing the dose, at least in women with a history of tonic-clonic seizures, should be considered in any case (Tomson et al., 2019). When AED doses have been increased during pregnancy, tapering after delivery will usually be required. TDM may also be useful if there is concern about toxicity during this time, although in practice the decision will usually be made on clinical grounds before any level is available. The other important test to do in relation to pregnancy is ensuring adequate vitamin D status ideally before conception, but also during pregnancy. Vitamin D is essential for foetal development, therefore checking 25-hydroxyvitamin D levels at least once early on, and supplementing accordingly, is recommended (Hart et al., 2015, Roth et al., 2017). Folate supplementation (all, at least 0.4 mg/day) is also recommended but does not require serum monitoring. Similarly, there is no requirement for monitoring vitamin K or clotting parameters in women, including those on enzyme-inducing AEDs. Oral or intramuscular vitamin K administration in neonates is standard care for all women in many countries, and there is no evidence that the historical practice of additionally supplementing the mother during the last trimester is necessary (Sveberg et al., 2015; Panchaud et al., 2018). OTHER CONSIDERATIONS IN RARE OR UNUSUAL CASES A range of rare but important neurometabolic disorders can cause epilepsy (Lee et al., 2018), the detailed discussion of which is beyond the scope of this article and will almost always require specialist assessment in a tertiary centre. Some are particularly important not to miss, as AEDs will often be ineffective, whereas targeted therapy for the underlying disorder, in the form of supplements or dietary modifications, can substantially improve outcomes. Glutamine transporter type 1 deficiency syndrome (Glut1DS): This classically presents in infancy with seizures that are treatment-resistant or influenced by fasting, associated with developmental delay, acquired microcephaly and a range of movement disorders. However, a much broader phenotype, including later onset and paroxysmal movement disorders, is also now recognized (De Giorgis and Veggiotti, 2013). Glut1 facilitates glucose transport across the blood-brain barrier and the initial diagnostic step, feasible worldwide, is a fasting lumbar puncture which will show relatively low CSF glucose (hypoglycorrhachia) compared to blood glucose and a low-to-normal lactate level. Genetic confirmation by analysis of the solute carrier family 2 (facilitated glucose transporter) member 1 (SLC2A1)gene may then be performed. Early diagnosis is critical because it allows prompt initiation of treatment with a ketogenic diet (Klepper and Leiendecker, 2007; De Giorgis and Veggiotti, 2013). Vitamin B6-dependent epilepsies: The B6 vitamins, in particular pyridoxal-5’-phophate (PLP), are involved in over 70 human pathways, including amino acid and neurotransmitter metabolism (Wilson et al., 2019). In any neonate or infant presenting with AED-resistant seizures, often myoclonic in the first days of life, plasma, urine and ideally CSF samples should be collected and frozen at -80̊C for biomarkers. Hypoglycaemia and lactic acidosis may be present in the acute phase, but testing should not delay a prompt empirical trial of treatment with pyridoxine in the first instance, with next steps dependent on response. Later-onset cases, including status epilepticus in adults, have also been reported but appear to be extremely rare. Mitochondrial disorders are another important group, characteristically causing a combination of different types of focal seizures and can pose a significant risk of SE (Bindoff and Engelsen, 2012). Indicators to consider onward referral include seizures developing in association with failure to thrive, developmental delay, ataxia and multiorgan involvement (Rahman, 2012). Whilst none are yet treatable, some are associated with a higher risk of potentially fatal adverse liver reactions with commonly used AEDs, such as valproate. Raised serum and/or CSF lactate may be another clue, but in the acute setting, is non-specific. Diagnosis is based on genetic testing, initially using blood to identify common mutations, but not infrequently, a muscle sample is required for genetic and biochemical analysis. Everolimus for tuberous sclerosis complex (TSC). The mTOR inhibitor (mammalian Target of Rapamycin), everolimus, which has been used for various benign tumours associated with TSC for some years, has more recently been licensed for the treatment of drug-resistant epilepsy associated with TSC (French et al., 2016). As well as monitoring of serum levels to determine appropriate dose, adverse events include hyperglycaemia, hypercholesterolaemia, hypertriglyceridemia, and worsening of proteinuria requiring regular monitoring on initiation and throughout treatment, alongside standard haematological, bone health, renal and liver function tests. Other genetic testing. Epilepsy genetics is a rapidly developing field and has not been covered in this article, but is becoming increasingly relevant in specialist practice both for diagnosis and drug development, and in some instances with respect to informing treatment choices. This has been recently reviewed elsewhere (Myers et al., 2019). CONCLUSIONS Laboratory investigations, whilst not essential to the diagnosis of seizures or epilepsy, can be fundamental to determining the cause and guiding management. Over 50% of first seizures have an acute symptomatic cause, including a range of metabolic, toxic or infectious causes. The same triggers can precipitate status epilepticus, either de novo or as part of a deterioration of control in individuals with established epilepsy. Some, such as hypoglycaemia or severe hyponatraemia can be fatal without prompt identification and treatment. Failure to identify seizures associated with recreational drug or alcohol misuse can lead to inappropriate AED treatment, as well as a missed opportunity for more appropriate intervention. In individuals with established epilepsy on treatment, some laboratory monitoring is desirable at least occasionally, in particular, in relation to bone health, as well as in situations where changes in AED clearance or metabolism are likely (extremes of age, pregnancy, comorbid disorders of renal or hepatic function). For any clinician managing people with epilepsy, awareness of the commoner derangements associated with individual AEDs is essential to guide practice. A very broad range of neurometabolic disorders can be associated with epilepsy, which may manifest as a presenting feature. Awareness of suggestive clinical features and onward referral to specialist centres is recommended, though in resource-poor settings, trials of dietary treatments or supplements may be appropriate as a first step. SUPPLEMENTARY DATA Summary didactic slides are available on the www.epilepticdisorders.com website. DISCLOSURES Prof. Cock reports personal fees from Sage Pharmaceuticals Ltd, personal fees from Eisai Europe Ltd, personal fees from UCB Pharma Ltd, personal fees from European Medicines Agency, personal fees from UK Epilepsy Nurse Specialist Association, non-financial support from Special Products Ltd, grants from U.S NIH Institute of Neurological Disorders and Stroke, non-financial support from International League Against Epilepsy, E-learning Task Force, non-financial support from European Academy of Neurology, and personal fees from Bial and Eisai, Novartis, and GW Research Ltd, outside the submitted work. Dr. von Oertzen reports grants, personal fees and non-financial support from Novartis Phama, personal fees from Roche Pharma, personal fees from Biogen Idec Austria, personal fees from Liva Nova, grants from Grossegger & Drbal GmbH, grants from Merck, personal fees from Indivior Austria GmbH, personal fees and non-financial support from gtec GmbH Austria, personal fees and non-financial support from Boehringer-Ingelheim, personal fees from Philips , personal fees and non-financial support from UCB Pharma, personal fees from Almirall , personal fees from Eisai, outside the submitted work; he is webeditor in chief of the European Academy of Neurology (EAN), co-chair of the EAN scientific panel for epilepsy, and vice-president of the Österreichische Gesellschaft für Epileptologie (Austrian ILAE chapter). Dr. Craiu reports grants from BioMarine, grants from UCB, grants from A&D pharma, outside the submitted work. Drs Sutton, Barca, Komoltsev, and Dr. Guekht report no conflicts. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License
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Josep Dalmau receives the “Scientific Breakthrough 2023” Award from the American Brain Foundation

From www.clinicbarcelona.org - May 23, 2023 2:38 PM
The accolade recognises the commitment of this Clínic Barcelona-IDIBAPS researcher to deepening our understanding of autoimmune neurological diseases such...
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IDIBAPS creates three multidisciplinary research programs to encourage collaboration among its groups

From www.clinicbarcelona.org - September 5, 2023 11:21 AM
They are the Translational cancer research program, the Synaptic autoimmunity in neurology, psychiatry and cognitive neuroscience program and the Lymphoid...
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ExTINGUISH: A Beacon of Hope for NMDAR Encephalitis

From youtu.be - August 6, 2023 7:10 PM
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MR Imaging Findings in a Large Population of Autoimmune Encephalitis | American Journal of Neuroradiology

MR Imaging Findings in a Large Population of Autoimmune Encephalitis | American Journal of Neuroradiology | AntiNMDA | Scoop.it
From www.ajnr.org - July 27, 2023 11:18 AM
Research ArticleAdult Brain MR Imaging Findings in a Large Population of Autoimmune Encephalitis S. Gillon, M. Chan, J. Chen, E.L. Guterman, X. Wu, C.M. Glastonbury and Y. Li American Journal of Neuroradiology July 2023, 44 (7) 799-806; DOI: https://doi.org/10.3174/ajnr.A7907 ArticleFigures & DataInfo & MetricsReferences PDF This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased. AbstractBACKGROUND AND PURPOSE: Autoimmune encephalitis is a rare condition in which autoantibodies attack neuronal tissue, causing neuropsychiatric disturbances. This study sought to evaluate MR imaging findings associated with subtypes and categories of autoimmune encephalitis.MATERIALS AND METHODS: Cases of autoimmune encephalitis with specific autoantibodies were identified from the medical record (2009–2019). Cases were excluded if no MR imaging of the brain was available, antibodies were associated with demyelinating disease, or >1 concurrent antibody was present. Demographics, CSF profile, antibody subtype and group (group 1 intracellular antigen or group 2 extracellular antigen), and MR imaging features at symptom onset were reviewed. Imaging and clinical features were compared across antibody groups using χ2 and Wilcoxon rank-sum tests.RESULTS: Eighty-five cases of autoimmune encephalitis constituting 16 distinct antibodies were reviewed. The most common antibodies were anti-N-methyl-D-aspartate (n = 41), anti-glutamic acid decarboxylase (n = 7), and anti-voltage-gated potassium channel (n = 6). Eighteen of 85 (21%) were group 1; and 67/85 (79%) were group 2. The median time between MR imaging and antibody diagnosis was 14 days (interquartile range, 4–26 days). MR imaging had normal findings in 33/85 (39%), and 20/33 (61%) patients with normal MRIs had anti-N-methyl-D-aspartate receptor antibodies. Signal abnormality was most common in the limbic system (28/85, 33%); 1/68 (1.5%) had susceptibility artifacts. Brainstem and cerebellar involvement were more common in group 1, while leptomeningeal enhancement was more common in group 2.CONCLUSIONS: Sixty-one percent of patients with autoimmune encephalitis had abnormal brain MR imaging findings at symptom onset, most commonly involving the limbic system. Susceptibility artifact is rare and makes autoimmune encephalitis less likely as a diagnosis. Brainstem and cerebellar involvement were more common in group 1, while leptomeningeal enhancement was more common in group 2.ABBREVIATIONS:AIEautoimmune encephalitisanti-Gq1banti-ganglioside Q1banti-LGI1anti-leucine-rich glioma inactivated 1CASPR2contactin-associated protein-like 2GABAgamma-aminobutyric acidGADglutamic acid decarboxylaseGFAPglial fibrillary acidic proteinNMDAN-methyl-D-aspartatePD-1programmed cell death protein 1VGCCvoltage gated calcium channelVGKCvoltage-gated potassium channel© 2023 by American Journal of NeuroradiologyView Full Text Log in using your username and password Username * Password * Forgot your user name or password? PreviousNext Back to top In this issue American Journal of Neuroradiology Vol. 44, Issue 7 1 Jul 2023 Table of ContentsIndex by authorComplete Issue (PDF) Print Download PDF Email Article Citation Tools Share Tweet WidgetFacebook LikeGoogle Plus One Purchase Related ArticlesNo related articles found.PubMedGoogle Scholar Cited By...No citing articles found.CrossrefGoogle Scholar More in this TOC Section Cost-Effectiveness Analysis of 68Ga-DOTATATE PET/MRI in Radiotherapy Planning in Patients with Intermediate-Risk Meningioma Choroid Plexus Calcification Correlates with Cortical Microglial Activation in Humans: A Multimodal PET, CT, MRI Study Show more ADULT BRAIN Similar Articles
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Elevated blood and cerebrospinal fluid biomarkers of microglial activation and blood‒brain barrier disruption in anti-NMDA receptor encephalitis | Journal of Neuroinflammation | Full Text

Elevated blood and cerebrospinal fluid biomarkers of microglial activation and blood‒brain barrier disruption in anti-NMDA receptor encephalitis | Journal of Neuroinflammation | Full Text | AntiNMDA | Scoop.it
From jneuroinflammation.biomedcentral.com - July 27, 2023 11:01 AM
Background Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disease characterized by complex neuropsychiatric syndrome and cerebrospinal fluid (CSF) NMDAR antibodies. Triggering receptor expressed on myeloid cells 2 (TREM2) has been reported to be associated with inflammation of the...
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Anti-N-methyl-d-aspartate receptor encephalitis and positive human herpesvirus-7 deoxyribonucleic acid in cerebrospinal fluid: a case report | Journal of Medical Case Reports | Full Text

Anti-N-methyl-d-aspartate receptor encephalitis and positive human herpesvirus-7 deoxyribonucleic acid in cerebrospinal fluid: a case report | Journal of Medical Case Reports | Full Text | AntiNMDA | Scoop.it
From jmedicalcasereports.biomedcentral.com - July 14, 2023 2:17 PM
Background Anti-N-methyl-d-aspartate receptor encephalitis is a neuroautoimmune syndrome typically presenting with seizures, psychiatric symptoms, and autonomic dysfunction. Human herpesvirus-7 is often found with human herpesvirus-6 and infects leukocytes such as T-cells, monocytes–macrophages,...
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We have a winner! - The Anti-NMDA Receptor Encephalitis Foundation Prize, 2023

We have a winner! - The Anti-NMDA Receptor Encephalitis Foundation Prize, 2023 | AntiNMDA | Scoop.it
From www.antinmdafoundation.org - June 25, 2023 2:58 PM
It’s that time of year again, when the Foundation is delighted to offer its annual Anti-NMDA Receptor Encephalitis Foundation Prize to a promising neurology trainee ...Read More...
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Antibodies Associated With Autoimmune Encephalitis in Patients With Presumed Neurodegenerative Dementia | Neurology Neuroimmunology & Neuroinflammation

Antibodies Associated With Autoimmune Encephalitis in Patients With Presumed Neurodegenerative Dementia | Neurology Neuroimmunology & Neuroinflammation | AntiNMDA | Scoop.it
From nn.neurology.org - June 19, 2023 9:45 PM
AbstractBackground & Objectives Autoimmune encephalitis (AIE) may present with prominent cognitive disturbances without overt inflammatory changes in MRI and CSF. Identification of these neurodegenerative dementia diagnosis mimics is important because patients generally respond to immunotherapy. The objective of this study was to determine the frequency of neuronal antibodies in patients with presumed neurodegenerative dementia and describe the clinical characteristics of the patients with neuronal antibodies.Methods In this retrospective cohort study, 920 patients were included with neurodegenerative dementia diagnosis from established cohorts at 2 large Dutch academic memory clinics. In total, 1,398 samples were tested (both CSF and serum in 478 patients) using immunohistochemistry (IHC), cell-based assays (CBA), and live hippocampal cell cultures (LN). To ascertain specificity and prevent false positive results, samples had to test positive by at least 2 different research techniques. Clinical data were retrieved from patient files.Results Neuronal antibodies were detected in 7 patients (0.8%), including anti-IgLON5 (n = 3), anti-LGI1 (n = 2), anti-DPPX, and anti-NMDAR. Clinical symptoms atypical for neurodegenerative diseases were identified in all 7 and included subacute deterioration (n = 3), myoclonus (n = 2), a history of autoimmune disease (n = 2), a fluctuating disease course (n = 1), and epileptic seizures (n = 1). In this cohort, no patients with antibodies fulfilled the criteria for rapidly progressive dementia (RPD), yet a subacute deterioration was reported in 3 patients later in the disease course. Brain MRI of none of the patients demonstrated abnormalities suggestive for AIE. CSF pleocytosis was found in 1 patient, considered as an atypical sign for neurodegenerative diseases. Compared with patients without neuronal antibodies (4 per antibody-positive patient), atypical clinical signs for neurodegenerative diseases were seen more frequently among the patients with antibodies (100% vs 21%, p = 0.0003), especially a subacute deterioration or fluctuating course (57% vs 7%, p = 0.009).Discussion A small, but clinically relevant proportion of patients suspected to have neurodegenerative dementias have neuronal antibodies indicative of AIE and might benefit from immunotherapy. In patients with atypical signs for neurodegenerative diseases, clinicians should consider neuronal antibody testing. Physicians should keep in mind the clinical phenotype and confirmation of positive test results to avoid false positive results and administration of potential harmful therapy for the wrong indication.GlossaryAD=Alzheimer dementia; AIE=autoimmune encephalitis; CBA=cell-based assays; DLB=dementia with Lewy bodies; IHC=immunohistochemistry; LN=live hippocampal cell cultures; PPA=primary progressive aphasia; PSP=progressive supranuclear palsy; RPD=rapidly progressive dementia; VGCC=voltage-gated calcium channelCognitive dysfunction can be the presenting and most prominent symptom in patients with autoimmune encephalitis (AIE).1,2 In contrast to neurodegenerative diseases, patients with antibody-mediated encephalitis might benefit from immunotherapy and improve considerably.3,4 The presence of neuronal antibodies has been reported predominantly in rapidly progressive dementia (RPD).5,6 However, AIE can present less fulminantly and is therefore potentially missed, resulting in diagnosis and treatment delay or even misdiagnosis.7,8 We hypothesized that a small—but not insignificant—part of dementia syndromes is indeed caused by antibody-mediated encephalitis and underdiagnosed, withholding these patients' available treatments. The wish to diagnose every single patient with autoimmune encephalitis is in opposition with the risk for false positive tests.9 Therefore, we strictly adhere to confirmation of positive test results with 2 different test techniques. In this study, we describe the frequency of neuronal antibodies in a cohort of patients diagnosed with various dementia syndromes in a memory clinic. In addition, we present clues to improve clinical recognition of AIE in dementia syndromes.MethodsPatients and Laboratory StudiesIn this retrospective multicenter study, we tested for the presence of neuronal antibodies in serum and CSF samples from patients diagnosed with neurodegenerative dementia diagnosis, included earlier prospectively in established cohorts at 2 large Dutch academic memory clinics (Erasmus University Medical Center, Amsterdam University Medical Centers, location VUmc)10 between 1998 and 2016 (84% last 10 years). All patients fulfilled the core clinical criteria for dementia, as defined by the National Institutes of Aging-Alzheimer Association workgroups.11 Patients were classified into 4 subgroups (based on diagnostic criteria): Alzheimer dementia (AD), frontotemporal dementia (FTD; both behavioral variant and primary progressive aphasia [PPA]), dementia with Lewy bodies (DLB), and other dementia syndromes.11,-,14 Rapidly progressive dementia was defined as dementia within 12 months or death within 2 years after the appearance of the first cognitive symptoms.15 Patients with vascular dementia were not included. Clinic information was retrieved from the prospectively collected data. A subacute deterioration was defined as a marked progression of symptoms in 3 months and a fluctuating course as a disease course fluctuating over a longer period (e.g., weeks to months; different from the fluctuations within a day as seen in some patients with DLB). Dementia markers were scored according to the reference values (per year and per center; included in Table 1).View inline View popup Table 1 Patient Characteristics of Auto-antibody Positive PatientsAll samples, stored in both cohorts' biobanks, were screened for immunoreactivity with immunohistochemistry (IHC), as previously described.16 Preferably, paired serum and CSF were tested for optimal sensitivity and specificity. Samples that were showing a positive or questionable staining pattern were tested more extensively using validated commercial cell-based assays (CBA) and in-house CBA (eTable 1, links.lww.com/NXI/A869). In addition, these samples were tested with live hippocampal cell cultures (LN).16,17 To ascertain specificity, only samples that could be confirmed by CBA or LN were scored as positive because there is a higher risk for false-positive test results in this population with a low a priori chance to have encephalitis.9,18 If IHC was suggestive for antibodies against intracellular (paraneoplastic) targets, this was explored by a different IHC technique.19 Anti-thyroid peroxidase (TPO), voltage-gated calcium channel (VGCC), or low titer glutamic acid decarboxylase antibodies were not tested for because these are generally nonspecific at these ages and are not associated with dementia syndromes.Antibody-positive patients were described exploratory and compared with a randomly selected antibody-negative group (ratio 1:4) matched for memory clinic, dementia subtype, sex, and age (±5 years). For these comparisons, medical records were additionally assessed for both the antibody-positive and antibody-negative patients. All antibody-positive patients were reviewed by a panel consisting of neurologists specialized in neurodegenerative (F.J., H.S., J.S.) or autoimmune diseases (J.V., P.S.S., M.T.), and a consensus classification of AIE vs AIE with a neurodegenerative dementia comorbidity was reached.Statistical AnalysisWe used IBM SPSS 25.0 (SPSS Inc) and Prism 8.4.3 (GraphPad) for statistical analysis. Baseline characteristics were analyzed using the Fisher exact test, the Fisher-Freeman-Halton test, or the Kruskal-Wallis test, when appropriate. For group comparisons, encompassing categorical data, we used the Pearson χ2 test or the Fisher-Freeman-Halton test, when appropriate. Continuous data were analyzed using the Mann-Whitney U test. All p-values were two-sided and considered statistically significant when below 0.05. We applied no correction for multiple testing, and therefore, p values between 0.05 and 0.005 should be interpreted carefully.Standard Protocol Approvals, Registrations, and Patient ConsentsThe study was approved by The Institutional Review Boards of Erasmus University Medical Center Rotterdam and Amsterdam University Medical Center, location VUmc. Written informed consent was obtained from all patients.Data AvailabilityAny data not published within this article are available at the Erasmus MC University Medical Center. Patient-related data will be shared on reasonable request from any qualified investigator, maintaining anonymization of the individual patients.ResultsIn total, 1,398 samples from 920 patients were tested (Figure; in 478, both CSF and serum [52%]). Three-hundred fifty-eight patients were classified as AD (39%), 283 FTD (31%), and 161 DLB (17%). The fourth subgroup with other dementia syndromes consisted of 118 patients (13%), including progressive supranuclear palsy (n = 48, 5%) and corticobasal syndrome (n = 29, 3%). The median age at disease onset was 62 years (range 16–90 years). Male patients were overrepresented (n = 542, 59%), and 60 patients (7%) fulfilled the criteria for rapidly progressive dementia (RPD; eTable 2, links.lww.com/NXI/A869).<img class="highwire-fragment fragment-image" alt="Figure" width="440" height="305" src="https://nn.neurology.org/content/nnn/10/5/e200137/F1.medium.gif">Download figure Open in new tab Download powerpoint Figure Flowchart of Patient Inclusion With Antibody ResultsIn total, 920 patients (1,398 samples) with a presumed neurodegenerative dementia syndrome were tested for the presence of neuronal antibodies in serum and CSF. Neuronal antibodies were detected in 7 patients (0.8%, 95% CI 0.2–1.3); five among the 358 Alzheimer disease patients. Subclassification of the ‘other’ group is provided in supplementary table eTable 2 (links.lww.com/NXI/A869). AD = Alzheimer disease; DLB = diffuse Lewy body dementia; DPPX = dipeptidyl aminopeptidase-like protein 6; FTD = frontotemporal dementia; IgLON5 = Ig-like domain-containing protein family member 5; LGI1 = leucin-rich glioma inactivated protein 1; NMDAR = N-methyl-d-aspartate receptor; S = serum.Neuronal antibodies were detected in 7 patients (0.8%; 5 in the AD group: 1.4%; Figure), including anti-IgLON5 (n = 3), anti-LGI1 (n = 2), anti-DPPX (n = 1), and anti-NMDAR antibodies (n = 1; Table 1). Among these 7, 4 patients were diagnosed retrospectively with an exclusive diagnosis of AIE, while 3 patients were classified to have AIE (anti-IgLON5 [n = 2] and anti-NMDAR antibodies [n = 1]) with a neurodegenerative dementia comorbidity. No patients with antibodies fulfilled the criteria for RPD, yet a subacute deterioration later in the disease was reported in 3 patients. Atypical clinical signs for neurodegenerative diseases were present in 7 of 7 antibody-positive patients (100% vs 21% in antibody-negative patients, p = 0.0003; Table 2). These included a subacute deterioration (n = 3), myoclonus (n = 2), a fluctuating disease course over months (n = 1), a history of autoimmune disease (n = 2), and epileptic seizures (n = 1; Table 1). Brain MRI of none of the patients demonstrated abnormalities suggestive for active AIE, in particular no hippocampal swelling nor increased T2-signal intensity. CSF pleocytosis was found in 1 patient. CSF biomarkers (t-tau, p-tau, and Aβ42) were tested in 5 of 7 patients, and t-tau and p-tau were increased in 4, while a low Aβ42 was seen in 2. Of note, only 1 patient had the combination of reduced Aβ42 and increased p-tau/t-tau, and was diagnosed with a comorbid AD. No patient received immunotherapy. Two patients still alive (1 anti-LG1, 1 anti-DPPX positive) were contacted but refused to visit our clinic to try very delayed immunotherapy trials. It is of interest that the patient with anti-DPPX antibodies showed spontaneous improvement of cognitive disturbances, atypical for a pure neurodegenerative disease.View inline View popup Table 2 Comparisons Between Patients With Neuronal Auto-antibodies and Antibody-Negative PatientsCompared with the patients without neuronal antibodies, subacute cognitive deterioration or fluctuating course was present more frequently (4/7 [57%] vs 2/28 [7%], p = 0.009). Although movement disorders (myoclonus) and autoimmune disorders were present in 2 of 7 patients each, this did not reach significance (Table 2).DiscussionIn this large, multicenter, cohort study consisting of patients with a presumed neurodegenerative dementia diagnosis, we show that a small, but clinically relevant proportion (0.8%) have neuronal antibodies. In this particular group, 4 of 7 antibody-positive patients presented with an atypical clinical course (subacute deterioration or fluctuating disease course), which is considered as a clinical clue (‘red flag’) for an antibody-mediated etiology of dementia.4 It is important that a fluctuating disease course was observed over a longer period (e.g., weeks or months) in AIE and should not be confused with shorter fluctuations of cognition or alertness (over the day) in DLB. Other known red flags, which we observed in these 7 patients, were myoclonus, epilepsy, pleocytosis, or a history of autoimmune disorders, as described earlier.1,4,-,6 Compared with antibody-negative patients, no significant difference was found related to these symptoms alone, probably due to the low number of positive patients and related low power. However, atypical clinical signs for neurodegenerative diseases together were seen significantly more frequently in the antibody-positive group. Within this cohort mostly devoid of patients with RPD, none of the antibody-positive patients fulfilled the criteria for RPD, nor ancillary testing showed specific signs for AIE in most patients. This implicates that AIE can resemble more protracted, progressive neurodegenerative dementia syndromes, as we reported earlier.1Three antibody-positive patients had IgLON5 antibodies, which is a very rare and known to have heterogeneous (chronic) clinical manifestations, including pronounced sleep problems, cognitive dysfunction, and movement disorders.20,21 Misdiagnosis with progressive supranuclear palsy (PSP) is reported, mainly associated with the preceding movement disorders. In addition, half of the patients have cognitive impairment of whom 20% fulfilled clinical criteria for dementia.21 It is of interest that IgLON5 disease shares features with neurodegeneration because autopsy studies showed tau deposits.22 However, there is a strong HLA association,20 and studies show that antibodies directly bind to surface IgLON5 on neurons and directly alter neuronal function and structure,23 suggesting a primary inflammatory disease.In previous research, a notably higher frequency (14%) of neuronal antibodies in patients with dementia was reported by Giannocaro et al.24 The discrepancy with our test results is probably explained by differences in patient selection and antibody testing methodology. First, 30% of the patients in the cohort described by Giannocaro et al. demonstrated CSF inflammatory abnormalities, indicating a relatively high pretest probability of antibody-positivity compared with our study.24 A lack of CSF pleocytosis probably better represents the population of memory clinics. Second, the previous study exclusively tested serum by cell-based assay without confirmatory tests nor testing antibodies in CSF.24 We only considered antibody test results positive when confirmed by additional techniques to avoid suboptimal specificity and false-positive test results.9Previous studies, including our own, suggested RPD as a relevant red flag for AIE,1,4,9,25 but we cannot determine this from our study based on the design of our study. We included patients at tertiary memory clinics without overt signs or symptoms suggestive for encephalitis. Therefore, the amount of patients with RPD included was very limited (7%), comparable with other large dementia cohort studies, as was the amount of patients with abnormal ancillary testing suggestive for AIE because this would have prompted a different approach than referral to a tertiary memory clinic. These patients with RPD and ancillary testing suggestive of AIE were not included in our study. Inclusion of those patients would have likely increased our rate of positivity.The strength of our study is the large number of paired samples (serum and CSF combined) from a cohort with various presumed neurodegenerative diseases without AIE suspicion, representative for academic memory clinics. A limitation is the lack of neuropathologic data to support our findings and make diagnoses of neurodegeneration or inflammation definite. To confirm if the symptoms are related to the presence of antibodies, we tried to overcome this concern in different ways. First, the presence of antibodies in serum and CSF was confirmed by different techniques (cell-based assay, tissue immunohistochemistry, and cultured live neurons), indicating optimal test specificity. Second, afterward patients were thoroughly reviewed by a panel of neurologists specialized in neurodegenerative or autoimmune disease to detect atypical signs and symptoms related to AIE. This is a very large cohort of patients with dementia examined for the presence of neuronal antibodies. Nevertheless, an important limitation of this study is the small number of antibody-positive patients, underpowering the probability to identify significant differences between antibody-positive and antibody-negative patients. The low number of patients with RPD has probably added to this small number, and a prospective study including patients with RPD is recommended. Nevertheless, several probable red flags could be identified. Diagnosing AIE in patients with dementia is highly relevant because these patients might respond to immunotherapy. Therefore, clinicians should test for neuronal antibody in patients demonstrating red flags suggestive for an autoimmune etiology, if possible early in disease course. When profound temporal lobe atrophy already has developed, little effect is to be expected. Red flags identified in this study are subacute deterioration or fluctuating course. Other red flags described previously, we also see reflected in our study, are autoimmune disorders, myoclonus, seizures, and pleocytosis,1,4,-,6 Preferably, both serum and CSF should be tested and confirmed by additional techniques. Always consider the possibility of a false positive test result, especially when only using a single technique (like the commercial cell-based assay). If the clinical phenotype is atypical, confirmation in a research laboratory should be mandatory. The use of antibody panels is discouraged, especially including the paraneoplastic blots, because these are associated with higher risks of lack of clinical relevance.26 This caution is even more warranted for tests not associated with neurodegenerative syndromes, but with a history of nonspecificity, including VGKC (in the absence of LGI1 or CASPR2), VGCC, anti-TPO, and low-titer anti-GAD65.27,-,30 Further research should focus on improving clinical recognition of AIE in patients with dementia determining the effect of immunotherapy in this specific patient category and assessing the frequency of AIE in RPD.In conclusion, we have shown that a clinically relevant, albeit small proportion of patients with a suspected neurodegenerative disease and nonrapidly progressive course have neuronal antibodies indicative of AIE.Study FundingM.J. Titulaer was supported by an Erasmus MC fellowship and has received funding from the Netherlands Organization for Scientific Research (NWO, Veni incentive), ZonMw (Memorabel program), the Dutch Epilepsy Foundation (NEF 14-19 & 19-08), Dioraphte (2001 0403), and E-RARE JTC 2018 (UltraAIE, 90030376505). F. Leypoldt has received funding from the German Ministry of Education and Research (01GM1908A) and the Era-Net funding program (LE3064/2-1).DisclosureA.E.M. Bastiaansen reports no disclosures. R.W. van Steenhoven reports no disclosures. Research programs of Wiesje van der Flier have been funded by ZonMW, now, EUFP7, EU-JPND, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health∼Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA Inc, Novartis-NL, Life-MI, AVID, Roche BV, Fujifilm, and Combinostics. W.M. van der Flier holds the Pasman chair. W.M. van der Flier is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). All funding is paid to her institution. WF has performed contract research for Biogen MA Inc and Boehringer Ingelheim. All funding is paid to her institution. W.M. van der Flier has been an invited speaker at Boehringer Ingelheim, Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), and Springer Healthcare. All funding is paid to her institution. W.M. van der Flier is consultant to Oxford Health Policy Forum CIC, Roche, and Biogen MA Inc. All funding is paid to her institution. W.M. van der Flier participated in advisory boards of Biogen MA Inc and Roche. All funding is paid to her institution. W.M. van der Flier is a member of the steering committee of PAVE and Think Brain Health. W.M. van der Flier was an associate editor of Alzheimer, Research & Therapy in 2020/2021. W.M. van der Flier is an associate editor at Brain. Research of C. Teunissen was supported by the European Commission (Marie Curie International Training Network, Grant Agreement No. 860197 (MIRIADE)), Innovative Medicines Initiatives 3TR (Horizon 2020, Grant No. 831434), EPND (IMI 2 Joint Undertaking (JU) under Grant Agreement No. 101034344) and JPND (bPRIDE), National MS Society (Progressive MS alliance) and Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands, and Alzheimer Association. C. Teunissen is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP-allowance, #LSHM20106). ABOARD also receives funding from Edwin Bouw Fonds and Gieskes-Strijbisfonds. C. Teunissen has a collaboration contract with ADx Neurosciences, Quanterix, and Eli Lilly, performed contract research or received grants from AC-Immune, Axon Neurosciences, Bioconnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Grifols, Novo Nordisk, PeopleBio, Roche, Toyama, and Vivoryon. She serves on editorial boards of Medidact Neurologie/Springer, Alzheimer Research and Therapy, and Neurology: Neuroimmunology & Neuroinflammation and is an editor of a Neuromethods book Springer. She had speaker contracts for Roche, Grifols, and Novo Nordisk. E. de Graaff holds a patent for the detection of anti-DNER antibodies. M.M.P. Nagtzaam reports no disclosures. M. Paunovic reports no disclosures. S. Franken reports no disclosures. M.W.J. Schreurs reports no disclosures. F. Leypoldt has received speakers honoraria from Grifols, Roche, Novartis, Alexion, and Biogen and serves on an advisory board for Roche and Biogen. He works for an academic institution (University Hospital Schleswig-Holstein) which offers commercial autoantibody testing. P.A.E. Sillevis Smitt holds a patent for the detection of anti-DNER and received research support from Euroimmun. J.M. de Vries reports no disclosures. H. Seelaar reports no disclosures. J.C. van Swieten reports no disclosures. F.J. de Jong reports no disclosures. Y.A.L. Pijnenburg Research of Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The chair of Wiesje van der Flier is supported by the Pasman stichting. M.J. Titulaer has filed a patent, on behalf of the Erasmus MC, for methods for typing neurologic disorders and cancer, and devices for use therein, and has received research funds for serving on a scientific advisory board of Horizon Therapeutics, for consultation at Guidepoint Global LLC, for consultation at UCB, for teaching colleagues by Novartis. MT has received an unrestricted research grant from Euroimmun AG and from CSL Behring. Go to Neurology.org/NN for full disclosure.AcknowledgmentThe authors thank all patients for their participation. The authors also thank Esther Hulsenboom and Ashraf Jozefzoon-Aghai for their technical assistance. M.W.J. Schreurs, F. Leypoldt, P.A.E. Sillevis Smitt, J.M. de Vries, and M.J. Titulaer of this publication are members of the European Reference Network for Rare Immunodeficiency, Autoinflammatory, and Autoimmune Diseases—Project ID No. 739543 (ERN-RITA; HCP Erasmus MC and University Hospital Schleswig-Holstein). H. Seelaar, J.C. van Swieten, and F.J. de Jong of this publication are members of the European Reference Network for Rare Neurological Diseases—Project ID 73910. Research of the VUmc Alzheimer center is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center VUmc is supported by Alzheimer Nederland and Stichting VUmc Fonds. The clinical database structure was developed with funding from Stichting Dioraphte.Appendix Authors<img class="highwire-fragment fragment-image" alt="Table" src="https://nn.neurology.org/content/nnn/10/5/e200137/T3.medium.gif"; width="599" height="2531">FootnotesGo to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.The Article Processing Charge was funded the authors.Submitted and externally peer reviewed. The handling editor was Editor Josep O. Dalmau, MD, PhD, FAAN.Received December 8, 2022.Accepted in final form May 8, 2023.Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.References1.↵Bastiaansen AEM, van Steenhoven RW, de Bruijn M, et al. Autoimmune encephalitis resembling dementia syndromes. Neurol Neuroimmunol Neuroinflamm. 2021;8(5):e1039.OpenUrlAbstract/FREE Full Text2.↵Lancaster E, Lai M, Peng X, et al. Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol. 2010;9(1):67-76.OpenUrlCrossRefPubMed3.↵Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013;12(2):157-165.OpenUrlCrossRefPubMed4.↵Flanagan EP, McKeon A, Lennon VA, et al. Autoimmune dementia: clinical course and predictors of immunotherapy response. Mayo Clin Proc. 2010;85(10):881-897.OpenUrlCrossRefPubMed5.↵Geschwind MD, Tan KM, Lennon VA, et al. Voltage-gated potassium channel autoimmunity mimicking creutzfeldt-jakob disease. Arch Neurol. 2008;65(10):1341-1346.OpenUrlCrossRefPubMed6.↵Grau-Rivera O, Sanchez-Valle R, Saiz A, et al. Determination of neuronal antibodies in suspected and definite Creutzfeldt-Jakob disease. JAMA Neurol. 2014;71(1):74-78.OpenUrl7.↵Titulaer MJ, McCracken L, Gabilondo I, et al. Late-onset anti-NMDA receptor encephalitis. Neurology. 2013;81(12):1058-1063.OpenUrlAbstract/FREE Full Text8.↵Gaig C, Graus F, Compta Y, et al. Clinical manifestations of the anti-IgLON5 disease. Neurology. 2017;88(18):1736-1743.OpenUrlAbstract/FREE Full Text9.↵Bastiaansen AEM, de Bruijn M, Schuller SL, et al. Anti-NMDAR encephalitis in The Netherlands, focusing on late-onset patients and antibody test accuracy. Neurol Neuroimmunol Neuroinflamm. 2022;9(2):e1127.OpenUrl10.↵van der Flier WM, Scheltens P. Amsterdam dementia cohort: performing research to optimize care. J Alzheimers Dis. 2018;62(3):1091-1111.OpenUrl11.↵McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7(3):263-269.OpenUrlCrossRefPubMed12.↵Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011;134(Pt 9):2456-2477.OpenUrlCrossRefPubMed13.↵Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology. 2011;76(11):1006-1014.OpenUrlAbstract/FREE Full Text14.↵McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium. Neurology. 2017;89(1):88-100.OpenUrlAbstract/FREE Full Text15.↵Geschwind MD. Rapidly progressive dementia. Continuum (Minneap Minn). 2016;22(2 Dementia):510-537.OpenUrl16.↵Ances BM, Vitaliani R, Taylor RA, et al. Treatment-responsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. Brain. 2005;128(Pt 8):1764-1777.OpenUrlCrossRefPubMed17.↵Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol. 2014;13(2):167-177.OpenUrlCrossRefPubMed18.↵Martinez-Martinez P, Titulaer MJ. Autoimmune psychosis. Lancet Psychiatry. 2020;7(2):122-123.OpenUrl19.↵van Coevorden-Hameete MH, Titulaer MJ, Schreurs MW, et al. Detection and characterization of autoantibodies to neuronal cell-surface antigens in the central nervous system. Front Mol Neurosci. 2016;9:37.OpenUrl20.↵Sabater L, Gaig C, Gelpi E, et al. A novel non-rapid-eye movement and rapid-eye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5: a case series, characterisation of the antigen, and post-mortem study. Lancet Neurol. 2014;13(6):575-586.OpenUrlCrossRefPubMed21.↵Gaig C, Compta Y, Heidbreder A, et al. Frequency and characterization of movement disorders in anti-IgLON5 disease. Neurology. 2021;97(14):e1367–e1381.OpenUrlAbstract/FREE Full Text22.↵Gelpi E, Hoftberger R, Graus F, et al. Neuropathological criteria of anti-IgLON5-related tauopathy. Acta Neuropathol. 2016;132(4):531-543.OpenUrlCrossRefPubMed23.↵Landa J, Gaig C, Plaguma J, et al. Effects of IgLON5 antibodies on neuronal cytoskeleton: a link between autoimmunity and neurodegeneration. Ann Neurol. 2020;88(5):1023-1027.OpenUrlCrossRefPubMed24.↵Giannoccaro MP, Gastaldi M, Rizzo G, et al. Antibodies to neuronal surface antigens in patients with a clinical diagnosis of neurodegenerative disorder. Brain Behav Immun. 2021;96:106-112.OpenUrl25.↵Hermann P, Zerr I. Rapidly progressive dementias - aetiologies, diagnosis and management. Nat Rev Neurol. 2022;18(6):363-376.OpenUrl26.↵Dechelotte B, Muniz-Castrillo S, Joubert B, et al. Diagnostic yield of commercial immunodots to diagnose paraneoplastic neurologic syndromes. Neurol Neuroimmunol Neuroinflamm. 2020;7(3):e701.OpenUrlAbstract/FREE Full Text27.↵van Sonderen A, Schreurs MW, de Bruijn MA, et al. The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies. Neurology. 2016;86(18):1692-1699.OpenUrlCrossRefPubMed28.↵Muñoz Lopetegi A, Boukhrissi S, Bastiaansen A, et al. Neurological syndromes related to anti-GAD65: clinical and serological response to treatment. Neurol Neuroimmunol Neuroinflamm. 2020;7(3):e696.OpenUrlAbstract/FREE Full Text29.↵Mattozzi S, Sabater L, Escudero D, et al. Hashimoto encephalopathy in the 21st century. Neurology. 2020;94(2):e217-e224.OpenUrlAbstract/FREE Full Text30.↵Flanagan EP, Geschwind MD, Lopez-Chiriboga AS, et al. Autoimmune encephalitis misdiagnosis in adults. JAMA Neurol. 2023;80(1):30-39.OpenUrl
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Research study - can you help?

Research study - can you help? | AntiNMDA | Scoop.it
From www.encephalitis.info - June 19, 2023 9:38 PM
Researchers at Kings College London are looking for young people to travel to London and help with an encephalitis study...
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Sociocultural Influences in Autoimmune Encephalitis Without Neurologic Symptoms

Sociocultural Influences in Autoimmune Encephalitis Without Neurologic Symptoms | AntiNMDA | Scoop.it
From www.psychiatrist.com - June 19, 2023 9:33 PM
This complex case highlights barriers to identifying autoimmune encephalitis when no neurologic symptoms are present, which are normally central to disease detection.
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Anti N-Methyl-D-Aspartate receptor antibody associated Acute Demyelinating Encephalomyelitis in a patient with COVID-19: a case report | Journal of Medical Case Reports | Full Text

Anti N-Methyl-D-Aspartate receptor antibody associated Acute Demyelinating Encephalomyelitis in a patient with COVID-19: a case report | Journal of Medical Case Reports | Full Text | AntiNMDA | Scoop.it
From jmedicalcasereports.biomedcentral.com - June 19, 2023 9:27 PM
Background Anti N-Methyl-D-Aspartate (NMDA) receptor antibody associated ADEM is a diagnosis that was first described relatively recently in 2007 by Dalmau et al. The recent COVID-19 pandemic has resulted in multiple neurological complications being reported.
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Autoimmune Encephalitis Consensus Criteria | Neurology Clinical Practice

Autoimmune Encephalitis Consensus Criteria | Neurology Clinical Practice | AntiNMDA | Scoop.it
From cp.neurology.org - June 14, 2023 7:42 PM
June 2023; 13 (3) Editorial Autoimmune Encephalitis Consensus CriteriaLessons Learned From Real-World Practice View ORCID ProfileJeffrey M. Gelfand, Chu-Yueh Guo First published April 25, 2023, DOI: https://doi.org/10.1212/CPJ.0000000000200155 Full PDF Citation Permissions Make Comment See Comments Downloads133 Share Article Info & Disclosures This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased. Autoimmune encephalitis (AE) encompasses a spectrum of neurologic disorders caused by brain inflammation, a subset of which is associated with autoantibodies to neuronal cell-surface antigens such as anti-N-methyl-d-aspartate (NMDA) receptor AE or anti-leucine-rich glioma-inactivated 1 (LGI1) AE.1 Up to half of patients with AE, however, do not have abnormal neuronal or glial autoantibodies identified and are classified as having “seronegative” AE.2 Clinical antibody testing can take several days to result, a time in which clinicians caring for patients with suspected AE may wish to initiate empiric immunosuppressive therapy. Antibody testing is also not readily accessible in some health care settings and, even when technically available, may require time-consuming advocacy with local clinical laboratories to justify relatively costly send-out testing. To add further complexity, some patients with immunoreactive (e.g., laboratory true-positive) antibodies do not have clinical AE, and over-reliance and misapplication of antibody testing were identified as important contributors to AE misdiagnosis in a 2023 multicenter analysis.3FootnotesFunding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.See page e200151© 2023 American Academy of NeurologyView Full Text AAN Members We have changed the login procedure to improve access between AAN.com and the Neurology journals. If you are experiencing issues, please log out of AAN.com and clear history and cookies. (For instructions by browser, please click the instruction pages below). After clearing, choose preferred Journal and select login for AAN Members. You will be redirected to a login page where you can log in with your AAN ID number and password. When you are returned to the Journal, your name should appear at the top right of the page. Google Safari Microsoft Edge Firefox Click here to login AAN Non-Member Subscribers Click here to login Purchase access For assistance, please contact: AAN Members (800) 879-1960 or (612) 928-6000 (International) Non-AAN Member subscribers (800) 638-3030 or (301) 223-2300 option 3, select 1 (international) Sign Up Information on how to subscribe to Neurology and Neurology: Clinical Practice can be found here Purchase Individual access to articles is available through the Add to Cart option on the article page. Access for 1 day (from the computer you are currently using) is US$ 39.00. Pay-per-view content is for the use of the payee only, and content may not be further distributed by print or electronic means. The payee may view, download, and/or print the article for his/her personal, scholarly, research, and educational use. Distributing copies (electronic or otherwise) of the article is not allowed. You May Also be Interested in Back to top Safety and Efficacy of Tenecteplase and Alteplase in Patients With Tandem Lesion Stroke: A Post Hoc Analysis of the EXTEND-IA TNK Trials Dr. Nicole Sur and Dr. Mausaminben Hathidara ► Watch Related Articles Autoimmune Encephalitis Criteria in Clinical Practice Topics Discussed All Clinical Neurology Autoimmune diseases Encephalitis Alert Me Alert me when eletters are published
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Predictive Value of Serum Neurofilament Light Chain Levels in Anti-NMDA Receptor Encephalitis

Predictive Value of Serum Neurofilament Light Chain Levels in Anti-NMDA Receptor Encephalitis | AntiNMDA | Scoop.it
From pubmed.ncbi.nlm.nih.gov - June 14, 2023 7:41 PM
Increased serum NfL levels reflect neuroaxonal damage in anti-NMDAR encephalitis. No relationship was identified with disease severity, whereas the association with outcome was confounded by age.The implied role of sampling timing on NfL levels also limits the applicability of NfL as a prognostic...
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Frontiers | The MOG antibody associated encephalitis preceded by COVID-19 infection; a case study and systematic review of the literature

Frontiers | The MOG antibody associated encephalitis preceded by COVID-19 infection; a case study and systematic review of the literature | AntiNMDA | Scoop.it
From www.frontiersin.org - September 5, 2023 11:22 AM
BackgroundNew neurological complications of COVID-19 infection have been reported in recent research. Among them, the spectrum of anti-MOG positive diseases, defined as anti-MOG antibody associated disease (MOGAD), is distinguished, which can manifest as optic neuritis, myelitis, or various forms...
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Enceph-IG Study - Institute of Infection, Veterinary and Ecological Sciences - University of Liverpool

Enceph-IG Study - Institute of Infection, Veterinary and Ecological Sciences - University of Liverpool | AntiNMDA | Scoop.it
From www.liverpool.ac.uk - August 6, 2023 7:27 PM
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A Rare Presentation of Steroid-responsive Encephalopathy Associated with Autoimmune Thyroiditis with Neuropsychiatric Symptoms: A Case Report

A Rare Presentation of Steroid-responsive Encephalopathy Associated with Autoimmune Thyroiditis with Neuropsychiatric Symptoms: A Case Report | AntiNMDA | Scoop.it
From touchneurology.com - July 27, 2023 11:22 AM
A 42-year-old woman presented in the emergency department with acute onset whole-body myoclonic jerks for 1 day.On enquiry, the patient’s parents advised...
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Pioneering Research in Autoimmune Neurology: Vanda Lennon, M.D., Ph.D.

Pioneering Research in Autoimmune Neurology: Vanda Lennon, M.D., Ph.D. | AntiNMDA | Scoop.it
From news.mayocliniclabs.com - July 27, 2023 11:05 AM
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New center to spotlight neurological autoimmune disorders

New center to spotlight neurological autoimmune disorders | AntiNMDA | Scoop.it
From bioengineer.org - July 14, 2023 2:19 PM
How do neurological disorders arise that are caused, triggered, or influenced by antibodies? What better possibilities are there for diagnosis – and above all for treatment? These are the questions addressed by the new Clinical Research Unit “BecauseY” headed by Charité – Universitätsmedizin Berlin.
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Progressive alliance advances science through patient-powered research

Progressive alliance advances science through patient-powered research | AntiNMDA | Scoop.it
From news.mayocliniclabs.com - July 14, 2023 2:16 PM
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ENCEPH-IG Trial: The Challenges Of Running A Rare Disease Trial - Centre for Trials Research

ENCEPH-IG Trial: The Challenges Of Running A Rare Disease Trial - Centre for Trials Research | AntiNMDA | Scoop.it
From blogs.cardiff.ac.uk - June 19, 2023 9:46 PM
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30 neurological disorders every doctor should know about –

30 neurological disorders every doctor should know about – | AntiNMDA | Scoop.it
From theneurologylounge.com - June 19, 2023 9:42 PM
Neurology is a jungle of disorders and syndromes. This creates a challenge for doctors and medical students... What to prioritise for learning and practice? *** To solve this conundrum... We combed the extensive database of Neurochecklists...
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A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis

A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis | AntiNMDA | Scoop.it
From pubmed.ncbi.nlm.nih.gov - June 19, 2023 9:34 PM
The NEOS score accurately predicts 1-year functional status in patients with anti-NMDAR encephalitis. This score could help estimate the clinical course following diagnosis and may aid in identifying patients who could benefit from novel therapies.
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Canadian Blood Services needs thousands more donors to roll up their sleeves | CBC News

Canadian Blood Services needs thousands more donors to roll up their sleeves | CBC News | AntiNMDA | Scoop.it
From www.cbc.ca - June 19, 2023 9:28 PM
Canadian Blood Services is looking to fill 150,000 appointments for people willing to donate their blood or plasma to tackle a shortage.
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A catatonic woman awakened after 20 years. Her story may change psychiatry – My Health CRM

A catatonic woman awakened after 20 years. Her story may change psychiatry – My Health CRM | AntiNMDA | Scoop.it
From myhealthcrm.com - June 14, 2023 7:43 PM
New research suggests that a subset of patients with psychiatric conditions such as schizophrenia may actually have autoimmune disease that attacks the brain...
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Case Report: Paroxysmal weakness of unilateral limb as an initial symptom in anti-LGI1 encephalitis: a report of five cases

Case Report: Paroxysmal weakness of unilateral limb as an initial symptom in anti-LGI1 encephalitis: a report of five cases | AntiNMDA | Scoop.it
From pubmed.ncbi.nlm.nih.gov - June 14, 2023 7:41 PM
Anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis is the second most common kind of autoimmune encephalitis following anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis.Anti-LGI1 encephalitis is characterized by cognitive impairment or rapid progressive dementia, psychiatric disorders...
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Medical Moment: The signs of ‘brain-on-fire’ disease

Medical Moment: The signs of ‘brain-on-fire’ disease | AntiNMDA | Scoop.it
From www.wndu.com - June 14, 2023 7:40 PM
(WNDU) - Imagine being totally fine one day, then the next, you’re having hallucinations, seizures, memory loss, and even trouble talking.It’s called “brain-on-fire” disease or anti-NMDA receptor encephalitis. It’s a rare neurological disorder that can cause inflammation in the brain.It occurs when the body’s immune system mistakenly attacks the NMDA receptors in the brain, which are responsible for regulating communication between nerve cells. Brain-on-fire disease is often misdiagnosed as other neurological disorders or psychiatric illnesses because its symptoms are similar to those of many other conditions.However, a blood or cerebrospinal fluid test can help diagnose the disease by detecting the presence of antibodies that attack the NMDA receptors in the brain. The disease is rare as it affects one in 1.5 million people a year.Katie Miller would be one of those people.Hunting, mountain biking, horseback riding - you name it, Katie Miler would do it... until she couldn’t.“I just didn’t feel like myself, like normal,” Katie recalled.“Katie said, ‘Mom, I feel like my brain snapped,’” said Colleen Miller, Katie’s mother.Local doctors admitted Katie into a psychiatric ward, but what was happening to Katie wasn’t mental; it was physical.“What happens is you’re perfectly normal one day, and suddenly overnight, this person can become paranoid, can start having visual hallucinations, auditory hallucinations,” explained Stacy Clardy, MD, PhD, an autoimmune neurologist at the University of Utah.Anti-NMDA receptor encephalitis is misdiagnosed as a psychiatric disorder in up to 40% of patients.“So, for many of the females, especially after puberty, they can develop what’s called an ovarian dermoid cyst or an ovarian teratoma,” Dr. Clardy said.These cysts often have hair and teeth in them. The immune system sees it as foreign and attacks it, but...“In these cysts, there is a component of tissue that really is brain tissue,” Dr. Clardy continued.Within four days, Katie was catatonic and needed a ventilator to breathe. There is no single approved treatment. That’s why a five-year, nationwide clinical trial is testing whether a drug called Inebilizumab will stop the assault on the brain. It has the potential to improve outcomes for patients who are not responding to other treatments and may also lead to fewer long-term neurological effects.Katie had her cyst removed; she can’t remember three months of her life. But now, with various medications, Katie is on her way to recovery.Up to 50% of patients can suffer long-term consequences, especially cognitive and mood symptoms.Copyright 2023 WNDU. All rights reserved.
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