Seizures & Epilepsy - Causes

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Causes of Seizures

Overview

• Here, we'll learn about the key causes of provoked seizures, seizures that stem from a secondary cause. The genetic epilepsy disorders, on the contrary, cause unprovoked seizures.
• Start a table.

Let's first review some key epidemiology that we addressed in our Seizures & Epilepsy tutorial.

• Denote that anywhere from 5 to 10% of people will have a seizure at some point in their life; most often in early childhood or late adulthood.
• Denote that anywhere from 1 to 4% of people will have epilepsy – a syndrome of recurrent seizures.
• Denote the following common etiologies for provoked seizures: stroke, brain tumor, brain injury, and CNS infection – we'll learn about them in detail in this tutorial.
• Denote that the parasitic disease neurocysticercosis is the most common cause of epilepsy, worldwide. It comes from the parasite taenia solium.
• Finally, denote that we use the term acute symptomatic seizure for seizures that occur soon after an acute CNS insult: for instance, within 1 week of an acute stroke or within 24 hours of a metabolic derangement.
  • Acute symptomatic seizures, as a whole, have a much lower risk of seizure recurrence than chronic symptomatic seizures or unprovoked seizures.

Vascular

Now, let's work through the cause of provoked seizures in detail, using the acronym VITAMINS C & D.

• Begin with vascular: the most common cause of provoked seizures in adults in the United States.

Subarachnoid Hemorrhage

• Draw a Head CT (bone is white and brain is gray).
• Include a bright white star-shaped abnormality in the center of the image to represent subarachnoid blood in the basal cisterns: this is the star sign of basal cistern subarachnoid hemorrhage.
  • Also show some dilation of the ventricular horns because basal cistern hemorrhage typically results in hydrocephalus.
• We highlight subarachnoid hemorrhage (SAH) because it's the type of hemorrhage with the greatest risk of inducing seizure ( ~ 35% of patients with SAH will develop a seizure).

Hemorrhagic vs Ischemic Stroke

• Next, indicate that hemorrhagic strokes are more epileptogenic (more likely to cause seizure) than ischemic strokes, but ischemic strokes are a more common cause of seizure, overall, simply because they are more prevalent.
  • Put another way: in a given individual, a hemorrhagic stroke has a greater risk of causing seizure, but, as a population, more seizures are due to ischemic strokes because they are more prevalent (according to the Centers for Disease Control and Prevention (CDC), 87% of strokes are ischemic).

Venous system strokes

• Now, include venous system strokes, we highlight them because they are often overlooked and are difficult to diagnose often present with non-focal, poorly localizing symptoms, such as headache and confusion.
• Specifically indicate: cerebral venous sinus thrombosis (clotting within the dural sinuses) and venous infarction (infarction of the cerebral veins).

Vascular malformations

• Next, vascular malformations, such as arteriovenous malformations (AVM) and cavernomas (aka cerebral cavernous malformations), which are important causes of seizure.
  • In ~ 25% of cases, cavernomas present with seizure and have an exceedingly high risk of seizure recurrence (~95%).

Cavernomas

• Cavernomas are multilobulated, endothelium‐lined caverns without mature vessel walls, so naturally they hemorrhage easily as they grow and evolve. Even still, approximately 50% are found incidentally on MRI, however.

Hypoxic-ischemic injury

• Next, include hypoxic-ischemic injury, which encompasses a wide variety of injuries: from perinatal asphyxia (a cause of ~ 75% of peri-natal status epilepticus) to anoxic encephalopathy (a common result of cardiac arrest in adults).
  • "Anoxic" encephalopathy is not just a result of poor oxygenation but also cerebral ischemia.

Vasculature dysregulation syndromes

• Now, create a subgroup for vasculature dysregulation syndromes.
• Within this subgroup, include eclampsia, posterior reversible encephalopathy syndrome (PRES), hypertensive encephalopathy, and cerebral vasospasm (an important complication of SAH).
  • These conditions cause seizures from a complicated mixture of hypo- and hyper- perfusion as well as vasogenic and cytotoxic edema.

Systemic stroke syndromes

• Lastly, list systemic stroke syndromes with a high likelihood of inducing seizure; they include (but are not limited to) moyamoya and lupus vasculopathy, as well as, sickle cell disease, and vasculitis.
  • Each of these has a different pathophysiological mechanism but all of them can result in seizure.

Infectious

Now, let's turn our attention to infectious causes of seizure.

Herpes simplex encephalitis, type 1 (HSV-1)

• Let's draw herpes simplex encephalitis, type 1 (HSV-1) because of its propensity to cause seizures.
• Draw an axial FLAIR signal MRI through the medial temporal lobes – show the soft tissues in white and the brain parenchyma in gray.
• Along the anterior, medial temporal lobe, show signal hyperintensity.
• Indicate that HSV encephalitis has a predilection for the anterior, medial temporal lobes, which is likely why it is so epileptogenic.

Let's categorize the various CNS infections that cause seizures.

Viral encephalitis

• For viral encephalitis, include HSV-1, plus many other viral encephalitides, as well as Human immunodeficiency virus (HIV) (primarily via opportunistic infections – parasites and TB), and, also, subacute sclerosing panencephalitis (SSPE), which is a late-stage (2 to 10 year post-infection) complication of measles (a paramyxovirus).

SSPE

• SSPE is one of the notable causes of high-voltage, generalized epileptiform discharges (GPEDs), along with anoxic injury (the most common cause), and also Creutzfeldt-Jakob disease (CJD).

Bacterial meningitis

• For bacterial meningitis, include two key granulomatous causes: tuberculosis and syphilis, which are especially important opportunistic infections in HIV. And pyogenic causes: meningococcus, pneumococcus, and haemophilus influenzae type B.

Parasitic meningitis

• For the parasitic meningitis, include: neurocysticercosis and cerebral malaria (plasmodium falciparum); these are the most common parasitic causes of seizures throughout the world.
  • In fact, neurocysticercosis is the most common cause of epilepsy, worldwide, via its generation of cystic lesions, which can cause mass effect, and its production of inflammatory and gliotic changes.
  • Cerebral malaria produces an encephalopathy that progresses from somnolence to seizures along with posturing and ocular dysmotility.
• Less common parasitic causes of seizure include:
  • Toxoplasmosis, a key opportunistic infection in HIV.
  • Toxocariasis, in which larvae can migrate from the intestine to the brain.
  • Schistosomiasis, a liver fluke, which causes causing liver and kidney failure and enters the CNS via the circulatory system through a breakdown in the blood brain barrier.

Fungal meningitis

• For fungal meningitis, simply indicate that seizures occur as part of a complex encephalopathy – no single fungal infection stands out as the primary cause of seizures.

Systemic infections

• Lastly, include systemic infections – emphasize urinary tract infections (UTIs) and pneumonias (PNAs), which are a common cause for breakthrough seizures in epileptic patients, amongst other systemic infectious causes.

Trauma

Next, trauma.

• Draw a zoomed-in view of a FLAIR MRI and draw a normal temporal lobe and then one that is cavitated.
• Indicate that there is encephalomalacia from prior trauma (ischemic, infectious, direct injury, or otherwise); these can all provoke seizures later in life.
• In addition, seizures can occur in trauma, acutely, as an acute symptomatic seizure with a much lower likelihood of recurrence than unprovoked seizures or seizures that stem from chronic encephalomalacia.

Autoimmune

Now, include autoimmune causes.

• We'll focus on two conditions, in particular, because they aren't discussed in detail elsewhere: Rasmussen encephalitis and anti-NMDA receptor encephalitis.

Rasmussen encephalitis

• First, Rasmussen encephalitis, draw a FLAIR MRI axial section through a normal hemisphere and then show the unilateral atrophy associated with Rasmussen encephalitis: show thinning of the insular cortex and hydrocephalus ex vacuo of one side of the brain.
  • Rasmussen encephalitis is a rare, chronic progressive inflammatory condition (believed to be an autoimmune condition) that is restricted to one hemisphere and manifests with refractory focal seizures and focal status epilepticus (epilepsia partialis continua) with progressive brain atrophy and resultant deterioration of neurological function from that hemisphere (weakness, cognitive dysfunction, etc…) that begins within 6 months of the onset of the seizures.

Anti-NMDA receptor encephalitis

• For anti-NMDA receptor encephalitis, draw a neuronal junction.
• Along the post-synaptic neuron, include NMDA receptors (we use stars to symbolize that they are the antigen), then draw a plasma cell, and show that the plasma cell produces antibodies, which attack the NMDA receptor.
• Anti-NMDA receptor encephalitis is one of the most common forms of autoimmune encephalitis and is especially common in young woman.
• While it can occur in the setting of ovarian teratoma (in which case it is considered paraneoplastic), the syndrome often occurs in the setting of no neoplastic trigger.
• There is often a progression from a flu-like illness for several days to a profoundly severe psychotic phase with delusions, agitation and disinhibition, paranoid hallucinations, and even catatonia; the presentation is so severe it is often mistaken for psychiatric illness.
• In addition to psychosis, there is cognitive dysfunction and the disease may progress to involve motor dyskinesias, autonomic instability, and seizures.

Pathology

• The NMDA receptor acts as a cell surface antigen and antibodies target an epitope at the N-terminal domain of the NR1 subunit of the NMDA receptor – autoantibodies to extracellular antigens are characteristically easier to treat than autoantibodies to intracellular antigens.

CSF Testing

• CSF testing can reveal a mild lymphocytic pleocytosis (mildly elevated WBC that is predominantly lymphocytes), a mild elevation in CSF protein, and the presence of oligoclonal bands (immunoglobulins found in the CSF but not the serum).

Serologies

• Anti-NMDA receptor testing in CSF is more sensitive than in serum, which can be falsely negative in at least ~ 15% of cases (85% sensitivity), so testing both fluids is recommended.

MRI

• MRI, however, is often normal (or displays mild, varied hyperintensities) and EEG is often nonspecific (with just slowing).

Other paraneoplastic encephalitides

• Other paraneoplastic encephalitides, such as anti-HU (ANNA-1) limbic encephalitis (from small cell lung cancer, most notably) cause seizures.

Common autoimmune systemic syndromes

• There are many autoimmune systemic syndromes, such as systemic lupus erythematosus, thyroiditis, glycemic dysregulation in diabetes mellitus, and inflammatory bowel conditions that are also associated with seizures.

Metabolic

Now, in regards to metabolic causes, we'll focus on electrolyte disturbances.

Glucose

• Indicate that either hypoglycemia or hyperglycemia can cause seizures.

Hyponatremia, hypocalcemia, and hypomagnesemia

• Then, indicate that hyponatremia, hypocalcemia, and hypomagnesemia are all causes of seizures.
  • Be aware that convulsive seizures can cause hypernatremia.
• We often think of these conditions in the setting of vomiting, diarrhea, or dehydration but it is generally recommended to assess for electrolyte disturbances in any patient with a first-time seizure.
• As far as the pathophysiology is concerned, overall, alterations of electrolyte gradients across cell membranes affect neuronal excitation and synchronicity, but other mechanisms are also at play.

Hyponatremia

• In acute hyponatremia (to levels less than 120 mEq/L), there is swelling of glial cells and neurons (to a lesser extent). Seizures can occur, as well as cerebral herniation.
• Draw a glial cell and show that in hyponatremia, there is an influx of water from the extracellular space into the glial cells (and, to a lesser extent, the neurons) to compensate for the extracellular hypo-osmolarity and hypotonicity, which causes cellular swelling.
• Along with this cellular swelling, on a macrolevel, there can be cerebral edema, as well. In chronic hyponatremia, the cells can slowly adjust, so levels can reach as low as 120 mEq/L before symptoms develop.
• It's helpful to know that just a 5mEq/L increase can be sufficient to treat the potential hazards of acute hyponatremia without the risk of osmotic demyelination, so a quick, small correction can make a big difference; however, larger increases must be done slowly to avoid the osmotic demyelination that can occur from excessive, overly rapid correction of hyponatremia.

Hypocalcemia

• In regards to hypocalcemia, it's easy to remember its potential for seizures when we consider the Chvostek's and Trousseau's signs of neuromuscular hyperexcitability that occur latent tetany from reduced ionized calcium levels.
  • Chvostek's sign refers to hemifacial twitch or spasm when we tap on the facial nerve anterior to the ear.
  • Trousseau's sign, refers to carpopedal spasm (wrist flexion/thumb adduction/finger extension) following prolonged hyperinflation of a blood pressure cuff.

Hypomagnesemia

• We can recall the role of hypomagnesemia in seizures when we consider the role of magnesium as a calcium channel antagonist; thus reduction in magnesium causes disinhibition of voltage-gated calcium channels.
  • Magnesium is the primary treatment in seizures secondary to eclampsia, likely secondary to its vasodilatory effects.
  • For reference, we typically give a 2 – 4 gram IV loading dose followed by maintenance dosing with a goal serum concentration of 3.5 mEq/L to 7 mEq/L.
• Hypermagnesemia induces loss of deep tendon reflexes (especially the patellar tendon), which is often used as a clinical marker of effective treatment. But overtreatment can be lethal; it can induce respiratory paralysis or cardiac arrest.

Iatrogenic/Illicit + Alcohol

• There are numerous medications that can potentially cause seizures. Some of the most common offenders are as follows:

Antidepressants

• Buproprion, venlafaxine, and tricyclic antidepressants.
  • Buproprion, venlafaxine, and certain tricyclic antidepressants increase noradrenergic activity, which results in CNS activation.

Analgesics

• Tramadol and meperidine
  • Tramadol is a widely used analgesic because of its safety profile, however, it is a common iatrogenic cause of seizures.
  • Meperidine, which metabolizes to normeperidine, which causes CNS activation and seizures.

Antibiotics

• Carbapenems (eg, imipenim), isoniazid (INH), and fluoroquinolones (especially trovafloxacin). - Carbapenems are known GABA antagonists (GABA stabilizes membranes via chloride channels, so its antagonism is destabilizing) and they are NMDA agonists (NMDA activitates calcium channels the presynaptic terminal, which induces cell activation).
  • Fluoroquinolones displace GABA from receptors.

Miscellaneous

• Amphetamines (like the activating antidepressants can cause CNS overactivation and seizures), diphenhydramine, cyclosporine (an immunosuppressant), and theophylline (an asthma medication less commonly used today).

Illicit drugs

• Cocaine and methamphetamine are common illicit drugs to cause seizures.

Withdrawal

• On the contrary, withdrawal of the medications can also cause seizures. Common offenders include the withdrawal of benzodiazepines and baclofen.

Alcohol

• Alcohol withdrawal is a common cause of seizures.

Neoplasia

Ganglioglioma

• For neoplasia, set-up another FLAIR axial MRI of the brain with a focus on the temporal lobes.
• Draw a ganglioglioma within the anterior temporal: temporal lobe gangliogliomas are the tumor with the highest likelihood of presenting with seizure (~ 75% of gangliogliomas present with seizure).

Gliomas vs brain METS and meningiomas

• Next, much like our comparison of ischemic and hemorrhagic strokes, indicate that gliomas (intra-axial glial-based tumors) are more epileptogenic (more likely to cause seizure) than meningiomas (extra-axial dural-based tumors) and brain metastases but the latter two are a more common cause of seizure, overall, simply because they are far more prevalent.
  • Put another way: in a given individual, gliomas have a greater risk of causing seizure, but, as a population, more seizures are due to brain METS and meningiomas because they are more prevalent.

Social

• In regards to social circumstances, indicate medication noncompliance, foremost, followed by alcohol withdrawal.
• Other key causes include sleep deprivation and emotional and physical stress.

Congenital

• In regards to congenital causes, there are many forms of childhood onset epilepsy, which are beyond the scope of this tutorial, but let's distal neonatal causes of seizures into four categories:
• Vascular (eg, hypoxic-ischemic encephalopathy)
• Infectious (eg, TORCH infections)
• Metabolic (eg, inborn errors of metabolism (and electrolyte disturbances))
• CNS congenital malformations.

Degenerative

Alzheimer's disease

• Finally, for degenerative, let's address Alzheimer's disease, which is the cause of 70% of dementia.
• The likelihood of seizures in Alzheimer's disease is ~ 5 times that of age-matched, healthy controls, and is significantly greater than that of patients with other forms of dementia.

Pathophysiology: amyloid

• The pathophysiological reason for this is hypothesized to be related to multiple factors.
• First, let's show that it is likely related to the accumulation of amyloid plaques – a key pathological finding in Alzheimer's disease: let's review these pathologies, now.
• First, draw amyloid-beta-42 oligomer, which is a 42-residue amyloid beta-protein fragment that is a particularly "sticky", soluble form of amyloid peptide and, thus, in pathologically high concentrations, it aggregates.
• Then, draw an amyloid-beta plaque (aka neuritic plaques), which comprise deposits of numerous, aggregated amyloid fibrils (a larger, less soluble aggregation of amyloid-beta peptide than the oligomers).
  • When broken down, the major cleavage products include amyloid-beta 42 and amyloid-beta 40.

Pathophysiology: mesial temporal sclerosis

• Now, let's address the role of mesial temporal sclerosis – as we've seen throughout this tutorial, the medial temporal lobe is highly epileptogenic.
• Draw a coronal section through a brain. Focus on the medial temporal lobe.
• Draw the hippocampal formation and the overlying temporal horn of the lateral ventricle.
• Show that in Alzheimer's disease, there is severe degeneration of the hippocampal formation and resultant dilatation of the temporal horn of the lateral ventricle.
• Pathology is especially promninent in CA1 (cornu ammonis, 1), the entorhinal cortex, and subiculum. As well as atrophy of the amygdala and parahippocampal gyrus. Ultimately, there is global gyral shrinkage and sulcal widening as atrophy progresses.

Febrile Seizures

• Finally, let's address febrile seizures.
• Draw a small child and indicate that febrile seizures are convulsions associated with an elevated temperature greater than 38 degrees Celsius in children 6 months to 5 years of age; they occur in 2 to 4 % of children younger than 5 years old and are slightly more common in males.
• Indicate that we subdivide febrile seizures into simplex and complex febrile seizures.

Simple

• Draw a brain and show that febrile seizures are considered simple if they are generalized seizures that last less than 15 minutes and do not recur within a 24-hour period.

Complex

• Draw another brain and show that febrile seizures are considered complex, if any of the following occur: they are focal seizures, last longer than 15 minutes, or occur more than once in a 24-hour period.
  • They are more commonly due to viral infections than bacterial (HHV-6 being the most commonly associated viral illness), they tend to occur early in the illness, and no explicit work-up is mandated but rather testing is patient-specific.

Febrile Seizure Exclusions

• The following exclude a possible diagnosis of febrile seizures:
  • CNS infection or inflammation
  • Systemic metabolic abnormalities
  • History of nonfebrile seizures.

References

• "A Clinical Guide to Epileptic Syndromes and Their Treatment - Google Books." Accessed January 1, 2020. https://www.google.com/books/edition/A_Clinical_Guide_to_Epileptic_Syndromes/30BdCQbMYU8C?hl=en&gbpv=1&dq=fencing+posture+arm+is+raised+and+extended&pg=PA399&printsec=frontcover.

• "A Definition and Classification of Status Epilepticus – Report of the ILAE Task Force on Classification of Status Epilepticus - Trinka - 2015 - Epilepsia - Wiley Online Library." Accessed January 3, 2020. https://onlinelibrary.wiley.com/doi/full/10.1111/epi.13121.

• "Acute Symptomatic Seizures Caused by Electrolyte Disturbances." Accessed December 30, 2019. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712283/.

• Almond, Christopher S.D., Andrew Y. Shin, Elizabeth B. Fortescue, Rebekah C. Mannix, David Wypij, Bryce A. Binstadt, Christine N. Duncan, et al. "Hyponatremia among Runners in the Boston Marathon." New England Journal of Medicine 352, no. 15 (April 14, 2005): 1550–56. https://doi.org/10.1056/NEJMoa043901.

• "Anti-NMDAR Encephalitis | Center for Autoimmune Neurology | Perelman School of Medicine at the University of Pennsylvania." Accessed February 5, 2020. https://www.med.upenn.edu/autoimmuneneurology/nmdar-encephalitis.html.

• Baudou, E., C. Cances, C. Dimeglio, and C. Hachon Lecamus. "Etiology of Neonatal Seizures and Maintenance Therapy Use: A 10-Year Retrospective Study at Toulouse Children's Hospital." BMC Pediatrics 19 (April 29, 2019). https://doi.org/10.1186/s12887-019-1508-5.

• Bonelli, Silvia Beatrice, Stefanie Lurger, Fritz Zimprich, Elisabeth Stogmann, Eva Assem-Hilger, and Christoph Baumgartner. "Clinical Seizure Lateralization in Frontal Lobe Epilepsy." Epilepsia 48, no. 3 (March 2007): 517–23. https://doi.org/10.1111/j.1528-1167.2006.00943.x.

• "Clinical Utility of EEG in Diagnosing and Monitoring Epilepsy in Adults | Elsevier Enhanced Reader." Accessed December 22, 2019. https://doi.org/10.1016/j.clinph.2018.01.019.

• DrupalAdmin. "FACTS AND FIGURES." Text. American Epilepsy Society, December 4, 2013. https://www.aesnet.org/for_patients/facts_figures.

• ENGLOT, DARIO J., EDWARD F. CHANG, and CHARLES J. VECHT. "Epilepsy and Brain Tumors." Handbook of Clinical Neurology 134 (2016): 267–85. https://doi.org/10.1016/B978-0-12-802997-8.00016-5.

• "Epilepsy." Accessed January 5, 2020. https://www.who.int/news-room/fact-sheets/detail/epilepsy.
  "Epilepsy Fast Facts | CDC," December 14, 2018. https://www.cdc.gov/epilepsy/about/fast-facts.htm.

• Epilepsy Foundation. "Febrile Seizures." Accessed February 12, 2020. https://www.epilepsy.com/learn/types-seizures/febrile-seizures.

• Fisher, Robert S., Carlos Acevedo, Alexis Arzimanoglou, Alicia Bogacz, J. Helen Cross, Christian E. Elger, Jerome Engel, et al. "ILAE Official Report: A Practical Clinical Definition of Epilepsy." Epilepsia 55, no. 4 (April 2014): 475–82. https://doi.org/10.1111/epi.12550.

• Ford, Brian, Alex McDonald, and Shilpa Srinivasan. "Anti-NMDA Receptor Encephalitis: A Case Study and Illness Overview." Drugs in Context 8 (August 30, 2019). https://doi.org/10.7573/dic.212589.

• Gankam Kengne, Fabrice, and Guy Decaux. "Hyponatremia and the Brain." Kidney International Reports 3, no. 1 (September 1, 2017): 24–35. https://doi.org/10.1016/j.ekir.2017.08.015.

• Giuliani, Corinna, and Alessandro Peri. "Effects of Hyponatremia on the Brain." Journal of Clinical Medicine 3, no. 4 (October 28, 2014): 1163–77. https://doi.org/10.3390/jcm3041163.

• Hammer, Erica S., and Marilyn J. Cipolla. "Cerebrovascular Dysfunction in Preeclamptic Pregnancies." Current Hypertension Reports 17, no. 8 (August 2015): 64. https://doi.org/10.1007/s11906-015-0575-8.

• "INFECTIOUS ETIOLOGY." Accessed February 4, 2020. https://www.epilepsydiagnosis.org/aetiology/infectious-groupoverview.html.

• Jan, Mohammed M.S., and John P. Girvin. "Seizure Semiology: Value in Identifying Seizure Origin." Canadian Journal of Neurological Sciences / Journal Canadien Des Sciences Neurologiques 35, no. 1 (March 2008): 22–30. https://doi.org/10.1017/S0317167100007526.

• Kaur, Sarabjot, Ravinder Garg, Simmi Aggarwal, Sumit Pal Singh Chawla, and Ranabir Pal. "Adult Onset Seizures: Clinical, Etiological, and Radiological Profile." Journal of Family Medicine and Primary Care 7, no. 1 (2018): 191–97. https://doi.org/10.4103/jfmpc.jfmpc_322_16.

• Kernan, J. C., O. Devinsky, D. J. Luciano, B. Vazquez, and K. Perrine. "Lateralizing Significance of Head and Eye Deviation in Secondary Generalized Tonic‐clonic Seizures." Neurology 43, no. 7 (July 1, 1993): 1308–1308. https://doi.org/10.1212/WNL.43.7.1308.

• Koubeissi, Mohamad Z., and Nabil J. Azar. Epilepsy Board Review: A Comprehensive Guide. Springer, 2017.

• Krumholz, A., S. Wiebe, G. Gronseth, S. Shinnar, P. Levisohn, T. Ting, J. Hopp, et al. "Practice Parameter: Evaluating an Apparent Unprovoked First Seizure in Adults (an Evidence-Based Review): [RETIRED]: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society." Neurology 69, no. 21 (November 20, 2007): 1996–2007. https://doi.org/10.1212/01.wnl.0000285084.93652.43.

• Krumholz, Allan, Andrew J. Cole, Shlomo Shinnar, Jacqueline French, Gary Gronseth, Samuel Wiebe, and Gregory D. Cascino. "Evidence-Based Guideline: Management of an Unprovoked First Seizure in Adults: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the American Epilepsy SocietyCommentary Author Response." Neurology 85, no. 17 (October 27, 2015): 1526–27. https://doi.org/10.1212/01.wnl.0000473351.32413.7c.

• Kushner, J. M., H. J. Peckman, and C. R. Snyder. "Seizures Associated with Fluoroquinolones." The Annals of Pharmacotherapy 35, no. 10 (October 2001): 1194–98. https://doi.org/10.1345/aph.10359.

• Ladépêche, Laurent, Jesús Planagumà, Shreyasi Thakur, Irina Suárez, Makoto Hara, Joseph Steven Borbely, Angel Sandoval, Lara Laparra-Cuervo, Josep Dalmau, and Melike Lakadamyali. "NMDA Receptor Autoantibodies in Autoimmune Encephalitis Cause a Subunit-Specific Nanoscale Redistribution of NMDA Receptors." Cell Reports 23, no. 13 (June 26, 2018): 3759–68. https://doi.org/10.1016/j.celrep.2018.05.096.

• Lancaster, Eric, Eugenia Martinez-Hernandez, and Josep Dalmau. "Encephalitis and Antibodies to Synaptic and Neuronal Cell Surface Proteins." Neurology 77, no. 2 (July 12, 2011): 179–89. https://doi.org/10.1212/WNL.0b013e318224afde.

• Lattanzi, Simona, and Mauro Silvestrini Claudia Cagnetti. "The Management of an Unprovoked First Seizure in Adults," December 22, 2019. https://n.neurology.org/content/management-unprovoked-first-seizure-adults.

• "Magnesium Sulfate for the Treatment of Eclampsia | Stroke." Accessed December 31, 2019. https://www.ahajournals.org/doi/full/10.1161/strokeaha.108.527788.

• "Magnesium Sulfate Treatment for the Prevention of Eclampsia: A Brief Review." Accessed December 31, 2019. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2663594/.

• "Meningitis and Encephalitis Fact Sheet | National Institute of Neurological Disorders and Stroke." Accessed February 4, 2020. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Meningitis-and-Encephalitis-Fact-Sheet.

• Neligan, Aidan, Alastair John Noyce, Tushar Divakar Gosavi, Simon D. Shorvon, Sebastian Köhler, and Matthew C. Walker. "Change in Mortality of Generalized Convulsive Status Epilepticus in High-Income Countries Over Time: A Systematic Review and Meta-Analysis." JAMA Neurology 76, no. 8 (August 1, 2019): 897–905. https://doi.org/10.1001/jamaneurol.2019.1268.

• Nicastro, Nicolas, Frédéric Assal, and Margitta Seeck. "From Here to Epilepsy: The Risk of Seizure in Patients with Alzheimer's Disease." Epileptic Disorders 18, no. 1 (March 1, 2016): 1–12. https://doi.org/10.1684/epd.2016.0808.

• O'Connor, Kathryn L., M. Brandon Westover, Michael T. Phillips, Nicolae A. Iftimia, Deidre A. Buckley, Christopher S. Ogilvy, Mouhsin M. Shafi, and Eric S. Rosenthal. "High Risk for Seizures Following Subarachnoid Hemorrhage Regardless of Referral Bias." Neurocritical Care 21, no. 3 (December 2014): 476–82. https://doi.org/10.1007/s12028-014-9974-y.

• "October 18, 2011 e-Pearl of the Week: Figure 4 Sign | Neurology." Accessed January 1, 2020. https://n.neurology.org/epearls/20111018.

• Panayiotopoulos, C. P. Idiopathic Generalised Epilepsies. Bladon Medical Publishing, 2005. https://www.ncbi.nlm.nih.gov/books/NBK2608/.

• Panczykowski David, Pease Matthew, Zhao Yin, Weiner Gregory, Ares William, Crago Elizabeth, Jankowitz Brian, and Ducruet Andrew F. "Prophylactic Antiepileptics and Seizure Incidence Following Subarachnoid Hemorrhage." Stroke 47, no. 7 (July 1, 2016): 1754–60. https://doi.org/10.1161/STROKEAHA.116.013766.

• Pandis, Dionysios, and Nikolaos Scarmeas. "Seizures in Alzheimer Disease: Clinical and Epidemiological Data." Epilepsy Currents 12, no. 5 (2012): 184–87. https://doi.org/10.5698/1535-7511-12.5.184.

• "Parietal Lobe Epilepsy: The Semiology, Yield of Diagnostic Workup, and Surgical Outcome. - PubMed - NCBI." Accessed January 2, 2020. https://www.ncbi.nlm.nih.gov/pubmed/15144429.

• Pohlmann-Eden, Bernd, Ettore Beghi, Carol Camfield, and Peter Camfield. "The First Seizure and Its Management in Adults and Children." BMJ : British Medical Journal 332, no. 7537 (February 11, 2006): 339–42.

• "Rasmussen Encephalitis." Accessed February 5, 2020. https://www.asnr.org/neurographics/2/1/1/10.shtml.
  NORD (National Organization for Rare Disorders). "Rasmussen Encephalitis." Accessed February 5, 2020. https://rarediseases.org/rare-diseases/rasmussen-encephalitis/.

• Reddy, Doodipala Samba, and Randy Volkmer. "Neurocysticercosis as an Infectious Acquired Epilepsy Worldwide." Seizure 52 (November 2017): 176–81. https://doi.org/10.1016/j.seizure.2017.10.004.

• Rosenow, Felix, Mario A. Alonso‐Vanegas, Christoph Baumgartner, Ingmar Blümcke, Maria Carreño, Elke R. Gizewski, Hajo M. Hamer, et al. "Cavernoma-Related Epilepsy: Review and Recommendations for Management—Report of the Surgical Task Force of the ILAE Commission on Therapeutic Strategies." Epilepsia 54, no. 12 (2013): 2025–35. https://doi.org/10.1111/epi.12402.

• Scheffer, Ingrid E., Samuel Berkovic, Giuseppe Capovilla, Mary B. Connolly, Jacqueline French, Laura Guilhoto, Edouard Hirsch, et al. "ILAE Classification of the Epilepsies: Position Paper of the ILAE Commission for Classification and Terminology." Epilepsia 58, no. 4 (April 2017): 512–21. https://doi.org/10.1111/epi.13709.

• "Seizure Semiology: Its Value and Limitations in Localizing the Epileptogenic Zone." Accessed January 1, 2020. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3540282/.

• Seneviratne, Udaya, Mark J. Cook, and Wendyl Jude D'Souza. "Electroencephalography in the Diagnosis of Genetic Generalized Epilepsy Syndromes." Frontiers in Neurology 8 (September 25, 2017). https://doi.org/10.3389/fneur.2017.00499.

• Sethi, Nitin K., Simona Lattanzi, Allan Krumholz, Claudia Cagnetti, Mauro Silvestrini, Shlomo Shinnar, Jacqueline French, Samuel Wiebe, and David Gloss. "Evidence-Based Guideline: Management of an Unprovoked First Seizure in Adults: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the American Epilepsy SocietyAuthor Response." Neurology 85, no. 17 (October 27, 2015): 1525–26. https://doi.org/10.1212/WNL.0000000000002093.

• Sethi, Nitin K., and New York Nitin K Sethi. "Unprovoked First Seizure: To Treat or Not to Treat?," December 22, 2019. https://n.neurology.org/content/unprovoked-first-seizure-treat-or-not-treat.

• Stefan, Hermann, and William H. Theodore. Epilepsy, Part II: Treatment. Newnes, 2012.
  NORD (National Organization for Rare Disorders). "Subacute Sclerosing Panencephalitis." Accessed February 5, 2020. https://rarediseases.org/rare-diseases/subacute-sclerosing-panencephalitis/.

• Suzuki, Yasuhiro, Yasuhisa Toribe, Yukiko Mogami, Keiko Yanagihara, and Masanori Nishikawa. "Epilepsy in Patients with Congenital Cytomegalovirus Infection." Brain & Development 30, no. 6 (June 2008): 420–24. https://doi.org/10.1016/j.braindev.2007.12.004.

• "The Causes of Epilepsy - Google Books." Accessed December 30, 2019. https://www.google.com/books/edition/The_Causes_of_Epilepsy/Xl6NDwAAQBAJ?hl=en&gbpv=1.

• "Treatment, Therapy and Management of Metabolic Epilepsy: A Systematic Review." Accessed December 30, 2019. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877732/.

• "Types of Stroke | Cdc.Gov," January 31, 2020. https://www.cdc.gov/stroke/types_of_stroke.htm.