Seizure Disorder - copy ppt download free

Seizure Disorder - copy ppt download free

1. Seizure Disorder Effort by: Zeeshan Akbar

2. A “seizure” is defined as the clinical manifestation of excessive or hypersynchronous activity of neurons within the cerebral cortex. Although the term often connotes an event characterized by an abrupt loss of consciousness with generalized muscle contraction and jerking (i.e., generalized tonic- clonic or grand mal seizure), the clinical manifestations of various seizure types are quite heterogeneous. Seizure

3. “Convulsions" and “Seizures" are used interchangeably, but there are some subtle differences between them. A seizure is a sudden and abnormal electrical activity in the brain that can cause a variety of symptoms. Seizures can manifest in different ways, depending on the area of the brain affected. These symptoms can include convulsions, but not all seizures involve convulsions. Convulsions , on the other hand, refer specifically to the rhythmic and involuntary muscle contractions and relaxations that can occur during certain types of seizures. Convulsions are characterized by jerking or shaking movements of the body, often involving the arms and legs. However, it's important to note that not all seizures result in convulsions. Seizures can also present as a temporary loss of consciousness, altered awareness, unusual sensations, or repetitive movements without convulsions. In summary, convulsions are a type of symptom that can occur during certain seizures, but seizures themselves can take various forms and may not always involve convulsions.

4. Common Causes of New Onset Seizures Primary or Acquired Neurological Disorders; Alzheimer’s Disease or other neuro-degenerative disorders B rain tumor CNS infections Cerebrovascular disease F ebrile seizures of childhood Genetic or developmental disorders H ead trauma I diopathic

5. Systemic or Metabolic Disorders; A lcohol abuse and withdrawal A noxia/ Ischemia D rug overdose Eclampsia H epatic failure H ypocalcemia H ypoglycemia H ypomagnesemia H yponatremia Porphyria R enal failure

6. Eclampsia Eclampsia is a serious medical condition that typically occurs during pregnancy and is characterized by the onset of seizures or convulsions in a woman with pre-existing preeclampsia. Preeclampsia is a disorder that affects pregnant women and is characterized by high blood pressure and damage to organs, such as the liver and kidneys. Here are some basic concepts related to eclampsia: Pre-eclampsia : Eclampsia is usually preceded by a condition called pre-eclampsia. Pre-eclampsia is characterized by high blood pressure (hypertension) and the presence of protein in the urine (proteinuria) after 20 weeks of pregnancy. It can also involve other symptoms such as swelling (edema), sudden weight gain, headaches, vision changes, and abdominal pain.

7. Onset of seizures : Eclampsia is diagnosed when a woman with pre-eclampsia develops seizures or convulsions that are not caused by other factors, such as epilepsy. These seizures are often generalized (affecting the whole body) and can be accompanied by loss of consciousness, muscle rigidity, and rhythmic jerking movements. Complications : Eclampsia is a medical emergency that requires immediate attention. Seizures can be life-threatening for both the mother and the baby. Eclampsia can lead to complications such as brain damage, stroke, organ failure, and even maternal or fetal death.

8. Treatment : The main treatment for eclampsia is the administration of medications to control and prevent seizures, such as magnesium sulfate. Blood pressure medications may also be used to manage hypertension. In severe cases, delivery of the baby may be necessary to protect the health of the mother and the baby. Eclampsia requires prompt medical attention, and pregnant women should receive regular prenatal care to monitor and manage conditions like preeclampsia to help prevent the development of eclampsia. If any symptoms of preeclampsia or eclampsia occur during pregnancy, it is essential to seek immediate medical assistance.

9. Porphyria Porphyria refers to a group of rare genetic disorders that affect the production of heme, an essential component of hemoglobin in red blood cells. Heme is involved in the transportation of oxygen throughout the body. Porphyria is characterized by the abnormal accumulation of certain chemicals called porphyrins or porphyrin precursors, which can cause a range of symptoms depending on the specific type of porphyria. Here are some basic concepts related to porphyria: Types of porphyria : There are several types of porphyria, including acute intermittent porphyria, variegate porphyria, hereditary coproporphyria , and others. Each type is caused by a specific genetic mutation that leads to a deficiency in one of the enzymes involved in the heme synthesis pathway.

10. Triggers : Porphyria symptoms are often triggered by factors such as certain medications, hormonal changes, exposure to sunlight, stress, fasting, and alcohol consumption. These triggers can disrupt heme production and lead to the accumulation of porphyrins, triggering symptoms. Symptoms : The symptoms of porphyria can vary depending on the type and severity of the condition. Some common symptoms include abdominal pain, nausea, vomiting, constipation, muscle weakness or paralysis, sensitivity to light (photosensitivity), skin rashes or blistering, neurological symptoms, and psychiatric disturbances.

11. Diagnosis : Porphyria is diagnosed through a combination of clinical evaluation, medical history, and laboratory tests. These tests may include urine, blood, and stool samples to measure the levels of porphyrins and their precursors. Treatment : Treatment for porphyria aims to manage symptoms, prevent attacks, and minimize triggers. This may involve avoiding triggers such as certain medications, sunlight exposure, and alcohol. In some cases, medications may be prescribed to control symptoms or to reduce the production of porphyrins. It's important to note that porphyria is a complex condition, and management requires the expertise of medical professionals familiar with the disorder. If you suspect you may have porphyria or have concerns about it, it is recommended to consult with a healthcare provider who can provide appropriate evaluation, diagnosis, and guidance.

12. D r ugs that have been associated withprovoking or Drugs that may exacerbate Seizures; Antimicrobials; B eta lactams I soniazid Q uinolones Anti-virals; Acyclovir G anciclovir Drugs of abuse; A mphetamine C ocaine E phedra M ethylphenidate

13. D r ugs that have been associated with provoking or Drugs that may exacerbate Seizures; Psychotropic Drugs; Antidepressants A ntipsychotics L ithium Sedative & Hypnotics withdrawal; A lcohol B arbiturates B enzodiazepines Miscellaneous; Ciclosporin F lumazeil (anti dot for Benzodiazepines) Theophylline (anti-asthmatic) T ramadol (Opioid analgesic) OKT3 (Monoclonal antibodies )

14. Monoclonal antibodies ( mAbs ) Monoclonal antibodies ( mAbs ) are immunoglobulins derived from a monoclonal cell line and which have a defined specificity. Their immunological activities are based on binding to a specific ligand or antigen and may also depend on other effector functions. These are the antibodies produced by a single clone (a single antibody forming cell or a single B Lymphocyte or plasma cell) and directed against a single antigenic determinant are known as Monoclonal antibodies. Monoclonal antibodies are clones of your body's antibodies that are made in a laboratory, meant to stimulate your immune system. Monoclonal antibodies as therapies are more targeted than some other types of treatments and have been more successful at treating some types of diseases, including some cancers

15. Hybridoma Technique used for manufacturing of Monoclonal Antibodies Hybridoma are somatic cell hybrids produced by fusing antibody forming spleen cells with myeloma cells. The resultant hybrid retains the antibody producing capacity of the spleen cell and the ability of the myeloma cells to multiply indefinitely. Animals (mice) are immunized with the desired antigen. Once the animal starts producing antibodies, their spleen is removed and the spleen cells are separated from each other and fused with myeloma cells (myeloma is a cancer or continuous proliferation of antibody forming cells) by the addition of polyethylene glycol, hich promotes membrane fusion. T hese fused cells derived from spleen cells and myeloma cells are called hybridomas.

16. Hybridoma Technique (Continue) T he mutant myeloma cells are grown in culture hich do not form immunoglobulins and are deficient in the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT). T he fused cels are transferred to a culture medium containing hypoxanthine, aminopterin and thymidine (HAT medium). A minopterin is a poison that blocks a specific metabolic pathay in the cells. M yeloma cells lack HGPRT enzyme that allows their growth in the presence of aminopterin. H owever the pathway is by-passed in speleen cells provided with the intermediate metabolites hypoxanthine and thymidine. A s a result, the hybridoma grow in HAT medium, but the myeloma cells die due to deficiency of HGPRT enzymes and metabolic defect and cannot employ the bypass or salvage pathway.

17. Hybridoma Technique (Continue) W hen the culture is initially established using the HAT medium, it contains lymphocytes, myeloma cells, hybidomas. T he unfused splenic lymphoid cells die naturally in culture within a week or two as they cannot replicate indefinitely and the myeloma cells die in the HAT medium as just described. I n contrast fused cells survive because they have the immortality of the myeloma cells and the metabolic bypass of the splenic lymphoid cells. H ybridomas are separated into indiviual ells of plastic dishes and allowed to grow in the clones. E ach hybridoma may produce monoclonal antibodies.

18. Seizures are caused by a perturbation in the normal balance of excitatory and inhibitory influences within the brain. Synchronized, high-frequency bursts of action potentials are the initiating event of a seizure. These bursts are caused by an influx of extracellular calcium followed by opening of voltage-dependent sodium channels. This depolarization phase is followed by a hyperpolarization phase that is mediated by the inhibitory neurotransmitter γ-aminobutyric acid (GABA) or by potassium channels. Most AEDs suppress seizures by altering ion flux through membrane channels or by altering neurotransmitter activity within the CNS. Pathophysiology

19. Stages of Seizures A  seizure  is an electrical disturbance that interferes with normal brain function.  It occurs when abnormal electric signals from the brain change the way the body functions. The way that a seizure presents itself can vary a lot between people with epilepsy, depending upon the type of seizures they experience and their particular form of epilepsy. In order to better understand what is occurring in the brain when a seizure occurs, it is helpful to understand the four distinct phases of a seizure. On this page, you’ll learn about each phase, including what makes them different, when they might occur, and common symptoms that a person with epilepsy might experience. The four phases of seizure are: Prodromal Early ictal (the “aura”) Ictal Postictal

20. BEFORE THE SEIZURE: PRODROMAL PHASE The  prodromal phase  is a subjective feeling or sensation that can occur several hours or even days before the actual seizure. Prodromal is defined as the period from when early symptoms begin to before the more obvious, diagnosable symptoms begin. The most common symptoms of a prodrome include confusion, anxiety, irritability, headache, tremor, and anger or other mood disturbances. About 20% of individuals with epilepsy experience this stage, 3  which may serve as a warning sign of seizure onset for those who experience it. Individuals experiencing the prodromal phase may even consider this phase empowering, as they may be warned of an impending seizure. Unlike an  aura  (defined below), this stage is not considered part of the seizure.

21. DURING THE SEIZURE: EARLY ICTAL AND ITCAL PHASES For many people with epilepsy, the earliest sign of seizure activity is an aura. Although it has traditionally been thought of as a warning of an oncoming seizure, an aura is the earliest sign of seizure activity and the beginning of the ictal phase. 3 The ictal phase includes the time between the beginning (aura, if present) and the end of the seizure.

22. EARLY ICTAL (THE AURA) It is reported that as many as 65% of people with epilepsy experience auras. Much like the prodrome , not everyone with epilepsy has auras, though they are common. For those who do, the specific symptoms vary depending on seizure type, severity, and affected brain region. Some common symptoms include: Bitter, acidic taste Déja Vu (feeling of familiarity with a person, place, or thing without having experienced it) Dizziness Flickering vision Hallucinations Head, arm, or leg pain Jamais vu (feeling of unfamiliarity with a person, place, or thing despite having already experienced it)

23. Nausea/stomachache Numbness Out-of-body sensation Ringing or buzzing sounds Strange, offensive smells Strong feelings of joy, sadness, fear, or anger Subtle arm or leg twitching Tingling Vision loss or blurring

24. ICTAL PHASE This is the stage of the seizure that most people are familiar with and would identify as a seizure.  This stage manifests in different ways for each person with epilepsy. A person may experience a variety of symptoms, including but not limited to:  9 Arm or leg stiffening Chewing or lip-smacking Confusion Difficulty breathing Distractedness Drooling Eye or head twitching movement in one direction Hearing loss Inability to move or speak Loss of bladder and/or bowel control Memory lapses Numbness Pale/flushed skin Pupil dilation

25. Racing heart Sense of detachment Strange sounds Sweating Tremors Twitching Unusual physical activity such as dressing/undressing Vision loss, blurring, flashing vision Walking/running

26. AFTER THE SEIZURE: POST-ITCAL PHASE The recovery period following a seizure is called the post-ictal phase. Some people recover immediately, while others may require minutes, hours or days to feel like they’re back at their baseline. The length of the post-ictal stage depends directly on the seizure type, severity, and region of the brain affected. Typical symptoms include: Arm or leg weakness Body soreness Confusion Difficulty finding names or words Drowsiness Feelings of fear, embarrassment, or sadness General malaise Headaches/migraines Hypertension Memory loss Nausea Thirst

27. Classification of Seizure and Epilepsy Types Seizures are classified as generalized or partial on the basis of their clinical features and findings on electroencephalogram (EEG). Generalized seizures are those that begin in both hemispheres of the brain and are subdivided into convulsive and non - convulsive generalized seizures according to the severity of associated motor disturbances. Non - convulsive generalized seizures included absence (petit mal), myoclonic, and atonic seizures. Clonic and tonic- clonic seizures were previously referred to as grand mal seizures.

28. Generalized tonic- clonic seizures are characteristic of maximal involvement of neurons of both hemispheres of the brain. Typically, these seizures begin with tonic (rigid) flexion of the extremities followed by extension. During this phase, contraction of the diaphragm forces air from the lungs across the larynx to produce an audible cry. The tonic phase of the seizure usually lasts 15 to 20 seconds and is quickly followed by the clonic (jerking) phase, during which there are spasms of the trunk and extremities and often biting of the tongue. Generalized Seizures; Generalized Tonic- Clonic Seizures

29. The clonic phase usually lasts 20 to 30 seconds and is followed by a postictal state, during which the patient may sleep or awaken confused and disoriented. There is then a gradual return of consciousness and orientation over a period of 15 to 30 minutes, after which the patient has no recall of the event. Increases in blood pressure and heart rate, incontinence of urine or feces, and a brief interruption of normal breathing with cyanosis commonly accompany this type of seizure. Generalized tonic- clonic seizures may begin in both hemispheres of the brain (referred to as primarily generalized seizures) or begin in a localized area of the cortex (a partial seizure) and subsequently spread to involve both hemispheres (referred to as secondarily generalized tonic- clonic seizures).

30. Absence (petit mal) seizures occur primarily during childhood and are characterized by an abrupt interruption of consciousness followed by a fixed stare. Automatisms (coordinated involuntary movements such as lip smacking, chewing, or grimacing) or mild clonic movements may also occur. During the seizure there is no loss of postural tone. The seizure usually lasts several seconds and ends as abruptly as it begins with the patient immediately regaining full alertness. Absence Seizures

31. Absence seizures may also cluster and occur as frequently as hundreds of times a day. When this happens the seizures are often initially perceived by family or teachers as daydreaming. This seizure type is characterized by a classic pattern on the EEG of bilateral 3-Hz spike and slow-wave discharges. Absence seizures usually have their onset between the ages of 4 and 12 years and remit during adolescence or early adulthood in 60% to 70% of patients. In the remainder, generalized tonic- clonic seizures usually develop. Atypical absence seizures differ from traditional absence seizures in having a longer duration, focal motor manifestations, different EEG pattern (<2.5-Hz spike and slow-wave), and a greater association with developmental delay.

32. Other Types of Generalized Seizures Atonic seizures are characterized by a sudden loss of muscle tone. Because the patient may fall abruptly, injuries are common, and it is often necessary to protect the patient's head by prescribing the use of a helmet during the daytime. Myoclonic seizures are characterized by jerking movements of a single or multiple muscle groups. Tonic seizures are similar to generalized tonic- clonic seizures except that they lack the usual clonic phase.

33. Partial seizures begin in one hemisphere of the brain and are often indicative of some underlying focal brain lesion (e.g., perinatal injury, trauma, injury due to bacterial or viral CNS infections, stroke, or brain tumor). Partial seizures are differentiated according to whether or not consciousness is impaired during the event. Complex partial seizures are associated with impairment of consciousness; simple partial seizures are not. Partial Seizures

34. Simple Partial Seizures Simple partial seizures or auras are characterized by motor manifestations (e.g., clonic jerking of one limb) or sensory symptoms (e.g., a foul odor or visual distortions). In some patients with motor symptoms the seizure may spread to contiguous areas of the cortex, resulting in the recruitment of additional muscle groups (“ jacksonian march”). Autonomic symptoms such as piloerection or pupillary dilatation or psychic symptoms such as feelings of déjà vu or fear may also accompany simple partial seizures; however, they are less common. In all cases, patients can respond to their environment throughout the attack.

35. Complex Partial Seizures Complex partial seizures (previously referred to as psychomotor or temporal lobe seizures) are characterized by impaired consciousness and a heterogeneous group of abnormal symptoms or behaviors. Although the variety of symptoms associated with complex partial seizures is wide, each individual usually reports stereotypical attacks. Auras precede complex partial seizures in many patients. Unusual epigastric sensations are the most common, although various motor, sensory, or psychic symptoms (as described for simple partial seizures) may occur.

36. Consciousness is then impaired for an average of about 2 minutes. During this time, patients may exhibit automatisms such as lip smacking, buttoning or unbuttoning of clothing, or wandering behavior. Less often, the behavioral abnormalities include violent outbursts, crying, or sexual actions. Simple or partial complex seizures may spread to involve both hemispheres of the brain (usually as a generalized tonic- clonic seizure). These events are termed “partial seizures with secondary generalization.”

37. Epilepsy Syndromes In some cases the seizure classification, etiologic diagnosis, patient age, and coexistent medical conditions can be used to define a specific epileptic syndrome. An epileptic syndrome is a constellation of signs and symptoms that tend to occur together. Identification of epileptic syndromes may provide useful information that is not necessarily implied by the etiologic diagnosis or the seizure classification, such as a specific choice of AED, the anticipated duration of AED therapy, natural history, and patient prognosis. Not all patients who have epilepsy can be classified as having an epileptic syndrome. Examples of epileptic syndromes include childhood absence epilepsy, juvenile myoclonic epilepsy, and Lennox- Gastaut syndrome.

38. Febrile Seizures Febrile seizures are defined as seizures that occur in association with a febrile illness. The seizure typically occurs in otherwise neurologically and developmentally normal children who do not have any evidence of a CNS infection or other identifiable causes for a seizure. Febrile seizures are the most common form of epilepsy in children and represent 40% of all first seizures. They occur in 2% to 5% of children less than 5 years of age with a peak onset at 14 to 18 months of age

39. A third of children will have a second febrile seizure before they outgrow the tendency to have febrile seizures. Febrile seizures are classified as simple or complex. Simple febrile seizures are usually benign, self-limiting, and associated with only a 2% to 3% risk of recurrent, nonfebrile seizures in later life. They last less than 15 minutes and do not recur within 24 hours. Complex febrile seizures are prolonged (>15 minutes), occur in series (two or more in 24 hours), or have associated focal features. Febrile seizures do not cause brain damage, nervous system problems, paralysis, mental retardation, or death. Although most parents are concerned about the development of epilepsy, children with a history of complex febrile seizures are at only a slightly higher risk (3%) of developing epilepsy by age 7 than children who have not had febrile seizures.

40. Most febrile seizures are self-limited and are not associated with acute or long-term neurological sequelae, therefore treatment with an AED is generally not required. The majority of febrile seizures occur within 24 hours of the onset of a febrile episode; however, most parents are not aware that their child has a fever until a seizure occurs. Parents should be instructed to contact their physician as the child may need evaluation, and specific treatment for the febrile illness. Given the risks and benefits of the effective therapies, neither continuous nor intermittent AED therapy is recommended for children with one or more simple febrile seizures. Although intermittent anticonvulsants (phenobarbital) may prevent recurrences, the likelihood of adverse effect (e.g., ataxia, lethargy, irritability) usually outweighs any benefit.

41. Children with complex febrile seizures, preexisting neurologic abnormalities, or a family history of nonfebrile epilepsy are at greater risk for the development of epilepsy in later life. Although there is no evidence that the risk of nonfebrile epilepsy is reduced, drug therapy for the prevention of febrile seizures may be considered for these patients. Phenobarbital is effective for the treatment of febrile seizures; however, it may cause serious adverse effects and must be administered continuously to ensure adequate drug concentrations at the onset of a febrile episode.

42. For these reasons, many clinicians prefer intermittent treatment with rectal diazepam. Rectal administration of diazepam (using the parenteral solution or Diastat ) results in rapid absorption and quickly provides protection from recurrent febrile seizures. Although valproic acid is also effective as prophylactic therapy, it is not used because of the risk of hepatotoxicity in this age group. Carbamazepine and phenytoin are not effective, and none of the newer AEDs have been evaluated for efficacy in febrile seizures.

43. Evaluation of the Patient with New-onset Seizures Patient history    Perinatal and developmental history     History of febrile seizures    History of central nervous system infection, trauma    Family history of epilepsy Physical examination Seizure description    Preictal phenomena (aura)    Ictal manifestations (including level of consciousness)    Postictal state    Provocative factors Laboratory assessment    Blood urea nitrogen    Cerebrospinal fluid profile (only if meningitis is suspected)    Complete blood count    Electrolytes and glucose    Osmolality    Toxicology screen (if indicated) Neurological examination    Electroencephalogram    Computed tomography (only for trauma)    Magnetic resonance imaging

44. Disorders That May Mimic Epilepsy Gastroesophageal reflux Breath-holding spells Migraine    Confusional   Basilar   With recurrent abdominal pain and cyclic vomiting Sleep disorders (especially parasomnias) Cardiovascular events    Pallid infantile syncope    Vasovagal attacks    Vasomotor syncope    Cardiac arrhythmias Movement disorders    Shuddering attacks    Paroxysmal choreoathetosis     Nonepileptic myoclonus    Tics and habit spasms Psychological disorders    Panic disorder    Hyperventilation attacks     Pseudoseizures    Rage attacks

45. Principles of Antiepileptic Drug Selection and Usage AED pharmacotherapy is the mainstay of epilepsy treatment and the likelihood of seizure recurrence informs the decision to initiate treatment. The goals of AED treatment are to completely control seizures and to minimize drug-related adverse effects. Specific end points must be individualized for each patient. The choice of AED should be based on the seizure type, the age and sex of the patient, concurrent medical conditions, available dosage formulation, potential adverse effects, likelihood for clinical important drug-drug or drug-nutrient interactions, and the pharmacokinetic and pharmacodynamic features of the individual drugs. When these factors are considered and the guiding principles of AED therapy are followed, good to excellent seizure control can be attained in most patients. However, some patients may continue to suffer from recurrent seizures despite appropriate drug treatment.

46. Monotherapy is preferred to polytherapy with AEDs because of lower costs associated with medications and laboratory monitoring, reduced potential for adverse reactions and undesirable drug interactions, and improved medication compliance with a more simplified drug administration schedule. Furthermore, evidence indicates that polytherapy offers no advantage over monotherapy for the majority of patients. For patients in whom single-drug therapy does not provide sufficient seizure control, polytherapy may be necessary to achieve the goals of treatment. (a). Preference for Monotherapy with Non - sedating Agents

47. In addition to selecting the minimum effective number of AEDs, it is important to choose agents on the basis of their adverse-effect profile. The specific adverse effects of each drug are discussed later; however, the use of sedating AEDs should be minimized or avoided. Phenobarbital, primidone , and benzodiazepines are examples of sedating AEDs; other drugs covered in this chapter are not. Although phenobarbital is as effective as phenytoin and carbamazepine for the treatment of secondarily generalized tonic- clonic seizures, the latter agents are preferred because of their relative lack of CNS depressant effects.

48. Sedation and decreased mentation are particularly common on initiation of therapy with barbiturate and benzodiazepines. However, over time an adaptive process occurs during which these effects become less noticeable. Despite the development of tolerance to the overt sedative effect of these drugs, evidence suggests that subtle effects on intelligence, memory, complex motor skills, and behavior often persist during treatment. These undesirable effects may be especially concerning in infants and young children during periods of neurological development and acquisition of learning skills. In some cases these changes are noted by patients or their families only after the drug is discontinued. Although it infrequently requires discontinuation of phenobarbital, the AED can cause paradoxical hyperactivity in children.

49. When possible, therapy should begin with one of the nonsedating AEDs such as phenytoin, carbamazepine, valproate, ethosuximide , or any of the newer AEDs. Phenobarbital and benzodiazepines should be reserved until nonsedating alternatives have failed. Although not available in the United States, nitrazepam and clobazam are associated with less sedation than clonazepam. In summary, sedating AEDs should be avoided when possible, and in many cases, the substitution of nonsedating alternatives can result in noticeable improvement in cognitive, motor, and behavioral function.

50. (b). Drug Selection Based on Seizure Classification Once the diagnosis of epilepsy has been made, the choice of AED therapy should be guided by the relative efficacy and toxicity of each agent. Proper classification of the patient's seizure type or epilepsy syndrome is the most important step in choosing the appropriate agent. The re are guidelines are using an evidence-based assessment of the efficacy, tolerability, and safety of gabapentin, lamotrigine, topiramate , tiagabine , oxcarbazepine, levetiracetam, and zonisamide .

51. Partial Seizures Overall, partial seizures do not respond to treatment as well as seizures that are generalized from their onset. Carbamazepine, phenytoin, phenobarbital, and primidone are equally effective for the treatment of partial seizures, including simple-partial, complex-partial, and secondarily generalized partial seizures. However, carbamazepine and phenytoin are usually tolerated better. Phenytoin has a long half-life that allows for once-daily dosing and carbamazepine is available in two extended-release dosage forms, which allow for twice-daily dosing. However, phenytoin is associated with cosmetic changes that make it less desirable for the treatment of epilepsy in children, adolescents, and women. Valproate is also useful for the treatment of partial seizures, but carbamazepine provides better seizure control and fewer long-term adverse effects.

52. Felbamate , gabapentin, lamotrigine, tiagabine , topiramate , levetiracetam, oxcarbazepine, zonisamide , and pregabalin are also effective for treating partial seizures. Lamotrigine and topiramate are effective as monotherapy and appear to be better tolerated than carbamazepine monotherapy. The other new agents are primarily used as adjunctive therapy if monotherapy has failed or for patients who are intolerant of standard AEDs (e.g., carbamazepine, phenytoin, and valproate). Prospective clinical trials have not compared the relative efficacy of the new AEDs. Approximately 65% of patients with partial seizures attain complete control of seizures with AED monotherapy .

53. Primary Generalized Tonic- Clonic Seizures Valproate, lamotrigine, and topiramate are the drugs of choice for the treatment of primary generalized tonic- clonic seizures . At the time the AAN Quality Standards Subcommittee guidelines were published, the members concluded that there were insufficient data to support the use of any of the new AEDs as monotherapy in newly diagnosed primary generalized tonic- clonic seizures; however, topiramate was recently approved as initial monotherapy for primary generalized seizures in those older than 10 years of age.

54. Valproate is often considered the drug of choice for the treatment of primarily generalized tonic- clonic seizures. Approximately 75% to 85% of patients achieve complete seizure control during monotherapy with this agent. Lamotrigine and topiramate are emerging as more often used therapies in children younger than 2 years of age because of the higher risk of valproate-associated hepatotoxicity in this population. Phenobarbital and primidone are also effective against generalized tonic- clonic seizures, but because of their potential for adverse effects, they are usually reserved for use as alternative second-line or third-line agents. Carbamazepine, phenytoin, and oxcarbazepine can rarely exacerbate seizures in patients with primary generalized epilepsy syndromes. These children should be monitored closely for worsened seizures or the emergence of a new seizure type.

55. Ethosuximide , valproate, and lamotrigine are effective for the treatment of absence seizures. Ethosuximide may be preferred over valproate when only absence seizures are involved because of the potential for fewer serious adverse effects. The AAN Quality Standards Subcommittee concluded that sufficient data existed to support the use of lamotrigine as monotherapy for absence seizures. Ethosuximide is not effective against generalize tonic- clonic seizures; therefore, valproate and lamotrigine are preferred if this seizure type is also present. The response to these agents is usually dramatic. In controlled trials, 70% to 90% of patients who were treated with ethosuximide or valproate experienced cessation or a dramatic reduction in absence seizures. The combination of ethosuximide and valproate is often effective when monotherapy fails to yield adequate results. Absence Seizures

56. Clonazepam is also effective against absence seizures. However, because of frequent dose-related adverse effects and the development of tolerance to the antiepileptic effect of this drug, it should be reserved for patients in whom ethosuximide and valproate fail. Carbamazepine and phenytoin are ineffective for the treatment of absence seizures and may even exacerbate these and other seizure types when used for the treatment of children with mixed seizure disorders. Levetiracetam, zonisamide , and felbamate have some evidence of efficacy in absence epilepsy, but formal studies have not been performed.

57. Myoclonic, Atonic, and Atypical Absence Seizures Valproate is effective for the treatment of myoclonic, atonic, and atypical absence seizures and is the initial drug of choice for patients with mixed seizure types. Valproate effectively controls myoclonic seizures in 75% to 90% of patients with generalized idiopathic and juvenile myoclonic epilepsy. Myoclonic seizures after anoxic encephalopathy are more resistant to treatment. Clonazepam is also effective as monotherapy or in combination with valproate when either drug alone does not provide adequate seizure control. Lamotrigine, topiramate , zonisamide , and felbamate are also effective against myoclonic, atonic, and atypical absence seizures.

58. AEDs are more frequently associated with adverse effects during initiation of therapy; therefore, treatment should begin with low doses and the dose should be gradually escalated according to the patient's clinical status. When therapy is initiated too aggressively, patients may experience uncomfortable adverse effects and are often unwilling to continue treatment with that agent despite a reduction in dosage. Patients should be told to monitor for and report adverse effects so that an adjustment in therapy can be made as soon as possible. Phenytoin, phenobarbital, and levetiracetam are usually tolerated well when they are initiated near the usual maintenance dosage. Upon initiation of therapy, patients should understand the goal of treatment and the time course over which response is anticipated. The importance of strict compliance with the prescribed regimen should also be emphasized and the practitioner should attempt to identify any obstacles to adherence. (c). Initiating Antiepileptic Drug Therapy

59. (d). Adjusting and Monitoring Antiepileptic Drug Therapy There is great interpatient variability in the dose-response relationship for all of the AEDs that are in common use. Therefore, after therapy is initiated, the optimal drug dose for each patient should be determined. This necessitates the titration of therapy until the desired clinical response is achieved or the patient experiences unacceptable adverse effects. The determination of acceptable seizure control requires input from the patient and clinician. Although complete control of seizures is always desirable, it may not be realistic given the magnitude and severity of the seizure type. Patients or parents may also choose to continue therapy that allows minimal interruption of their lifestyle even though seizures occasionally recur. The clinician must assess the temporary disability and potential for harm (to the patient and others) that may accompany a seizure. Use of this information, with input from the patient, should be used to determine if dosage adjustments should be made.

60. If the first agent does not achieve the desired goal, then an alternative AED that is appropriate for the patient's seizure type should be gradually substituted rather than added. Typically, after monotherapy has failed (usually with two or three agents) poly - therapy should be tried. The first drug is usually removed once a successful dose or desired plasma concentration of the new agent is attained. AED therapy fails for many reasons. Although various drugs may demonstrate equal efficacy in large populations of patients, an individual may respond better to one agent than to others. Additional factors that should be considered include poor medication compliance, erroneous diagnosis or seizure classification, progressive neurological disease, and lifestyle factors that compromise the efficacy of treatment (e.g., recreational drug or alcohol abuse, sleep deprivation).

61. Noncompliance with treatment is a common cause of AED therapy failure, and this possibility should be carefully investigated. It is essential that the clinician create a culture that encourages the patient/family to discuss their compliance, or lack thereof, without fear of judgment. Common reasons for noncompliance include complicated dosing regimens, fear about chronic adverse effects of AED therapy or teratogenicity, and denial of the need for treatment. Patients who report a change in the character of their seizures (e.g., seizures are now preceded by an aura, whereas previously there was no warning) or frequent seizures after a long period of complete control should be referred for a thorough medical evaluation to rule out other neurological disease.

62. The widespread availability of blood concentration monitoring of AED therapy has had a dramatic effect on the use of these agents. For example, combination AED regimens were frequently begun (e.g., phenytoin and phenobarbital) before clinicians had the ability to individualize the doses for either agent. On the basis of past experience in which a single drug was occasionally ineffective and above-average doses sometimes led to toxicity, it was assumed that most patients would benefit if multiple drugs were used. Blood concentration monitoring and knowledge of the pharmacokinetic properties of AEDs are now used to maximize efficacy, minimize adverse effects, and evaluate compliance. The “therapeutic” range of plasma concentrations is a useful guide for titrating therapy. Within this range, many patients achieve seizure control without unacceptable side effects. However, it is also common to observe an adequate response at concentrations below the lower end of the defined therapeutic range, and some patients tolerate and indeed require plasma concentrations above the upper limit of the range to maintain seizure control. Plasma Antiepileptic Drug Monitoring

63. Thus, although these limits are useful as guides to therapy, the clinician should strive to determine the optimum AED plasma concentration for each individual patient rather than relying on published ranges. While a therapeutic range is available for the new AEDs, these reflect concentrations achieved during clinical trials and do not necessarily correspond with efficacy or toxicity. However, they may still be helpful in defining the optimum AED concentration for a given patient, evaluating compliance, and making adjustments in patients with altered renal function. Assays for the new AED are generally not available in clinical laboratories; hence, it may require weeks to obtain results.

64. When indicated, plasma concentration monitoring of AEDs is most useful under the following conditions: (a) to document the plasma concentration associated with good seizure control or failures, (b) to guide subsequent dosage adjustments that are required on a clinical basis, (c) to evaluate noncompliance, (d) to evaluate alterations in pharmacokinetics that are due to patient diversity, disease, or drug-drug interactions, and (e) to evaluate possible concentration- related adverse effects. The timing of blood sampling for drug concentration determination is important, particularly during therapy with AEDs that have a short half-life (e.g., carbamazepine and valproate).

65. For these agents, blood concentrations can fluctuate significantly over the course of the dosing interval. Comparisons between drug concentrations may be inaccurate unless the blood is sampled at a consistent time relative to the dose. For most patients it is recommended that blood samples be taken in the morning, before the first daily dose of medication. An exception is patients with repeated, transient symptoms that are suggestive of dose- related drug toxicity or individuals who experience “break through” seizures at the end of a dosing interval. For these patients, blood sampling should coincide with the event so that the contribution of the drug can be assessed.

66. Plasma concentration monitoring of AEDs is often overused and misused. It is common (and arguably appropriate) to document drug concentrations on an occasional basis in patients whose epileptic condition is well controlled (e.g., every 12 months). However, other drug concentration determinations should not be done unless there is clinical indication of their necessity. Likewise, there is often a tendency to adjust AED therapy on the basis of the concentration without considering the patient's clinical status. For example, it may be tempting to decrease the drug dose when the reported blood concentration is above the usual therapeutic range. However, some patients require higher concentrations than usual to achieve the desired pharmacological effect. Likewise, patients whose seizures are controlled with concentrations less than the therapeutic range neither need a dose increase nor should be assumed to no longer require AED treatment.

67. (e). Withdrawal of Antiepileptic Drug Therapy Several community-based studies have shown that among patients with epilepsy who are followed for more than 10 years, more than half attain a 2-year to 5-year remission from seizures during drug therapy. Remission rates tend to be highest for patients who have primary generalized seizures and range from 60% for those with tonic- clonic seizures to 80% for children with typical absence attacks. In general, patients who remain free of seizures for 2 years or more may be considered candidates for AED withdrawal. The potential benefits of drug withdrawal include avoidance of the cognitive and behavioral effects of AED therapy, reduction in the risk of adverse drug reactions and drug interactions, and a return by the patient to a lifestyle that is unencumbered by the need for chronic medication. However, the decision to withdraw AED therapy is complex, medically and socially, and requires a clear explanation to the patient of the risks and benefits.

68. In particular, it is important to consider the age at onset of epilepsy, seizure type, EEG abnormalities, and rate of drug withdrawal in assessing the risk of seizure recurrence. Relapse rates after AED withdrawal in patients who have been free of seizures for 2 years or more are approximately 30% for children and 40% for adults with epilepsy. Thus, 60% to 70% of patients will remain free of seizures when AED therapy is withdrawn after a 2-year remission.

69. The rate of AED withdrawal may also affect seizure recurrence. Gradual withdrawal is preferred and most practitioners discontinue therapy over a period of 1 to 3 months, depending on the patient and the drug. Abrupt withdrawal is a risk factor for status epilepticus. Furthermore, rapid removal of AED therapy itself may precipitate seizures due to drug withdrawal (as distinct from a recurrence of seizures due to the underlying epileptic condition). Seizures during withdrawal are most common with benzodiazepine or barbiturates. However, because there are no means to determine reliably whether recurrent seizures are related to a withdrawal phenomenon or the lack of a beneficial effect, the need for continued drug therapy is unclear unless the rate of taper is long enough to effectively rule out a drug withdrawal phenomenon.

70. Any decision to withdraw AED therapy on the basis of a favorable medical prognosis must also include a careful assessment of the patient's work and social environments. Not only should patients clearly understand the risks and benefits of drug withdrawal, they must also be encouraged to participate actively in the decision. Patients who have been seizure-free for long intervals, often have valid concerns about the possible recurrence of seizures at home, at work, or while driving. During AED withdrawal it is often recommended that the patient not drive for several months. Furthermore, in some areas a recurrent seizure during this period may result in the suspension of driving privileges until AED therapy is restarted and adequate control is demonstrated. These and other patient-specific social factors should be discussed with each individual for whom AED withdrawal is considered.

71. (f). Treating the Pregnant Woman who has Epilepsy Considerable controversy continues to surround the treatment of pregnant women who have epilepsy. Central issues are the risk of fetal malformations that are attributable to individual seizures and to the epileptic diathesis, the degree of additional risk that is attributable to AED therapy, and the antiepileptic agent of choice for minimizing the risk of fetal malformations. Although a detailed discussion of these issues is beyond the scope of this chapter, several important principles should be considered. The reader is referred to other reviews for additional discussion of this topic.

72. Considerations that are unique during pregnancy include (a) changes in maternal seizure control, (b) the choice of antiepileptic agents, (c) alteration of AED pharmacokinetics, and (d) the potential for AED-associated coagulopathy in the newborn. Approximately 60% of women with epilepsy will have no change in seizure frequency during pregnancy. Among the remaining patients, worsening of seizures occurs in approximately one third of pregnant women. This may be attributable to several factors, including reduced medication compliance caused by fears that the medication may injure the developing fetus, pharmacokinetic changes in AED disposition, and sleep deprivation.

73. Overall, the incidence of fetal abnormalities in children of epileptic mothers is approximately 6%, roughly twice that found in the general population. Although there is considerable controversy about which AED has the lowest teratogenic risk, there is a clear association between some AEDs and fetal malformations. Currently, there is no conclusive evidence on which to base a preference for the use of carbamazepine, phenobarbital, phenytoin, or valproate during pregnancy. No AED is clearly less teratogenic than the others, therefore the preferred AED during pregnancy is the drug that best controls the patient's seizures.

74. The North American AED Pregnancy Registry does suggest that monotherapy with valproate and monotherapy with phenobarbital have higher rates of major malformations than other AED. Phenytoin has been associated with a constellation of anomalies including craniofacial malformations, mental retardation, deficiencies in growth, mental or motor performance, and limb defects that have been grouped as the fetal hydantoin syndrome. However, similar abnormalities have been associated with other AEDs. It is clear that AED polytherapy is associated with a greater risk of fetal malformations. When possible, it is recommended that monotherapy (with the lowest effective dose) be used and that a dosage formulation that minimizes plasma peak to trough AED concentrations be used.

75. The safety of newer AEDs (gabapentin, lamotrigine, oxcarbazepine topiramate , and tiagabine ) has yet to be established; however, all of the newer AEDs are Food and Drug Administration (FDA) category C while the older AED are classified as category D. Neural tube defects (specifically, with spina bifida) have been associated with maternal use of valproate (1%–2%) and carbamazepine (0.5%–1%) during pregnancy. The mechanism of teratogenesis caused by AEDs is unknown but may be related to folic acid deficiencies or to arene oxide intermediates that are generated during the metabolism of aromatic AEDs. Deficiencies of folate have been implicated in the development of neural tube defects. For this reason, all women with childbearing potential who have epilepsy should receive folic acid supplementation.

76. The optimal dose is unknown but most practitioners use 1 to 2 mg daily. Although folic acid supplementation in women of childbearing years has become a standard recommendation, it is unclear if folic acid supplementation protects against the embryotoxic and teratogenic effects of AEDs. Despite supplementary folic acid, women taking valproate or carbamazepine should undergo perinatal diagnostic ultrasound to rule out neural tube defects. Pregnancy is associated with significant changes in the pharmacokinetic properties of AEDs. These changes include acceleration of hepatic drug metabolism, increased apparent volume of distribution, and alterations in plasma protein binding. The result is a decline in plasma AED concentrations and in some patients, loss of seizure control.

77. Consequently, AED plasma concentrations and the clinical status of the patient should be monitored regularly during pregnancy. When assays are available, monitoring of unbound plasma concentrations of phenytoin, valproate, and carbamazepine is recommended due to protein binding changes associated with pregnancy. Plasma concentrations with these AEDs and with lamotrigine should be determined approximately every 3 months during pregnancy. After delivery, AED plasma concentrations should be determined weekly, and appropriate dosage adjustments should be made. Approximately 50% of the infants who are born to mothers taking phenytoin, phenobarbital, and primidone during pregnancy are deficient in vitamin K-dependent clotting factors at birth.

78. Although neonatal hemorrhage is uncommon, infants should be treated with 1 mg vitamin K intramuscularly immediately at birth. Clotting should then be monitored every 2 to 4 hours, and repeat doses of vitamin K should be administered as needed. Preferably, coagulopathy can be prevented by treating the mother with vitamin K 10 mg orally each day for 4 weeks before delivery. All AEDs are excreted in breast milk to some degree. The ratio of breast milk to plasma concentration is 80% to 100% for ethosuximide , 40% to 50% for phenobarbital, 40% for carbamazepine, 18% to 20% for phenytoin, and 1% to 10% for valproic acid.

79. Although most epileptic mothers may safely breastfeed their infants, the potential effect of drug transfer to the baby should be considered, especially if the infant appears to be lethargic or irritable, or feeds poorly. Despite the concern of parents and clinicians about the risks of epilepsy and AED therapy during pregnancy, it is important to realize that more than 90% of epileptic women have normal children. However, women with epilepsy must understand the value of prepregnancy planning and the risks for fetal abnormalities. They must also understand the potential consequences of medication noncompliance and the need for close monitoring of plasma concentrations during pregnancy and for several weeks after childbirth.

80. Antiepileptic Drugs

81. All barbiturates have anticonvulsant activity but only phenobarbital and primidone are used commonly for the chronic treatment of epilepsy because they are effective at subhypnotic doses. . However, because of adverse effects on the CNS, this agent is now used primarily as an alternative when monotherapy with first-line agents has failed. Phenobarbital is most useful for the treatment of partial and generalized tonic- clonic seizures. It elevates the seizure threshold and prevents the spread of electrical seizure activity. Phenobarbital modulates the inhibitory action of GABA by increasing its binding to the GABA A receptor. (1). Phenobarbital [ Debritone ]

82. Formulation and Dosage Phenobarbital is available as the sodium salt in a variety of dosage forms, including oral capsules and tablets, elixir, and injectable preparations . The usual maintenance dose of phenobarbital for adults is 90 mg every day (q .i. d) and 3 to 5 mg per kilogram in neonates and children. Phenobarbital is usually given as a single daily dose at bedtime to avoid peak sedative effects during the day. Its long half-life causes significant delays in the achievement of steady-state concentrations; hence, a loading dose should be administered when a prompt effect is needed.

83. Pharmacokinetics Phenobarbital is nearly completely absorbed after oral and intramuscular administration, with peak concentrations occurring in less than 4 hours. Neonates have delayed and incomplete absorption of oral phenobarbital. Although food may delay absorption. Phenobarbital is 45% to 60% bound to plasma proteins Phenobarbital is eliminated by a first-order process. . The half-life of phenobarbital ranges from 3 to 6 days in adults but varies significantly with age. Approximately 25% of the dose is excreted in the urine unchanged.

84. Adverse Effects CNS adverse effects during phenobarbital therapy are generally dose-related and include sedation, nystagmus, dizziness, and ataxia. A noticeable improvement in behavior may be seen when phenobarbital is replaced with valproate or carbamazepine.

85. Drug Interactions Most drug interactions with phenobarbital are characterized by alterations of metabolism. By increasing the synthesis and retarding the degradation of hepatic enzymes, phenobarbital accelerates the metabolism of many agents that are metabolized by the mixed-function oxidase system including theophylline, warfarin, cyclosporine, chloramphenicol, chlorpromazine, haloperidol, oral contraceptives, and tricyclic antidepressants. It also affects the clearance of valproate, felbamate , lamotrigine, oxcarbazepine, topiramate , and zonisamide . Carbamazepine concentrations may remain unchanged or decline during phenobarbital coadministration. Phenobarbital can also inhibit the metabolism of some drugs, presumably by competition for similar metabolic pathways.

86. Primidone is structurally related to the barbiturates, and like phenobarbital, it is effective for the treatment of partial and generalized tonic- clonic seizures. Primidone is an active anticonvulsant, as are its two major metabolites, phenobarbital and phenylethylmalonamide . Although the clinical use of primidone is similar to that of phenobarbital, adverse effects are more commonly a limiting factor during long-term primidone therapy. Some patients may respond to primidone therapy despite the failure of phenobarbital to control seizures. (2). Primidone [ Mysoline ]

87. Formulation and Dosage Primidone is available as oral tablets and suspensio n . Primidone should be initiated slowly, to allow the development of tolerance to the acute gastrointestinal and sedative effects of the parent drug. For those older than 8 years of age, therapy is started at a dose of 100 to 125 mg with gradual dosage increases every 4 to 7 days in 125-mg to 250-mg increments until the effective dose is reached. Doses are given twice a day (bid) or three times daily ( tid ).

88. Metabolic transformation of primidone to phenobarbital and phenylethylmalonamide occurs by oxidative metabolism and pyrimidine ring cleavage, respectively. Primidone and its metabolites are also excreted by the kidney to a significant extent. The half-life of primidone is relatively short, therefore the drug is usually given in divided doses to maintain more consistent plasma concentrations of the parent drug and reduce the likelihood of transient side effects at times of peak primidone concentrations. Pharmacokinetics

89. Adverse Effects The adverse effects of primidone are similar to those of phenobarbital. Thus, the potential for primidone -related neurotoxicity is of concern during long-term therapy. In addition, primidone itself is frequently associated with initial dose-related adverse effects, including sedation, dizziness, and nausea. Decreased libido and impotence appear to be more common during primidone therapy than with other AEDs.

90. The metabolism of primidone or its metabolites can be affected by other AEDs, including phenytoin and valproate. Phenytoin increases phenobarbital concentrations during coadministration with primidone . The result is an approximate doubling of the phenobarbital: primidone concentration ratio. Conversely, valproate has a negligible effect on the plasma concentrations of primidone. Carbamazepine may increase the metabolism of primidone, although in many patients this interaction is not clinically important. Drug Interactions

91. Ethosuximide is a member of the succinimide class of AEDs, which includes phensuximide and methsuximide . Ethosuximide is effective for the treatment of absence seizures, and is often preferred for young children because of the potential for valproate-associated hepatotoxicity. Ethosuximide has no activity against partial and generalized tonic- clonic seizures.. (3). Ethosuximide [ Zarontin ]

92. Formulation and Dosage Ethosuximide is available as a capsule and syrup for oral use. The initial dose of ethosuximide is 250 mg daily for children 3 to 6 years of age and 500 mg for children 6 years and older. The dose should be increased at weekly intervals in 250-mg increments as necessary. Infants require larger doses on a weight basis than adolescents and adults. Despite the long half-life of ethosuximide , the drug is often given in divided doses to minimize gastrointestinal distress.

93. Ethosuximide is metabolized hepatically to inactive hydroxylated products that are then excreted. Approximately 20% of a given dose is excreted in the urine unchanged. Plasma concentration monitoring helps to guide therapy, but the upper end of the therapeutic range is loosely defined. Many patients tolerate concentrations greater than 100 mg per milliliter, and plasma concentrations of 150 mg per milliliter or greater are occasionally required for optimal treatment. Pharmacokinetics

94. Sedation, nausea, anorexia, and headache are the most common adverse effects reported on initiation of ethosuximide therapy. Adverse Effects

95. Drug Interactions Ethosuximide concentrations may be reduced by carbamazepine and increased by valproate, presumably by enzyme induction and inhibition, respectively.

96. Carbamazepine is a highly lipophilic iminostilbene compound that is structurally related to the tricyclic antidepressant imipramine. Carbamazepine is very effective for the treatment of partial and secondarily generalized tonic- clonic seizures, but it is not effective against myoclonic, absence, or febrile seizures. The antiepileptic effect of carbamazepine is attributed to the drug's ability to affect sodium channels to limit sustained, repetitive firing and alter synaptic transmission. (4). Carbamazepine [ Tegral , Teril , Seizunil ]

97. Carbamazepine ( Tegretol , Carbatrol , and generic) is available as oral and chewable tablets, as a suspension, and as a controlled-release oral dosage fo rm . The initial adult dose is gradually titrated, in 200-mg increments, every 3 to 7 days. . Children should be started on carbamazepine in doses ranging from 5 to 10 mg/kg/day divided bid or tid as tablets, or four times daily ( qid ) as suspension. Maintenance dose above 35 mg/kg/day are rarely needed. Loading doses of carbamazepine are not recommended for usual outpatient therapy because of gastric disturbances. However, single carbamazepine doses of 8 mg per kilogram (using tablets or suspension) are useful in patients for which rapid attainment of a therapeutic concentration is desired. Formulation and Dosage

98. Absorption of carbamazepine from the gastrointestinal tract is slow and erratic and often does not follow first-order pharmacokinetics. The time to peak plasma concentrations after oral administration may vary from an average of 4 to 8 hours to as long as 24 hours. Food has no consistent effect on the bioavailability of carbamazepine. Carbamazepine is almost exclusively cleared by hepatic metabolism. Pharmacokinetics

99. Only 2% of the dose is recovered unchanged in the urine. The half-life of the drug after a single dose may range from 24 to 45 hours.

100. Initial, dose-related adverse effects of carbamazepine are common and include dizziness, drowsiness, anorexia, and nausea. Extended-release carbamazepine products are often useful for ameliorating these symptoms. Adverse Effects

101. Other dose-related neuropsychiatric adverse effects include depression, irritability, mental sluggishness, and impairment of concentration and short-term memory.

102. Drug Interactions Protein binding is low and drug interactions due to this mechanism are not clinically important. Although multiple interactions have been reported between carbamazepine and other drugs, a mechanistic approach to interactions should be considered whenever a medication is added to a patient's regimen.

103. Phenytoin is effective for the treatment of partial and secondarily generalized tonic- clonic seizures, but it has no activity against absence and febrile seizures. The specific mechanism of the anticonvulsant effect is unknown. Phenytoin blocks neuronal sodium and calcium conductance, and calcium-mediated excitatory neurotransmission, which probably is involved in its ability to regulate neuronal excitability under abnormal conditions. (5). Hydantoins (Phenytoin and Fosphenytoin ) [Dilantin]

104. Phenytoin (Dilantin) is available as the free acid in suspension and chewable tablets. The sodium salt of phenytoin is contained in phenytoin capsules and phenytoin injectable; for these dosage forms, phenytoin content is expressed in milligrams of sodium phenytoin. Formulation and Dosage

105. Fosphenytoin is rapidly converted to phenytoin by circulating phosphatases with a half-life of 15 minutes.

106. Doses of fosphenytoin are expressed as phenytoin equivalents (PE), which are the milligram amounts of phenytoin released by the action of phosphatases on the parent drug. For example, a fosphenytoin dose of 500 mg PE releases 500 mg of phenytoin in the presence of phosphatases. Doses of fosphenytoin should be checked carefully to ensure that they are written as intended. Only extended-release phenytoin capsules (e.g., Dilantin Kapseals , Phenytek ), are approved for once daily maintenance dosing. Although the suspension has been given successfully once a day, it is generally given in divided doses. The parenteral dosage form should be given in divided daily doses.

107. Pharmacokinetics Phenytoin is poorly water-soluble at acidic pH. Very little drug exists in solution in the stomach, and its absorption takes place primarily in the proximal part of the small intestine. The time to peak drug concentration after an oral loading dose of phenytoin may be delayed, because the rate of drug dissolution in intestinal fluid is dose-dependent. The bioavailability of phenytoin approaches 100% for most well-formulated products, but it is prudent to avoid changing dosage forms and products because small changes in bioavailability can result in large changes in plasma concentration (and seizure control).

108. Phenytoin is eliminated primarily by hepatic metabolism.

109. Adverse Effects Acute, dose-related adverse effects of phenytoin include ataxia, diplopia, dizziness, drowsiness, encephalopathy, and involuntary movements. Horizontal nystagmus is a dose-related effect that may occur at plasma concentrations within the therapeutic range and does not necessitate a reduction in dosage.

110. Drug Interactions Phenytoin is a potent inducer of hepatic microsomal enzymes and increases the metabolism of many medications. Phenytoin can reduce the effectiveness of oral contraceptives, warfarin, corticosteroids, cyclosporine, and theophylline. It increases the metabolism of carbamazepine, valproate, felbamate , lamotrigine, topiramate , tiagabine , oxcarbazepine, zonisamide , and clonazepam, resulting in a decrease in plasma concentrations and a potential reduction in the clinical anticonvulsant effect. Phenytoin also may increase the ratio of primidone to phenobarbital concentrations when it is administered to patients whose conditions are stabilized with primidone .

111. Valproate is a unique AED because of its chemical structure and broad activity against partial and generalized seizures. Many clinicians consider valproate to be the drug of choice for the treatment of primary generalized epilepsies including tonic- clonic and absence seizures. Ethosuximide and valproate are each effective against absence seizures. . Valproate is also effective as monotherapy for treating patients who have a combination of generalized tonic- clonic seizures and absence or myoclonic seizures. The mechanism of action of valproate has not been completely elucidated but probably involves blockade of voltage-dependent sodium channels as well as potentiation of GABA, the primary inhibitory neurotransmitter within the CNS. (6). Valproate [ Dapakan , Epival ]

112. Formulation and Dosage Valproate is available as valproic acid in soft gelatin capsule and syrup form, and as divalproex sodium in enteric-coated tablets, extended- release tablet, sprinkle capsule, and parenteral dosage form. The sprinkle product may be emptied onto food. Divalproex sodium dissociates into valproate in the gastrointestinal tract. The parenteral product is available as an alternative for patients who cannot take medication by the oral route. Product labeling indicates that the administration rate for the IV product should not exceed 20 mg per minute; however, it has been given over 5 to 10 minutes (1.5–6 mg/kg/min) without problems. IM administration of parenteral valproate is not recommended as it has been associated with muscle necrosis in animals. Once started the medication should be gradual titrated every 3 to 7 days to an effective dose. Twice-daily dosing of the delayed release (enteric coated) formulation can be used in some patients; however, three times daily dosing is recommended when valproate is given concomitantly with enzyme-inducing AEDs. Extended release valproate can be give once or twice daily.

113. The bioavailability of valproate is close to 100% for all oral dosage forms, but the rate of absorption may vary. Peak concentrations occur within 2 hours after administration of valproate syrup and capsules. Enteric-coated tablets were developed to minimize the gastric distress associated with the plain capsule by prolonging the rate of drug dissolution. Consequently, the time to peak concentration is delayed and may vary from 3 to 8 hours. Although food has no significant effect on the absorption of the soft gelatin capsules, the rate of valproate absorption from enteric-coated tablets is delayed. Pharmacokinetics

114. Adverse Effects The most common adverse effects during valproate therapy are gastrointestinal. Nausea, vomiting, anorexia, or other symptoms of gastrointestinal discomfort are reported by as many as 35% of patients treated with capsules or syrup. Patient tolerance can be improved by using the enteric-coated (tablets or sprinkles) or extended release products, and most patients prefer them.

115. Metabolic interactions between valproate and other AEDs are common. Unlike phenytoin, carbamazepine, phenobarbital, and primidone , valproate is not an enzyme-inducing drug. Conversely, valproate inhibits the metabolism of drugs that are biotransformed by CYP2C9, epoxide hydrolase, and UGT enzymes. Drug Interactions

116. Gabapentin is a chemically unique cyclohexane derivative of GABA that was synthesized to cross the blood-brain barrier and mimic the inhibitory effects of this neurotransmitter on the CNS. Gabapentin increases occipital lobe brain GABA concentrations; however, it is not known if this contributes to the drug's anticonvulsant effect. Gabapentin is effective as adjunctive (add-on) therapy for patients with partial and secondarily generalized tonic- clonic seizures. The drug has little or no activity against primarily generalized tonic- clonic and absence seizures. In addition to its use for epilepsy, gabapentin is primarily prescribed for the treatment of pain and psychiatric disorders. (7). Gabapentin [ Neogab , GABA, Gabix , Neupentin ]

117. Gabapentin (Neurontin) is available as capsules, tablets, and as an oral solution. Therapy with gabapentin can be titrated to an effective dose rapidly, giving 300 mg on the first day, 300 mg twice on the second day, and 300 mg three times on the third day. Many practitioners now initiate gabapentin at a dose of 300 mg tid and find this to be well tolerated. Thereafter, therapy should be titrated according to patient response. . The starting dose in children ranges from 10 to 15 mg/kg/day divided into three daily doses. The dose is titrated over approximately 3 days to a maintenance dose of 25 to 40 mg/kg/day. Dosages up to 50 mg/kg/day have been well tolerated in a long-term clinical study. Formulation and Dosage

118. Bioavailability is approximately 60% after oral administration of doses between 900 and 1,800 mg daily in adults and is significantly lower in children (30%). Further dosage increases result in less than proportional increases in plasma concentrations. Pharmacokinetics

119. Adverse Effects Overall, gabapentin is well tolerated and is associated with mild adverse effects, primarily affecting the CNS. Although infrequent, there have also been reports of CNS-related adverse events in children 3 to 12 years of age. These adverse effects appear to be dose-related and can be managed by adjustments of gabapentin dosage or the doses of concomitant agents. . Additional adverse effects may include weight gain (usually <10% of the baseline weight), movement disorders (dystonia or myoclonus), and lower extremity edema.

120. Drug Interactions Gabapentin is neither metabolized nor bound to plasma proteins, therefore it has a much lower potential than other AEDs to interact with other drugs. Gabapentin does not affect the plasma concentrations of carbamazepine (including its epoxide metabolite), phenytoin, phenobarbital, or valproate. Likewise, these AEDs do not alter the disposition of gabapentin.

121. (8). Zonisamide [Zonas] Zonisamide is chemically classified as a sulfonamide and should not be given to someone who is allergic to sulfa-type medications. The mechanism of action is unknown, but it does block sodium channels and reduce voltage-dependent, transient inward currents (T-type Ca 2+ currents), consequently stabilizing neuronal membranes and suppressing neuronal hypersynchronization .

122. Formulation and Dosage Zonisamide ( Zonogran ) is available for oral administration as a capsule and is indicated as adjunctive therapy in the treatment of partial seizures in those older than 16 years of age. Therapy should be initiated at a dose of 50 to100 mg daily. After two weeks, the dose may be increased to 200 mg per day for at least two weeks. It can then be increased to 300 to 400 mg per day. It may take up to 2 weeks to achieve steady-state concentrations because of its long half-life.

123. Pharmacokinetics The absorption of zonisamide is excellent. Although food has no effect on its bioavailability, the time to maximum concentration is delayed. Zonisamide extensively binds to erythrocytes, resulting in an eightfold higher concentration in red blood cells (RBCs) than in plasma. The apparent volume of distribution is about 1.45 L per kilogram with approximately 40% bound to plasma proteins. Zonisamide is excreted primarily in urine (62%) as parent drug and as the glucuronide of a metabolite.

124. Adverse Effects The adverse effect profile of zonisamide is very similar to that of topiramate . The most common adverse events were somnolence, fatigue and/or ataxia (6%), anorexia (3%), difficulty concentrating (2%), difficulty with memory, mental slowing, nausea/vomiting (2%), and weight loss (1%). The most serious adverse effect is a potentially fatal dermatological reaction that includes Stevens-Johnson syndrome and toxic epidermal necrolysis; hence, zonisamide should be discontinued in anyone who develops an unexplained rash. Decreased sweating ( oligohidrosis ) and hyperthermia have been associated with zonisamide .

125. Drug Interactions Zonisamide does not affect steady-state plasma concentrations of phenytoin, carbamazepine, or valproate nor does it inhibit the clearance of other drugs that are metabolized by cytochrome P-450 isozymes. Concurrent medication with drugs that induce or inhibit CYP3A4 would be expected to alter plasma concentrations of zonisamide . Drugs that induce liver enzymes (phenytoin, carbamazepine, or phenobarbital) increase the metabolism and clearance of zonisamide and decrease its half-life. Protein binding of zonisamide is unaffected in the presence of therapeutic concentrations of phenytoin, phenobarbital, or carbamazepine.

126. (9). Tiagabine [ Gabitril ] Tiagabine , a nipecotic acid derivative with a chemical structure unique among AEDs, inhibits the reuptake of GABA into presynaptic neurons and glial cells. This is thought to be the mechanism of its anticonvulsant effect. The drug is approved as adjunctive therapy in adults with partial and secondarily generalized tonic- clonic seizures. Tiagabine ( Gabatril ) is available as oral tablets. When administered with enzyme-inducing AEDs, it should be initiated at a dose of 4 mg daily and increased in 4 mg daily increments at weekly intervals. Usual maintenance dosages of tiagabine are 32 to 56 mg daily given in two to four divided doses. With doses larger than 32 mg daily, tid or qid dosing is often necessary to minimize transient adverse effects associated with peak blood concentrations. More conservative dose titration is usually needed when tiagabine is used with noninducing AEDs (e.g., valproate, gabapentin, or lamotrigine).

127. Pharmacokinetics The oral bioavailability of tiagabine is 90%. It is absorbed quickly with peak blood concentrations occurring 1 hour after administration. The extent of drug absorption is not affected by food. Tiagabine is highly bound to plasma proteins, primarily albumin and α 1 -acid glycoprotein. Drug elimination is primarily by metabolism via CYP3A4 and glucuronidation enzymes. The half-life of tiagabine is 7 to 9 hours in healthy volunteers after a single dose, and it is shortened by 50% to 65% when coadministered with enzyme-inducing AEDs.

128. Adverse Effects Common adverse effects reported during placebo-control, adjunctive therapy trials with tiagabine include dizziness (27%), lack of energy (20%), somnolence (18%), nausea (11%), and nervousness (10%). These adverse effects are usually dose-related and respond to a reduction in dosage or slowing of the rate of dose escalation. Other adverse effects that occur occasionally include tremor, generalized muscle weakness, and difficulty with concentration or attention. Toxic encephalopathy and nonconvulsive status epilepticus have been reported in patients taking doses larger than 56 mg per day.

129. Drug Interactions Tiagabine does not induce or inhibit the metabolism of other AEDs. Although it is highly protein-bound, tiagabine does not appear to displace other highly protein-bound drugs such as phenytoin, valproate, or warfarin; however, tiagabine itself is displaced from protein binding sites by naproxen, valproate, and salicylates. The clinical significance of tiagabine displacement interactions is unknown. Drugs that inhibit CYP3A4 would be expected to reduce its metabolism. However, the effect of erythromycin (a CYP3A4 inhibitor) on tiagabine metabolism is inconsistent. Until further data are available, erythromycin, ketoconazole, and other inhibitors of CYP3A4 should be used cautiously with tiagabine . Enzyme-inducing AEDs enhance the metabolism of tiagabine by 50% to 65%.

130. (10). Levetiracetam [ Lumark , Devanda , Xeticam Triacitam ] Levetiracetam is a single enantiomer that is chemically unrelated to existing AEDs. Mechanism(s) by which it exerts its anticonvulsant effect are related to its effects on zinc and glycine binding sites to beta- carboline and by binding to a synaptic vessel protein. It does not affect the binding affinity for a variety of known receptors [(e.g., benzodiazepines, GABA, glycine, NMDA (N-methyl-D-aspartate)], reuptake sites, and second messenger systems. It also does not appear to affect voltage-gated sodium or T-type calcium currents or to directly facilitate GABAnergic neurotransmission. It has been reported to oppose the activity of negative modulators of GABA-gated and glycine-gated currents in neuronal cell culture. Levetiracetam is indicated as adjunctive treatment of partial onset seizures in adults with epilepsy.

131. Formulation and Dosage Levetiracetam ( Keppra ) is available as a tablet and solution. Treatment should be initiated with a daily dose of 500 to 1,000 mg per day, given as twice daily dosing. Additional dosing increments may be given (1,000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3,000 mg. Although there is a tendency toward greater response with larger doses, a consistent increase in response to increased doses has not been shown. Dosing should be individualized in those with a CrCl less than 80 mL/min/1.73 m 2 .

132. Pharmacokinetics Levetiracetam is rapidly and completely absorbed after oral administration with peak plasma concentrations occurring in about an hour following oral administration. The tablets and oral solution are bioequivalent in rate and extent of absorption. Although food does not affect the extent of absorption, it may decrease the maximum concentration by 20% and delays the time to that concentration by 1.5 hours. The pharmacokinetics is linear and time-invariant, with low intrasubject and intersubject variability. More than half of a dose is renally excreted unchanged via glomerular filtration with subsequent partial tubular reabsorption. The major metabolic pathway of levetiracetam is an enzymatic hydrolysis of the acetamide group, and not dependent on any hepatic cytochrome P-450 isoenzyme . The metabolites have no known pharmacologic activity and are renally excreted. Studies have shown plasma half-life of levetiracetam is relatively short and is increased in the elderly and in those with renal impairment.

133. Adverse Effects Levetiracetam has not been associated with significant adverse effects. It has been noted to cause somnolence and fatigue, coordination difficulties (i.e., ataxia, abnormal gait, or incoordination), and behavioral abnormalities. Somnolence, asthenia, and coordination difficulties occurred most frequently within the first month of treatment. Although extremely rare, mood disorder, psychosis, and hallucinations have been reported. These generally occur during the first weeks of therapy and resolve after a reduction or dose or discontinuation levetiracetam. Other behavioral symptoms (e.g., aggression, agitation, anxiety, depression, emotional lability) have been reported and generally resolve when the dose is reduced or the drug is discontinued.

134. Drug Interactions Levetiracetam is unlikely to produce, or be subject to, pharmacokinetic drug interactions. Levetiracetam and its major metabolite are neither inhibitors of, nor high affinity substrates for, hepatic cytochrome P-450 isoenzymes , epoxide hydrolase, or uridine diphosphate (UDP)- glucuronidation enzymes. Levetiracetam and its major metabolite are less than 10% bound to plasma proteins; hence, clinically significant interactions with other drugs through competition for protein binding sites are unlikely.

135. Glossary Migraine: “A migraine is  a type of headache . It may occur with symptoms such as nausea, vomiting, or sensitivity to light and sound. In most people, a throbbing pain is felt only on one side of the head.” Confusional Migraine: “ ACM is  a migraine variant that manifests with acute confusion, agitation, disorientation, altered mental status, speech difficulties and memory deficits ” Basilar Migraine: “ Migraine with brainstem aura  or MBA (formerly known as basilar migraines) are headaches that start in the lower part of the brain, called the brainstem. They cause symptoms such as dizziness, double vision, and lack of coordination. ”

136. Parasomnia: “ In clinical terms, parasomnia refers to  an abnormal or unusual behavior during sleep . Parasomnias encompass a broad spectrum of events including abnormal motor, behavioral, and sensory experiences. ” Pallied Infantile Syncope: “ Pallid syncope ( reflex anoxic seizures ) Breath holding attacks are familiar to family doctors and paediatricians as non-epileptic episodes occur- ring in some infants and young children as a consequence of a physical or psychological hurt. ” Vasovagal Attack: “ Vasovagal syncope occurs when you faint because your body overreacts to certain triggers, such as the sight of blood or extreme emotional distress. It may also be called  neurocardiogenic syncope . The vasovagal syncope trigger causes your heart rate and blood pressure to drop suddenly. ”

137. Vasomotor syncope: “ Vasomotor syncope is the most common cause of syncope. It  occurs when a large proportion of blood is pooled in the legs . This causes a fall in BP, lack of blood flow to the brain, and syncope. ” Shuddering attack: “ shuddering attacks could be a variant of  benign myoclonus  of early infancy, which can present with similar movements and can also be triggered by eating and excitement. However, this condition tends to have spasmic rather than tremulous movements and generally remits by 2 years of age. ”

138. Paroxysmal choreoathetosis: “ Paroxysmal choreoathetosis (also known as paroxysmal kinesigenic choreathetosis ) is  a neurological disorder that involves episodes of unwanted, uncontrollable movements, often of the muscles in the arms, legs, face, and body . One or both sides of the body may be affected. ” Non-epileptic myoclonus: “ Myoclonus is  a sudden, involuntary jerking of a muscle or group of muscles . Some simple forms of myoclonus, like hiccups, occur in normal, healthy persons, but others can be symptoms associated with multiple diseases and conditions. ”

139. Tics: “ Tics are  sudden twitches, movements, or sounds that people do repeatedly . People who have tics cannot stop their body from doing these things. For example, a person with a motor tic might keep blinking over and over, or a person with a vocal tic might make a grunting sound unwillingly. ” Constellation: “ a set of conditions, symptoms, that fall into or appear to fall into a situation. ” Anomaly: “ a deviation from normal especially of a bodily part . ”

140. NTD: “ NTDs  occur when the neural tube does not close properly . The neural tube forms the early brain and spine. These types of birth defects develop very early during pregnancy, often before a woman knows she is pregnant. The two most common NTDs are spina bifida (a spinal cord defect) and anencephaly (a brain defect). ” Spina bifida: “ Spina bifida is  a birth defect in which an area of the spinal column doesn't form properly, leaving a section of the spinal cord and spinal nerves exposed through an opening in the back . Spina bifida occurs in 1 per 2,000 live births in the United States and is the most common central nervous system birth defect. ”

141. Paradoxical hyperactivity: “ The paradoxical effect  occurs when a medication causes side effects in direct opposition to its intended outcome  – an anti-nausea medication triggering sickness, for instance. Paradoxical drug reactions are commonplace among people with attention-deficit hyperactivity disorder (ADHD). ” Subtle: “ not immediately obvious or comprehensible. ” Morbiliform : “ Morbilliform ( measles-like ) eruptions are the most common cutaneous manifestations of drug-induced eruptions in children. In this eruption, fine erythematous macules and papules are distributed over the trunk. The rash often spreads centripetally from the trunk to the extremities. ”

142. Stevens-Johnson Synndrome : “ Stevens-Johnson syndrome (SJS) is  a rare, serious disorder of the skin and mucous membranes . It's usually a reaction to medication that starts with flu-like symptoms, followed by a painful rash that spreads and blisters. ” Exfoliative dermatitis: “ Generalized exfoliative dermatitis, or erythroderma, is  a severe inflammation of the entire skin surface . This is due to a reaction to certain medicines, a pre-existing skin condition, and sometimes cancer. In approximately 25% of people, there is no identifiable cause. ” Osteomalacia : “ Osteomalacia is  softening of the bones . It most often occurs because of a problem with vitamin D, which helps your body absorb calcium. Your body needs calcium to maintain the strength and hardness of your bones. In children, the condition is called rickets. ”

143. Frank Psychosis: “ frank psychosis in a person with positive symptoms such as hallucinations and delusions, and negative symptoms such as affective flattening (lack of spontaneity or reactivity of mood), avolition (lack of drive), anhedonia (lack of pleasure), attention deficit, or impoverishment of speech and language. ” Ataxia: “ Ataxia means  without coordination . People with ataxia lose muscle control in their arms and legs. This may lead to a lack of balance, coordination, and trouble walking. Ataxia may affect the fingers, hands, arms, legs, body, speech, and even eye movements. ”

144. Macules and Papules: “ Macule —  a small patch of skin that is altered in colour , but is not elevated . Patch — a large area of colour change, with a smooth surface. Papule — elevated, solid, palpable lesion that is ≤ 1 cm in diameter. They may be solitary or multiple. ” Urticaria: “ "Urticaria" is the medical term for  hives , which are red, itchy welts that can appear on the skin, sometimes accompanied by swelling. Hives can be caused by an allergic reaction, but some hives can appear without any known reason. ” Lymphadenopathy: “ lymphadenopathy is a swelling of the lymph nodes, usually caused by inflammation associated with a viral infection such as rubella . ”

145. Hepatomegaly: “ Hepatomegaly is an  enlarged liver , which means it's swollen beyond its usual size. ” Splenomegaly: “Splenomegaly is  a larger-than-normal spleen . The spleen is an organ in the upper left part of the belly.” Vasculitis: “ Vasculitis is  an inflammation of the blood vessels . It occurs when the immune system mistakenly attacks the blood vessels, whether because of an infection, medication, or another disease. This can limit blood flow and cause damage to organs and tissues. ”

146. Systemic lupus erythematosus (SLE): “It is the most common type of lupus. SLE is  an autoimmune disease in which the immune system attacks its own tissues, causing widespread inflammation and tissue damage in the affected organs . It can affect the joints, skin, brain, lungs, kidneys, and blood vessels.” Leucopenia: “ Leukopenia ( low white blood cell count ) happens when you have a lower-than-normal number of white blood cells. Specifically, you have fewer neutrophils than normal. Neutrophils are white blood cells that act as your immune system's first line of defense. ” Aplastic anemia: “ Aplastic anemia is  a rare but serious blood condition that occurs when your bone marrow cannot make enough new blood cells for your body to work normally . It can develop quickly or slowly, and it can be mild or serious. At this time, there is no way to prevent aplastic anemia. ”

147. Petechiae: “These are  pinpoint, round spots that form on the skin . They're caused by bleeding, which makes the spots look red, brown or purple. ” SIADH: “ Syndrome of inappropriate antidiuretic hormone ADH release (SIADH) is  a condition defined by the unsuppressed release of antidiuretic hormone (ADH) from the pituitary gland or nonpituitary sources or its continued action on vasopressin receptors . ” Encephalopathy: “ "Encephalopathy" means  damage or disease that affects the brain . It happens when there's been a change in the way your brain works or a change in your body that affects your brain. ”

148. Dyskinesia: “ Dyskinesias are  involuntary, erratic (not even or regular), writhing movements of the face, arms, legs or trunk . They are often fluid and dance-like, but they may also cause rapid jerking or slow and extended muscle spasms. They are not a symptom of Parkinson's disease (PD) itself. ” Gingival hyperplasia: “ Gingival hyperplasia is a condition that refers to  an overgrowth of your gums  (also known as your gingiva). Whereas some people have too little gums to cover their teeth, those with this condition have too much gum tissue. ” Facial Coarsening: “ Absence of fine and sharp appearance of brows, nose, lips, mouth, and chin, usually because of rounded and heavy features or thickened skin with or without thickening of subcutaneous and bony tissues. ”

149. Peripheral neuropathy: “ Peripheral neuropathy  happens when the nerves that are located outside of the brain and spinal cord (peripheral nerves) are damaged . This condition often causes weakness, numbness and pain, usually in the hands and feet. It also can affect other areas and body functions including digestion and urination. ” Hirsutism: “ Hirsutism means  the growth of excessive male-pattern hair in women after puberty . It affects facial and body areas dependent on androgens, namely mustache and beard, pubic hair, buttocks, and thighs. ” Osteoporosis: “ Osteoporosis is  a bone disease that develops when bone mineral density and bone mass decreases, or when the quality or structure of bone changes . This can lead to a decrease in bone strength that can increase the risk of broken bones (fractures). Pregnancy, Breastfeeding, and Bone Health. ”

150. Erythema multiforme: “ Erythema multiforme is  a skin disorder that's considered to be an allergic reaction to medicine or an infection . Symptoms are symmetrical, red, raised skin areas that can appear all over the body. They do seem to be more noticeable on the fingers and toes. ” Erythema necrolysis: “ Toxic epidermal necrolysis is  a life-threatening skin disorder characterized by a blistering and peeling of the skin . This disorder can be caused by a drug reaction—often antibiotics or anticonvulsants. ” Agranulocytosis: “ Agranulocytosis is  a condition in which the absolute neutrophil count (ANC) is less than 100 neutrophils per microlitre of the blood . Agranulocytosis may be acquired or inherited. It is a serious condition and can be life-threatening.  ”

151. Hydantoin Syndrome: “ Fetal hydantoin syndrome is a characteristic pattern of mental and physical birth defects that results from maternal use of the anti-seizure (anticonvulsant) drug phenytoin (Dilantin) during pregnancy. ” Paresthesia: “ “ Paresthesia ” is the technical term for the sensation of tingling, burning, pricking or itching, “pins and needles” or numbness on or just underneath your skin. It can affect places on and throughout your body and happens without an outside cause or warning. ” Fulmitant hepatitis: “ Fulminant hepatitis is a rare syndrome of rapid (usually within days or weeks), massive necrosis of liver parenchyma and a decrease in liver size (acute yellow atrophy); it usually occurs after infection with certain hepatitis viruses, alcoholic hepatitis, or drug-induced liver injury (DILI). ”