Adrenaline (Epinephrine): Action, Uses, Dosage, Administration and Side Effects

 Epilepsy and seizures

Epilepsy is defined as a group of disorders in which there are recurrent episodes of altered cerebral function associated with paroxysmal excessive and hypersynchronous electrical discharge of cerebral neurons. Each episode of neurologic dysfunction is called a seizure, which may be convulsive or nonconvulsive.

Classification of Epileptic Seizures

1. Partial Seizures

• Simple partial seizure (with motor, sensory, autonomic, psychic signs)
• Complex partial
• Partial seizure with secondary generalisation.

2. Primarily Generalised Seizures

• Absence (Petit mal)
• Tonic-clonic (Grand mal)
• Tonic 
• Atonic
• Myoclonic

3. Unclassified Seizures

• Neonatal seizure
• Infantile spasms

4. Status Epilepticus

• Tonic-clonic 
• Absence status
• Epilepsia partialis continua

5. Reflexly Induced Seizures

• Specific precipitants
• Non-specific precipitants

Precipitating Factors for Epilepsy

1. Common 

• Sleep deprivation
• Emotional stress
• Physical and mental exhaustion
• Infection and pyrexia
• Drug or alcohol ingestion or withdrawal 
• Flickering light, visual patterns ( proximity to the TV screen.)
• Hormonal changes associated with menstruation 

2. Uncommon

• Loud noise, music, hot baths, reading

Adrenaline (Epinephrine): Action, Uses, Dosage, Administration and Side Effects

Causes of Epilepsy and seizures

Generalised seizures

1. Primary (idiopathic) of genetic origin; There is a positive family history.

2. Secondary causes

• Infections

• Meningitis
• Encephalitis
• Abscesses
• Subdural empyema
• Syphilis
• Tuberculosis
• HIV
• Toxoplasmosis
• Cysts

• Vascular

• Malformations
• Aneurysms
• Infarction
• Haemorrhage

• Trauma

• Head Injury
• Birth injury

• Anoxia 

• Birth injury

• Metabolic 

• Hypocalcaemia
• Hyponatraemia
• Hypoglycaemia
• Porphyria
• Hypoxia
• Renal and hepatic failure

• Drugs and toxins

• Alcohol
• Antidepressants
• Phenothiazines
• Amphetamine
• Local anaesthetics
• Metronidazole

• Collagen vascular disease

• SLE
• Sarcoidosis

• Tumours

Clinical Features of Epilepsy

Partial Seizures: can be simple or complex

1, Simple Partial Seizures

• Motor: Seizure starting in one part of the body and spreading gradually to involve the whole side is known as Jacksonian epilepsy. Paresis or paralysis of muscles of affected limb lasting for several hours after prolonged episodes of seizures is known as Todd's palsy is a sign of focal origin of seizure activity.

• Sensory: Seizure is perceived as a tingling or electric sensation in the contralateral face and limbs.

• Versive: Forced deviation of the eyes to the opposite side due to frontal epileptic focus (frontal eye field).

• Visual: Occipital epileptic focus causing visual hallucinations.
• Psychomotor
• Seizure manifests as alteration of mood, memory and perception (arise from medial temporal lobe).
• It is a common form of seizure to produce both partial and secondary seizures.
• Simple partial temporal lobe seizures produce disorder of perception.
• Undue familiarity (deja vu)
• Unreality ( jamais vu)
• Complex hallucination of sound, smell, taste, vision.
• Emotional changes
• Visceral sensations like nausea, epigastric discomfort can occur.

2. Complex Partial Seizures

• Preceded by aura (lasting for seconds or minutes)
• Loss of awareness (lasting for several minutes)
• Patient may stare and be unresponsive to questions
• Automatic movements ( lip-smacking, swallowing)

Generalised Seizure (Grand mal)

This is common form of epilepsy. It consists of:

• Prodromal Phase
• Several hours or days
• Aura
• Seconds or minutes
• Tonic Phase
• 10-30 seconds
• Clonic Phase
• 1-5 minutes
• Post-ictal phase
• a few minutes to hours

Classic Absence (Petit mal)

This is an uncommon form of epilepsy and is mostly seen in children. Child suddenly stops activity, stares, may blink, roll up the eyes and fail to respond to commands. The attack lasts for only a few seconds.

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Reflexly Induced Seizure

It can occur sporadically or randomly with or without apparent triggering pattern.

With specific precipitants

• Photomyoclonic or photoconvulsive epilepsy (triggered by photic stimulation)
• Musicogenic epilepsy ( triggered by specific musical compositions)
• Somatosensory induced epilepsy ( tactile stimulation)
• Reading or language epilepsy (induced by reading)
• It usually consist of brief myoclonic jerks of the jaw, cheek and tongue which can occur during silent/oral reading and may progress to generalised tonic-clonic convulsion.

 Investigations for Epilepsy and seizures

1. Routine tests (blood urea, sugar, serum creatinine, electrolytes)

2. Liver Function Tests

3. Tests for syphilis and HIV

4. ECG

5. EEG

• Routine
• Sedated
• 24-hour ambulatory ECG or EEG.

6. CT scan: It is indicated in the following conditions

• Epilepsy starting after the age of 20 years
• Clinical evidence of focal features of seizures (in all ages)
• EEG evidence of focal seizure
• Uncontrollable seizures or deterioration of clinical conditions
• Change in the pattern of epilepsy in a known epileptic.

7. MRI: It is superior to CT in scanning for the detection of cerebral lesions associated with epilepsy.

8. PET/SPECT: Used in the evaluation of patients with medically refractory seizures.

9. Magnetic Encephalography (MEG)

• Non-invasive
• To measure magnetic field produced by seizure activity
• These source estimates can then be plotted on an anatomic image of the brain such as an MRI, to generate a magnetic source imaging to locate seizure foci.

Treatment and Management of Epilepsy

Immediate Treatment

• Keep the patient away from danger (fire, water, machinery)
• Keep the airways clean and turn the patient to semi-prone position.
• Keep a padded gag or rolled handkerchief between the teeth to prevent tongue bite.

Principles of Anticonvulsants

• Begin with a single drug in a small dose and increase gradually over a period of 4-6 weeks.

• The drug dosage should be adjusted with the minimal level of the therapeutic range in uncontrolled seizures.

• Try 3 single drugs individually before changing into drug combination.

• During the change to new drug, the initial drug may be gradually reduced.

• The withdrawal of drug may be considered after 2-4 years of complete control of seizures.

• Absence seizure in childhood carries good prognosis for successful drug withdrawal.

• To withdraw anticonvulsants in adults is to decrease the dose by 10% every four weeks for carbamazepine, phenytoin, and valproate and by 10% every eight weeks for phenobarbitone, benzodiazepines and ethosuximide.

Anticonvulsants Medication Dosage

Phenytoin

• Dosage: 300-400 mg/day or 3-5 mg/kg
• Side Effects: Ataxia, in-coordination, confusion, cerebellar signs, skin rashes, gum hyperplasia.
• Uses: Tonic-clonic (grand mal), partial seizures.

Carbamazepine

• Dosage: 600-1200 mg/day or 20-30 mg/kg
• Side Effects: Ataxia, dizziness, diplopia, vertigo, bone marrow suppression, gastrointestinal irritation, hepatotoxicity.
• Uses: Tonic-Clonic (grand mal), partial seizures.

Phenobarbitone

• Dosage: 60-120 mg/day or 1-5 mg/kg body weight
• Side Effects: Sedation, ataxia, confusion, dizziness, decreased libido, depression and skin rashes.
• Uses:  Tonic-Clonic (grand mal), partial seizures.

Primidone

• Dosage: 750-1000 mg/day (10-25 mg/kg)
• Side Effects: Sedation, ataxia, confusion, dizziness, decreased libido, depression and skin rashes.
• Uses:  Tonic-Clonic (grand mal), partial seizures

Sodium Valproate

• Dosage: 750-1250 mg/day (30-60 mg/kg)
• Side Effects: Ataxia, sedation, tremor, hepatotoxicity, bone marrow suppression, gastrointestinal irritation, alopecia and hyperammonemia
• Uses: Absence seizures (typical & atypical), myoclonic seizures.

Felbamate

• Dosage: 3600 mg/day
• Side Effects: Insomnia, headache, dizziness, gastrointestinal irritation, nausea, anorexia.
• Uses: Partial, secondarily generalised seizures.

Ethosuximide

• Dosage: 750-1250 mg/day (20-40 mg/kg/day)
• Side Effects: Ataxia, lethargy, GI irritation, skin rash, bone marrow suppression
• Uses: Absence (petit mal) seizures

Clonazepam

• Dosage: 1-12 mg/day ( 0.1-0.2 mg/kg/day)
• Side Effects: Ataxia, sedation, lethargy, anorexia.
• Uses: Absence (typical & atypical)

Lamotrigine

• Dosage: 300-500 mg/day
• Side Effects: Headache, dizziness, ataxia, diplopia, skin rash, nausea.
• Uses: Partial seizures.

Gabapentine

• Dosage: 900-1200 mg and up to 2400 mg
• Side Effects; Dizziness, somnolence, ataxia, GI irritation
• Uses: Partial seizures.

Topiramate

• Dosage: 400 mg/d BD
• Side Effects: sedation, speech problem, paraesthesia, 
• Uses: Partial, tonic-clonic

Tiagabine

• Dosage:30-60 mg/d BD-QID  
•  Side Effects: sedation, speech problem, paraesthesia, psychosis
• Uses: Partial, tonic-clonic, Lennox-Gastaut syndrome

Levetiracetam

• Dosage: 1-3 g/d BD
• Side Effects: Sedation, incoordination, psychosis, anaemia, leukocytopenia.
• Uses: Partial

Zonisamide

• Dosage: 200-800 mg/d
• Side Effects: sedation, confusion, anorexia, renal calculi.
• Uses: Partial

Oxcarbazepine

• Dosage: 900-2400 mg/d BD
• Side Effects:  Ataxia, dizziness, diplopia, vertigo, bone marrow suppression, gastrointestinal irritation, hepatotoxicity.
• Uses: Partial

Drugs of Choice in Seizure Disorder

Primary generalised Tonic-Clonic 

• First Line: Valproic acid, Lamotrigine, Topiramate
• Alternatives: Phenytoin, Carbamazepine, Primidone, Phenobarbitone, Felbamate

Partial

• First Line: Carbamazepine, Phenytoin, Valproic acid, Lamotrigine, Oxcarbamazepine
• Alternatives: Gabapentin, Topiramate, Tigabine, Primidone, Phenobarbitone

Absence

• First Line; Ethosuximide, Valproic acid
• Alternatives: Lamotrigine, Clonazepam

Atypical absence myoclonic, atonic

• First Line: Valproic acid, Lamotrigine, Topiramate
• Alternatives: Clonazepam, Felbamate

Ectopic pregnancy: Causes, Symptoms, Diagnosis, and Complications

Precautions after the Seizure Attack

• Avoid cycling and swimming until at least 6 months of freedom from seizure (Driving is allowed after 2 years of good control of seizure)
• Swimming should be always in the company of someone who is aware of his seizure disorder.
• Avoid activity in places where communication is difficult (mountaineering).

Treatment of Refractory Epilepsy

Vagus nerve stimulation

This involves the placement of a bipolar electrode on the mid-cervical portion of the left vegus nerve. The mechanism of action may be the stimulation of vagal nuclei leading to activation of cortical and subcortical pathways and an associated increased seizure threshold.

Surgery

Temporal lobectomy and lesionectomy can be done. Hemispherectomy and stereotactic radio surgery can also be useful in some cases.

Status Epilepticus

It is defined as a state in which the patient suffers a series of seizures without fully recovering consciousness between these seizures.

Duration: 15-30 minutes.

Classification of Status Epilpticus

1. Convulsive status

• Generalised tonic-clonic status
• Partial ( Epilepsia partialis continua)

2. Nonconvulsive status

• Absence status
• Complex partial seizures ( psychomotor)
• Prolonged convulsive seizures lasting for 30 minutes should also be treated similarly.
• Nonconvulsive status and convulsive status of brief duration do not warrant aggressive combination drug therapy, In the above situations, single anticonvulsant and supportive measures may be adequate.

Precipitating Factors

1. Structural Abnormalities

• Trauma
• Tumours
• Central nervous system infections
• Cerebrovascular disorders.

2. Nonstructural Abnormalities

• Hypoglycaemia
• Hyperglycaemia (Nonketotic hyperosmolar coma)
• Hyponatraemia
• Hypocalcaemia
• Uraemia
• Anoxia
• Alcohol
• Sedative drug withdrawal
• Drug intoxication  (theophylline, amphetamine, INH).

Most common cause in children in-- Ideopathic

Most common cause in adults-- noncompliance or subtherapeutic level of anticonvulsants.

Causes of Status Epilepticus

• Abrupt withdrawal of antiepileptic drugs in a known epileptic patient.
• Cerebrovascular disease due to venous thrombosis
• Meningoencephalitis
• Metabolic disturbance
• Alcohol withdrawal
• Hypertensive encephalopathy

Complications of Status Epilepticus

• Anoxia
• Hyperthermia
• Acidosis
• Hypoglycaemia
• Cardiac dysrhythmias
• Reflex pulmonary oedema
• Rhabdomyolysis
• Myoglobinuria
• Aspiration pneumonia
• Shock

Treatment and Management of  Status Epilepticus

• Maintenance of airway, breathing and circulation.

• Routine tests for blood ures, sugar, creatine, and electrolyte.

• Inj Lorazepam 0.1 mg/kg at 2 mg/min, up to 4 mg or inj Diazepam 0.2 mg/kg at 5 mg/min, up to 10 mg. It can repeated after 5 minutes.

• Administration of long-acting anticonvulsants like inj Phenytoin 20 mg/kg as loading dose, followed by a maintenance dose of 5-10 mg/kg at 50 mg/mt, given via glucose free IV fluid to avoid precipitation in the tubing. Watch for arrhythmias.

• Wait for 15-20 min, if seizure continues give inj Phenobarbitone 20 mg/kg at the rate of <50 mg/min. If the seizures are still uncontrolled, additional dose of 5-10 mg/kg may be given. Watch for arrhythmias and hypotension.

• In some patients, continous Diazepam infusion is preferred. IV infusion can be given at a rate of 10-50 mg/hr in an IMCU set-up with respiratory support.

• If seizures still persist general anaesthesia with neuromuscular blockade is required (IV midazolam, pentobarbital).

• Once the status has been successfully treated, causative factors are identified and managed and anticonvulsants are maintained.( phenytoin 4-7 mg/kg/d, Phenobarbitone 1-5 mg/kg/d IV or oral BD).

Epilepsy in Pregnant Women

Epilepsy in pregnant women is a special situation where the following guidelines may be observed.

• 50% - No alteration of seizure frequency
• 30% -Seizure frequency increases
• 20%- Seizure frequency decreases

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Guidelines for Counseling Women With Epilepsy Who Plan Pregnancy

• The risk of major malformations, minor anomalies, and dysmorphic features are two-fold to three-fold higher in infants of mothers with epilepsy who receive treatment with AEDs compared with the risk in infants of mothers without epilepsy.

• A possibility exists that some of the risks is caused by a genetic predisposition for birth defects inherent in certain families. Both parents family histories should be reviewed for birth defects.

• Possibilities for prenatal diagnosis of major malformations should be discussed. If valproate or carbamazepine is the necessary AED, the likelihood of amniocentesis and ultrasound examinations during pregnancy should be discussed. Ultrasound examination for a variety of major malformations can be done during 18-22 weeks.

• Effects of tonic-clonic seizures on the fetus during pregnancy are not well established. However, tonic-clonic convulsions might be deleterious to the fetus, injure the mother, and lead to miscarriage.

• The diet before conception should contain adequate amounts of folate.

• If the patient is seizure-free for at least 2 years ( e.g. free from absences, complex partial, or tonic-clonic attacks), withdrawal of AED should be considered. 

• If AED treatment is necessary, a switch to monotherapy should be made if possible.

• The lowest AED dose and plasma level that protects against tonic-clonic, myoclonic, absence, or complex partial seizures should be made if possible. Closed-circuit television electroencephalographic monitoring should be used if necessary.

Guidelines for Antiepileptic Drug (AED) Use During Pregnancy

• Use the first-choice drug for seizures type and epilepsy syndrome.

• Use AED as monotherapy at the lowest dose and plasma.

• Avoid valproate and carbamazepine when there is a family history of neural tube defects.

• Avoid polytherapy, especially the combination of valproate, carbamazepine, and phenobarbital.

• Monitor plasma AED levels regularly and, if possible, free or unbound plasma AED levels.

• Continue folate daily supplement, and ensure normal plasma and red cell folate levels during the period of organogenesis in the first trimester.

• In cases of valproate treatment, avoid high plasma levels of valproate. Divide doses over 3-4 administrations per day.

• In cases of valproate or carbamazepine treatment, offer amniocentesis for ∝-fetoprotein at 16 wk and real-time ultrasonography at 18-19 wk, looking for neural tube defects. Ultrasonography at 22-24 wk can detect oral clefts and heart anomalies.

• Folate supplementation (1-4 mg)/ day is essential.

References: Alagappan medicine