Status epilepticus sign and symptoms, etiology ,pathogenesis , diagnostic tests and treatment protocol

1.  STATUS
EPILEPTICS
Dr Jaind khan
PHARM-D
Pharmaceutical science
University of sindh

2. CONTENTS
STATUS EPILEPTICUS
1: Introduction of Status Epilepticus
2: Sign and symptoms
3: Etiology
4: Pathogenesis
5: EEG pattern & interpretation
6: Diagnostic tests and their interpretation
7: Detailed Treatment protocols for management of status epilepticus (Describe each drug
in detail)
8: Protocols for prevention of episodes of status epilepticus
9: Role of clinical pharmacists in management of status epilepticus
10: Role of pharmacist to prevent the episodes of status epilepticus

3. INTRODUCTION
Status epilepticus (SE) is a medical emergency associatedwith significant morbidity,it is a
common neurologic disorder , (SE) one of the a life threatening condition .
In that requires emergency care mostly consisting of parentral administration of a fast
acting agents like Benzodiazepine, over slower acting agents such as phenytoin,
fosphenytoin,divalproex and levetiracetam.
Status epilepticus usually three types includes Focal seizure , myoclonic seizure,
generalized tonic–clonic seizure (GTCS) , generalized tonic clonic seizure is a common
types of status epilepticus .
Status epilecpticus:
Continuous seizures or repetitive discrete seizures with impaired or harm consciousness ,
( seizures more then 5 minutes in duration ).
OR
Continuous seizures activity lasting for more then five minutes without returning to
normal .
Classified in
Convulsive status epilepticus. This type occurs with convulsions. It may be more likely to
lead to long-term injury. Convulsions may involve jerking motions, grunting sounds,
drooling, and rapid eye movements.
Nonconvulsive status epilepticus. People with this type may appear confused or look like
they're daydreaming. They may be unable to speak. They may also behave in an irrational
way.
If repetitive seizure s consciousness is not regained between.
most frequently status epilepticus due to anticonvulsant withdrawal ,metabolic disorder ,
drug toxicity central nerves systeminfection ,tumor, head trauma et cetera .

4. CLINICAL FEATURES
increase sympathetic activity
Hyperthermia( rise body temperature ) >98.6F*.
Tachycardia (rise heart rate ) >100 per min.
Hypertension (rise blood pressure )>140/90mmHg.
SYMPTOMS OF STATUS EPILEPTICUS
Muscle spasms( contraction in muscle)
Falling (moving from a higher to a lower level, typically rapidly and without control)
Confusion
Unusual noises
Loss of bowel or bladder control
Clenched teeth (Clenching is simply holding the teethtogether and tightening the jaw
muscles.)
Irregular breathing
Strange behavior
Trouble speaking.
ETIOLOGY
*Low level of automated external defibrillator (AED)
An automated external defibrillator (AED) is a portable electronic device that
automatically diagnoses the life-threatening cardiac arrhythmias of ventricular fibrillation
(VF) and pulseless ventricular tachycardia, and is able to treat them through defibrillation.
*Stroke
*Alcohol withdrawal
*Anoxic brain injury and remote brain injury

5. *Metabolic disturbance
*infections ( viral or bacterial exp.. Meningitis)
*Brain neoplasms (Brain tumors )
*idiopathic ( UNKNOWN CAUSE OF DISEAS ) disease or condition which arises
spontaneously or for which the cause is unknow.
in children, the main cause of status epilepticus is an infection with a fever.
PATHOGENESIS
Mechanism of status epilepticus
Clinical and experimental studies have appear that Status epilepticus progress through
an initiation phase to a maintenance phase.
In the initiation phase the Activate stimuli give rise to discrete seizures that tend to abate
as soon as the stimulus is removed.
In the subsequent maintenance phase discrete seizures combine together into a continuum,
with activate stimuli no longer required to sustain a train of seizures.
The intensity and duration of the stimulation has a direct influence on the transition from
the initiation phase to the maintenance phase.
A variety of signaling molecules such as GABA-A (γ-aminobutyric acid) antagonists,
glutamate agonists, cholinergic (muscarinic) agonists, tachykinins, galanin antagonists, and
opiate k antagonists have been found to be involved in the initiation phase.
In contrast to this, much less is known about the maintenance phase. In fact only a limited
number of molecules have been found that block the maintenance phase (e.g., NMDA and
Ampa (N-methyl-D aspartate) antagonists, substance P antagonist, galanin, and
dynorphin)
The adaptation of a single seizure to Status epilepticus depends on several factors.
In experimental electrogenic Status epilepticus , at least 30 min of stimulation is required to
produce self-sustained SEtus epilepticus .

6. The limbic system is clearly at increased risk for injury during Status epilepticus and, due
to its nature and connections with the rest of the brain, it may play a crucial role in
generating seizures, it has prevents excitatory stimulation from spreading through the
hippocampus until a point of maximal dentate activation is reached.
Once this point is increase, excitatory inputs can spread through the hippocampus and
may then propagate to involve widespread neocortical areas.
It is likely that ineffective recruitment of inhibitory neurons, together with excessive
neuronal excitation, plays a role in the initiation and propagation of the electrical
disturbance occurring in Status epilepticus .
GABA is the major inhibitory neurotransmitter in the CNS, It is releasedfrom GABAgic
neurons and binds to several types of GABA receptors such as , GABA-A (GABA type A),
GABA-B, and GABA-C receptors.
GABA receptors are macromolecular proteins that form a chloride ion channel complex
and contain specific binding sites for GABA and a number of allosteric ( modified the
shape of protein) regulators. including barbiturates, benzodiazepines, and a number of
anesthetic agents.
GABA receptor–mediated inhibition may be responsible for the normal termination of a
seizure.
the activation of the NMDA receptor by the excitatory neurotransmitter glutamate may be
required for the propagation of seizure activity.
The activation of NMDA receptors results in enhance or increase the levels of intracellular
calcium, which may responsible for the nerve cell injury seenin patients with Status
epilepticus .
This phenomenon has important clinical suggestion . Benzodiazepine-like drugs, which
potentiate GABAergic inhibition, have an important role in the early initiation phase of
Status epileptics but they may prove ineffective in the advanced stages of SE.when NMDA
antagonists have the potential to be beneficial. Prolonged epileptiform bursting results in a
reduction of GABA-mediated synaptic inhibition.
*Reversible post-translational modification of proteins (Protein phosphorylation )
In early stage of millisecond or second ,Ions channels opening and closing
neurotransmitter release .
*Receptor trafficking
Second stage of second minutes Reduce the level inhibitory Gama amino butyric
acid (GABAA) neurotransmitter and beta2 and gama subunit effects to reduce the
GABAergic activity in the cell effected in the seizures discharge .

7. Increase in excitatory N-methyl-D-aspartate receptor (NMDA receptor) and α-
amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor AMPA receptor .
*Neuropeptide Expression
In third stage of minutes hours At this stage increase the level of excitatory
substances p.
Alteration in neuropeptide expression in status epilepticus
Hippocampus
It is a type of brain which control the loss of memory .
Example (in hippocampus decrease in inhibitory piptides, dynorphin
,Galanin,somatostatin and neuropeptide Y. and increase in proconvulsant
tachykinins ,substance P ( is an undecapeptide (a peptide composed of a chain of 11
amino acid residues) member of the tachykinin neuropeptide family.
It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator.and
neurokinin B (Neurokinin B belongs in the family of tachykinin peptides.
Neurokinin B is implicated in a variety of human functions and pathways such as
the secretion of gonadotropin-releasing hormone. Additionally, NKB is associated
with pregnancy in females and maturation in young adults
Insufficient renewal inhibitory neuropeptide Y.
Genetic and epigenetic modification
Gene expression
at the fourth stage of days weeks Gene expression is the process by which
information from a gene is used in the synthesis of a functional gene product. These
products are often proteins, but in non-protein-coding genes such as transfer RNA
or small nuclear RNA genes, the product is a functional RNA.
Gene methylation
Process in which CH3yl groups added to DNA molecules, it can alter the activity of
a DNA segments without changing the sequence .
Tuning or regulation microRNA.

8. ELECTROENCEPHALOGRAM (EEG) INTERPRETATION
Below terms to express (EEG) patterns in status epileptics :
POSITION: generalized (including bilateral synchronous patterns )lateralized,
bilateral free multifocal .
NAME OF THE PATTERNS : periodic discharge rhythmic delta activity or spike
and wave ,sharp and wave pulse sub type.
MORPHOLOGY : sharpness numbers of phases like (triphasic morphology)
absolute and relative amplitude ,polarity .
TIME RELATED FEATURES OR CHARACTERISTIC:
prevalence ,frequency ,duration daily patterns duration and index onset
(sudden verses gradual ), and dynamics(evolving, fluctuating or static or rest)
MODULATION : stimulus induced vs, spontaneous.
EFFCT OF INTERVENTION : medication on Electroencephalogram (EEG)
STANDARD OR CARITERIA FOR NON-CONVULSIVE SEIZURES
Some patterns lasting at least 10 seconds satisfying any one of the following criteria.
Primary: a) focal spikes , sharp waves, spike and wave or sharp and slow wave
complexes or repetitive generalized at greater -3 per second .
b) repetitive generalized or focal spikes , sharp waves, spike and wave or sharp
and slow wave complexes at less then 3 per second and secondary criterion.
c) Sequential rhythmic periodic or quasi periodic wave at greater – 1per second and
unequivocal evolution in frequency morphology or position .
.
Secondary: a) significant improvement in clinical state or appearance of
previously absent normal EEG patterns such as posterior dominant rhythm
temporally coupled to acute administration of a fast acting automated external
defibrillator (AED).

9. b) Resolution of the epileptiform discharges , leaving diffuses slowing without
clinical improvement and without appearance of previously absent normal EEG
patterns , would not Satisfy the secondary criterion .
DIAGNOSTIC TESTS AND THEIR INTERPRETATION IN (SE)
The diagnostic examination should be done one the patient is stabilized and appropriate
pharmacotherapy for Status epileptics is initiated .
DIAGNOSTIC THRASH (OUT) OR WORKUP ALL PATIENTS
Monitor vital signs ABC
get intravenous access
Head CT Scan (Computerized Tomography)appropriate for most cases )
Laboratory Blood glucose ,
renal function tests
, test for electrolytes
,AED level ,
Continuous EEG (cEEG)monitoring .
Examination based on clinical presentation
Brain MRT(Magnetic resonance imaging)
Lumber puncture , Toxicology panel ( examples isoniazid (TCAs) Theophylline
cocaine sympathomimetic organophosphates, cyclosporine )

10. DETAILED TREATMENT PROTOCOLS FOR MANAGMENTS OF STATUS
EPILEPTICUS (EXPLAIN EACH DRUG IN DETAILS)
The first line of therapy in status epileptics are Benzodiazepines
MOA: mechanism of action
These drugs bind to the gamma-aminobutyric acid (GABA)-A receptors, increasing
channel opening central ion channels at the receptor, result influx of chloride conductance
and neuronal hyper polarization, leading to enhanced inhibitory neurotransmission and
antiepileptic action
Lorazepam (Intravenous (IV) and Intranasal (IN)
Lorazepam can be administered either intravenously or intranasally, although to date most
evidence in the treatment of Status epileptics refers to its IV use.
Although it has a longer initial duration of action than diazepam, lorazepam administered
intravenously is usually preferred as initial treatment of early Status epileptics , because it
is less lipid-soluble and consequently does not undergo the rapid redistribution into
peripheral tissues seenwith diazepam. lorazepam long therapeutic half life anti seizures
effects 6 to 12 hours , 2mg dose uptoa max dose of 8mg in total .
Dose 0,1-0.5mg/kg iv upto 4-6mg over 1-2 minutes
If Status epileptics persists repeat every 5 to 10 minutes
Diazepam (IV, Rectal) Diazepam is a highly lipophilic benzodiazepine, which rapidly
enters into the brain but subsequently is rapidly redistributed into peripheral tissues.
The pharmacokinetic property of Diazepam is responsible for its fast anticonvulsant effect
in spite of its longer elimination half-life.
Diazepam can be administered either intravenously or rectally, with demonstrated
significantly higher efficacy over placebo in terms of controlling acute repetitive convulsive
seizures in adults and children for both methods of administration.
Dose -10mg iv push over 30-60 seconds
Repeat after 10-15 mins upto 40mg (5mg/min)

11. Repeat after2-4 hours (max 100mg/day)
Bolus dose should be given undiluted from at rate not exceeding 2-5mg per minutes
Midazolam (IV, Intramuscular (IM), Intranasal, Buccal)
Midazolam is a benzodiazepine with the advantage of multiple routes of administration,
due to its water solubility.
At physiologic pH the ring structure of midazolam closes and it becomes highly lipophilic,
crossing the blood-brain barrier rapidly midazolam administered intravenously was found
to be similar in terms of seizure recurrence to IV diazepam or IV lorazepam in a pediatric
non-randomized, controlled trial, with no significant differences in mean duration to
clinical seizure cessation.
Dose 10mg intramuscularly
Common ADRS They include drowsiness, dizziness, and decreased alertness and
concentration. Lack of coordination may result in falls and injuries, in particular, in the
elderly.
Second stage Phenytoin and Fosphentoin
MOA
These antiepileptic drug blockade the voltage gated sodium channels by selectively binding
to the channels in the inactive state and showing recovery ,it is effective for treatments of
focal and generalized tonic clonic seizures and status epilepticus .
Phenytoin: extravasations purple glow syndrome .
Dose 20mg per kG body weight .
Fosphentoin: prodrug more water soluble non irritating .

12. 20mg prt kG body weight .
Barbiturates
Phenobarbital (IV, IM)
MOA
These drugs potentiate GABA action on chloride entry into the neuron by prolonging the
duration of the chloride channel openings , addition barbiturates blockade excitatory
glutamate receptor ,these molecular action lead to decreased neuronal activity .
In a randomized, controlled trial on CSE, IV phenobarbital was at least as effective as a
combination of diazepam and phenytoin.
The central depressive effect of phenobarbital, especially following the use of
benzodiazepines, limits its clinical utility, when alternatives are available. However, over
the years wide experience has been gained in adults and children, as well as in the
newborn. These drug produce respiratory and CNS depression .
Dose 20mg per kg, 100mg per minute
Common ADRS Dizziness.Drowsiness.Fatigue.Nausea.Tremor.Rash.Weight gain.
Valproic Acid (IV)
MOA
This drug is a also anticonvulsant effect has been attributed to the blockade of voltage-
gated sodium channels and increased brain levels of gamma-aminobutyric acid (GABA).
Dose 20-40mg per kg continuous infusion 1-5 mg per kg per hours

13. Levetiracetam (IV)
Levetiracetam is an efficacious and well tolerated drug with a broad spectrum of efficacy
against all seizure types and a low potential for interactions due to minimal hepatic
metabolism and low plasma protein binding.
The safety profile of levetiracetam is advantageous, with a very low rate of adverse effects
reported (most often somnolence and sedation, and rarely agitation and
thrombocytopenia)( is a condition in which you have a low blood platelet count)
MOA
Levetiracetam exhibit anticonvulsant activity it binds and modulate synaptic vesicle
glycoprotein 2A (SV2A) in the brain .
(SV2A) is a protein expressedin neurons and endocrine cells and involved in the regulation
of neurotransmitter release)
Dose 30-60mg per kg
Lacosamide (IV)
This is anticonvulsant drug which decrease the irregular electrical activities in brain.
It generally used bolus dose 400 mg, followed by a daily dose of 200–400 mg.
MOA
There are multiple mechanism of action of locosamide , it affects voltage gated sodium
channels resulting in stabilization of hyper-excitable neuronal membranes and inhibition
of repetitive neuronal shooting.
Dose bolus dose was 200-400mg over 3-5 minutes
Maintenance dose 100mg (BD) twice a day.
Common ADRS sedation Dizziness.Drowsiness.Fatigue.Nausea.Tremor.Rash.Weight gain.

14. OTHER AGENTS USED IN STATUS EPILEPTICUS
Propofol , iv
Propofol is an anesthetic agent, acting as an N-methyl-D-aspartate (NMDA) antagonist in
vitro, with a shorter duration of action and lower tendency to accumulate in the body than
barbiturates.
It may cause hypotension, but reduces intracranial pressure and brain metabolic
requirements, no difference was found between the drugs with respect to control of seizure
activity .
MOA
These anesthetic drug which increasing GABA-mediated inhibatory tone in the CNS,
It reduce the rate of dissociation of the GABA from the receptor, thereby increasing the
duration of the GABA-activated,opening of the chloride channel with resulting hyper
polarization accurse in cell membranes.
Dose intravenous loading dose of 3mg per kg although 3-5mg per kg .1-2mg per kg load iv.
Infusion 1-15mgper kg per hours .
Ketamine (IV infusion)
Ketamine has a strong antagonistic effect on the NMDA-glutamate receptor. It has a half-
life of 2–3 h and is extensively metabolized by the hepatic cytochrome P450 pathway to its
active metabolite, norketamine.
MOA
It is a antagonist for the NMDA receptors and inhabit the excitatory signals that are
found in nerve cells. These receptors are involved in processing central nervous system
input.
Ketamine blocks this sensory input. This action is what accounts for most of the effects
seenfrom ketamine.
Dose 1.5-4.mg per kg in iv load and 2.75.5mg per kg/hours .
Common ADRS
High blood pressure (hypertension) Increased cardiac output
Increased intracranial pressure Fast or slow heart rate Involuntary eye movement.

15. Protocols for prevention of episodes of status epilepticus
Treatment should begin immediately with a benzodiazepine. Use lorazepam 0.1 mg/kg IV
or midazolam 0.2 mg/kg IM.
Avoid giving midazolam IV because this is more likely to cause respiratory arrest and force
endotracheal intubation upon a patient who might not have required it.
Guidelines for the treatment of status epilepticus Treatment should begin immediately
with a benzodiazepine. Use lorazepam 0.1 mg/kg IV or midazolam 0.2 mg/kg IM.
Avoid giving midazolam IV because this is more likely to cause respiratory arrest and force
endotracheal intubation upon a patient who might not have required it.
Immediately after an appropriate dose of benzodiazepine is given, obtain medications
necessary to support the patient if they develop respiratory failure or hypotension. This
involves preparing medications for endotracheal intubation .
Refractory status epilepticus Refractory status epilepticus is treated with general
anesthesia and mechanical ventilation.
If a patient have epilepsy, taking your medicines as directed may help him prevent status
epilepticus. If patient had status epilepticus, patient may need to begin taking seizure
medicines or change medicines patients already taking. Avoiding other causes of this
condition, such as alcohol abuse or low blood sugar, may also help prevent it.
The healthcare provider will want to end the seizure as quickly as possible and treat any
underlying problems that are causing it. you may receive oxygen, have blood tests, and an
intravenous (IV) line. you may be given glucose (sugar) if low blood sugar may be causing
the seizure.
Status epilepticus has many causes. Some can be prevented such as low blood glucose or
alcohol and drug abuse.
Individuals who have epilepsy must take their medicine as directed.
A seizure that lasts more than 5 minutes, or having more than 1 within a 5 minute period is
an emergency that requires immediate medical care.
healthcare providers suggest to give protocol as use anti-seizure medication for prevents
the problem, including.
Diazepam,Lorazepam ,Phenytoin ,Fosphenytoin ,Phenobarbital ,Valproate ,Levetiracetam
,Lacosamide ,Propofol , Ketamine.gabapenten also.

16. Role of clinical pharmacists in management of status epilepticus
analyzed the effectiveness of clinical pharmacists in improving medical records and patient
with status epilepticus .compliance with outpatient drug regimens.
Records of patients followed up in a SE and were reviewed and compared with their
pharmacy files.
Records were evaluated for completeness and accuracy of drugs ordered by the clinic
physician.
Compliance was estimated by examining drug refills.
This review was performed before (control group) the introduction of a clinical pharmacist
into the clinics.
A six-month analysis demonstrates that the pharmacist significantly improved drug
documentation,
decreased the duplication of prescriptions, and improved compliance of prescribed drugs.
The study suggests that the pharmacist improves documentation of drug therapy and
estimated patient compliance .
the decrease in duplicate prescriptions could prevent the risk of overdose and does reduce
drug costs.
Our review indicates that pharmacists are involved in the following clinical activities for the
cprevention of patient with status epileptic :
A ) Therapeutic drug monitoring
b ) medication review
c) pharmacotherapeutic d ) pharmaceutical counseling,
f) systematic measurement and evaluation of health results from the drug treatment.

17. Role of pharmacist to prevent the episodes of status epilepticus
Status epilepticus is a chronic disorder that continues to be a huge economic burden.
Although newer AEDs aim to increase treatment success and decrease the risk for adverse
effects, there is still a strong need for improving patient outcomes.
Pharmacists can play a significant role in optimizing therapy for patients with SE.
1: Patient counseling on the potential adverse effects of AEDs is important.
2: Patients and family members should be educated on expectedCNS and cognitive side
effects, potential skin reactions, and the risk for suicidal behavior
3: Patient education should also address the importance of medication adherence.
4: Patient medication profiles should be reviewed for possible drug interactions,
and dosage adjustments or alternative agents should be recommended if necessary.
5: Additionally pharmacists can advise clinicians on appropriate therapeutic drug
monitoring..
Its treatment is complex and may involve the use of antiepileptic drugs (AEDs), a special
diet, immunotherapy, and neurostimulation.
pharmacists are important health professionals in counseling and monitoring patients with
status epileptics, because they are easily accessible and know about pharmacotherapy,
health education, and management of chronic diseases .
pharmacist can detect the emergence of health problems and can help prevent the
progression of comorbidities.
pharmacists evaluated medication use, identified therapeutic problems, and proposed
changes in prescriptions to a health team, when the pharmacotherapy was not appropriate.
Thus, pharmacists performed pharmaceutical counseling and pharmacotherapeutic
follow-up, as well as systematic measurement and development of results.
pharmacists provided guidance to ensure the adequacy of the pharmacotherapy through
therapeutic drug monitoring.