Seizures and Epilepsy
Let’s begin by discussing general points about Seizures and Epilepsy:
•
Incidence of epilepsy: 40 /100,000 children / yr
•
About 1 % of children will have at least one afebrile seizure by age 14 yrs
•
0.4 %-0.8 % (4/1000- 8/1000) will have epilepsy by age 11 yrs
•
Epilepsy is the most common neurologic problem in childhood
Now how can we differentiate between seizures and epilepsy?
•
A seizure is a sudden, involuntary, time-limited alteration in neurologic function
(movement, behavior) secondary to abnormal discharge of neurons in the CNS
•
Epilepsy is a chronic condition characterized by 2 or more unprovoked seizures.
Therefore we have recurrent seizures. In some textbooks it is stated as 2 attacks of
unprovoked seizures and in others it is stated as 3 or more attacks of unprovoked
seizures.
Epilepsy is considered as a clinical diagnosis. Therefore when someone has 2-3
attacks of unprovoked seizures (not precipitated by fever, hypocalcaemia,
hypoglycemia, etc) this person is diagnosed as having epilepsy. Seizures provoked by
the above factors are simply called secondary seizures and NOT epilepsy. Thus
epilepsy is now said to be idiopathic or gene-related.
As you all know, the brain has an electrical discharge which consists of 4 brain waves:
1.
2.
3.
4.
Beta
Alpha
Theta
Delta
Of course these electrical frequencies vary according to level of alertness, whether one is
asleep, etc. They can be recorded by an EEG (Electroencephalograph) or a video EEG. The
video EEG is a very important and reliable modality for diagnosis because there can be
conditions which mimic seizures. For example, the video EEG is connected to a little boy. If
he moved his arm suddenly and there was no change in the EEG then this is not considered
a seizure.
Neonatal Seizures
As you know the neonatal period limited to :
- First 28 days for term infants
- 44 weeks gestational age for pre-term infants.
A stereotypic, paroxysmal spell of altered neurologic function (behavior, motor, and/or
autonomic function) occuring during this period is called a neonatal seizure.
The incidence – 1-5: 1000 live births
Neonatal seizures differ from seizures that occur in older children and from epilepsy.
What is the cause of this difference?
It is due to their immature CNS which cannot sustain a synchronized, well orchestrated
generalized seizure. This is because the CNS requires 2 to 3 years to obtain complete
myelination thus many nerve fibers are still uncovered.
What is the anatomical difference in neonates?
1. Dendritic and axonal ramifications are still in process
2. Synaptogenesis is not complete
3. Deficient myelination in cortical efferent systems
What is the physiological difference in neonates?
1. In limbic and neocortical regions—excitatory synapses develop before inhibitory
synapses (therefore any stimulation of neurons could cause abnormal electrical
discharge)
2. Immature hippocampal and cortical neurons more susceptible to seizure activity
than mature neurons
3. Deficient development of substantia nigra system for inhibition of seizures
4. Impaired propagation of electrical seizures, whether synchronous or asynchronous,
as recorded by EEG.
Probable Mechanisms of Some Neonatal Seizures
Probable Mechanism
-Failure of Na + -K + pump secondary to
adenosine triphosphate
-Excess of excitatory neurotransmitter
-Excess of excitatory neurotransmitter
Deficit of inhibitory neurotransmitter
Disorder
Hypoxemia, ischemia, and hypoglycemia
Hypoxemia, ischemia and hypoglycemia
Pyridoxine dependency
Pyridoxine dependency
(i.e., relative excess of excitatory
neurotransmitter)
Membrane alteration— Na +
Permeability
Hypocalcemia and hypomagnesemia
Neonatal Seizures
Classification
Clinical
Subtle
Tonic
Electroencephalographic
Clonic
Myoclonic
Epileptic
NonEpileptic
Now let’s talk about each one separately:
Subtle Seizure:
More in preterm than in term
Eye deviation
Blinking, fixed stare
Repetitive mouth and tongue movements
Apnea
Pedaling and tonic posturing of limbs
Tonic:
Primarily in Preterm
May be focal or generalized
Sustained extension of the upper an
and
d lower limbs (mimics decerebrate posturing)
Sustained flexion of upper with extension of lower limbs (mimics decorticate
posturing)
Signals severe ICH (intracranial hemorrhage) in preterm infants
Clonic:
Primarily in term
Focal or multifocal
Clonic limb movements(synchronous or asynchronous, localized or often with no
anatomic order of progression)
Consciousness may be preserved
Signals focal cerebral injury
Myoclonic :
Rare
Focal, multifocal or generalized
Lightning-like jerks of extremities (upper limbs > lower limbs)
Note: It is very important to differentiate between jitterness and seizures:
CLINICAL FEATURE
JITTERINESS
SEIZURE
Abnormality of gaze or eye
movement
O
+
Movements are stimulus
sensitive (if you irritate the
child or put him under stress,
jitterness will increase but
seizure will not)
+
O
Predominant movement
4 times)
Tremor
(extension=flexion)
Clonic jerking <unequal>
(extends arm once, flexes 3-
Movements cease with passive
flexion (stops shaking when you
touch the limb)
+
O
Autonomic changes
O
+
Etiology of Neonatal Seizures:
Importance of knowing the etiology:
•
•
•
•
It is critical to recognize neonatal seizures, and to determine their etiology, as
sometimes the underlying cause is treatable and at others it can be due to a brain
insult, and of course the prognosis depends on the underlying cause.
For example, a baby has hypoglycemia as he was born to a diabetic mother, this
patient will have a good prognosis if discovered early before acquiring a brain insult.
However, if the seizure was due to infection, hemorrhage or malformation, the
prognosis will be bad. Thus we can recognize the importance of knowing the
etiology.
Seizures are usually related to significant illness, sometimes requiring specific
therapy
Neonatal seizures may interfere with important supportive measures, such as
alimentation and assisted respirations for associated disorders. For example, a
neonate may have apnea as the presenting symptom of a seizure (subtle seizure). If
you do not deal with the apnea the neonate may develop anoxia hence brain anoxia
hence brain damage.
Experimental data give some reason for concern that under certain circumstances
the seizure per se may be a cause of brain injury.
What helps us in determining the etiology?
Clinical history provides important clue
Family history may suggest genetic syndrome
In the absence of other etiologies, family history of seizures may suggest poor
prognosis. (the doctor said poor but in the slides it’s good)
Pregnancy history is important
Search for history that supports TORCH infections – TORCH infections may cause
meningitis, encephalitis, etc which could result in a brain insult.
History of fetal distress, preeclampsia or maternal infections
Delivery history
Type of delivery and antecedent events
Apgar scores are extremely important, especially the 5 minute and 10 minute scores
(which are important for the neonate).
The 1 minute score is important for the physician not the neonate. This is because if
an infant has a 1 minute APGAR score below 3, this means that the baby is severely
distressed, thus the physician must perform CPR, intubation, etc. However, the 1
minute score does NOT reflect the prognosis.
The 5 and 10 minute score however, if they are below 7, we will be worried that the
child may develop HIE (hypoxic ischemic encephalopathy) if it is associated with
abnormal manifestations of the CNS. However sometimes the APGAR score can be
misleading. If the baby has a low APGAR score yet was not in need of resuscitation,
then we must look for other causes of the seizure besides HIE.
HIE is a terminology used in the term infant to describe the clinical manifestation of
brain injury starting immediately or up to 48 hours after asphyxia(critical reduction in
oxygen delivery to the fetus antenatally, during labour or delivery)
Postnatal history (metabolic disturbances, sepsis)
Neonatal seizures in infants without uneventful antenatal history and delivery may
result from postnatal cause
Tremors may be secondary to drug withdrawal or hypocalcemia
Temperature and blood pressure instability may suggest infection (sepsis)
Comparison of prominent etiologic diagnoses of seizures in the newborn period. (Data
modified from Mizrahi and Kellaway, 1987; Rose and Lombroso, 1970)
As we can see from observing the chart above, the largest number of cases is due to
Hypoxia-ischemia (approximately half of all cases).
The second is metabolic, specifically hypocalcaemia
Then we have infection, trauma, hemorrhage, etc
Now if an infant is suspected or found to have neonatal seizure, what laboratory tests must
be done to rule out the above causes one by one, bringing us closer to the correct etiology?
Complete blood count, differential, platelet count
urinalysis
Blood glucose , Ca, Mg
Blood oxygen and acid-base analysis (pH)
Blood, CSF and other bacterial cultures
CSF analysis (to rule out meningitis)
EEG
Ultrasound (this can be performed on any infant with open fontanelles to see if
there is Ivh – Intraventricular hemorrhage)
CT or MRI
Serum immunoglobulins, TORCH antibody titers, and viral cultures (if we suspect any
infection)
Blood and urine metabolic studies (bilirubin, ammonia, lactate, FeCl³, reducing
substance.) – if we suspect a metabolic cause like hypoglycemia, hypocalcemia
Blood and urine toxic screen
Blood and urine amino and organic acid screen (as urea cycle defects as well as
organic acidemia may present with convulsions)
Treatment
Identify the underlying cause and treat accordingly:
Hypoglycemia - D10 solution
Hypocalcemia - Calcium gluconate
Hypomagnesemia- Magnesium sulfate
Meningitis- initiation of antibiotics
Pyridoxine deficiency- Pyridoxine (if you give the baby whatever was deficient, and you treat
him with phenobarbitone, and there was no improvement, this should give you a hint that
this seizure could be caused by pyridoxine deficiency. When you start giving this baby
pyridoxine, you will notice on the EEG that the icteric activity will disappear and the seizures
will cease. )
Why do we treat patients with neonatal seizures?
To minimize brain damage
Some controversy exists about when to start anticonvulsants
If seizure is prolonged (longer than 3 minutes), frequent or associated with
cardiorespiratory disturbance, we must give anticonvulsants.
Drug Therapy for Neonatal Seizures
Standard Therapy
AED
Initial Dose
Route
Phenobarbital 20mg/kg
lV, lM, PO
Phenytoin
20 mg/kg
lV, PO
Fosphenytoin
20 mg/kg
lV, lM
Lorazepam
0.05 to 0.1 mg/kg
lV
Diazepam
0.25 mg/kg
lV
AED= antiepileptic drug; IV= intravenous; IM= intramuscular; PO= oral
Regarding the doses, just know that the initial dose for the first three medications is 20
mg/kg which is different from the maintenance dose.
Notes about the table:
Fosphenytoin is just a newer version of Phenytoin
Lorazepam preferred over diazepam, however it is not available in Jordan.
Since Phenobarbital is given IV, IM and orally it can be used for the acute phase and
for maintenance; however Lorazepam and Diazepam can only be used for the acute
phase.
So for a baby with neonatal seizures not caused by metabolic disturbances, it is
preferable to give only these two medications – Diazepam and Phenobarbital.
Acute therapy of neonatal seizures:
When an infant is seizing, the first thing you do is take a dipstick and the samples you
need then:
If with hypoglycemia – give glucose
If no hypoglycemia- Phenobarbital:20mg/kg IV loading dose
If necessary : additional phenobarbital: 5 mg/kg IV to a max of 20 mg/kg (consider
omission of this additional Phenobarbital if the baby is asphyxiated)
Phenytoin: not given nowadays due to extensive side effects
Lorazepam
What are the determinants of the duration of the anticonvulsant therapy for neonatal
seizures?
Neonatal neurological examination
Cause of neonatal seizure
Electroencephalogram
Guidelines:
If a baby in the neonatal period is on Phenobarbital and the seizures stop, we evaluate
him:
If neonatal neurological examination becomes normal discontinue therapy
If neonatal neurological examination is persistently abnormal, consider etiology
and obtain EEG
In most such cases- Continue phenobarbital
- Discontinue phenytoin
- Reevaluate in 1 month
One month after discharge
If neurological examination has become normal, discontinue phenobarbital
If neurological examination is persistently abnormal, obtain EEG
If there is seizure activity on EEG we continue Phenobarbital for another month
If there is no seizure activity on EEG, discontinue phenobarbital
This usually goes on for 6 months.
Complications of Neonatal Seizures:
Cerebral palsy
Hydrocephalus
Epilepsy
Spasticity (severe)
Feeding difficulties
By this we finish the first half of this lecture, and now we will begin with the second half:
Epilepsy in Childhood
Objectives:
•
Review the international classification of seizures.
•
Review some epilepsy syndromes that occur during infancy and childhood
•
Discuss the evaluation process of seizures in children
•
Discuss the medications used to treat pediatric seizures
•
Discuss alternative therapies for intractable epilepsy
What are the steps in evaluation of pediatric epilepsy?
Steps in evaluation:
1. Is the spell a seizure event?
2. What is the differential diagnosis?
3. Is it epilepsy (does it fit the clinical diagnosis of epilepsy)?
4. Is it part of an epilepsy syndrome?
5. What tests are needed?
6. What is the therapy?
International Classification of Seizure Types:
Seizure Classification
Partial
Generalized
Simple
Complex
No change in
consciousness
Consciousness is
impaired or lost
Diffuse onset
Partial Seizures: arise from specific foci (an area in part of one hemisphere is affected).
Partial seizures can become generalized.
Generalized Seizure: from the beginning both hemispheres are affected thus it has a diffuse
onset.
Partial Seizures:
–
–
–
Simple Partial Seizures
•
With motor signs
•
with somatosensory or special sensory symptoms
•
With autonomic symptoms
•
With psychic symptoms
Complex Partial sz (CPS)
•
Simple partial + iimpaired consciousness
•
Consciousness impaired at onset
CPS evolving to secondary generalized
Generalized Seizures:
–
Myoclonic seizures
–
Tonic seizures
–
Absence seizures
–
Tonic-clonic seizures
–
Atonic seizures
Conditions that mimic childhood epilepsy:
•
Syncope
•
Breath-holding spells
•
Cataplexy
•
Behavioral staring
•
Movement disorders ( e.g. tics)
•
Parasomnias( night terrors, sleep walking,..)
•
Migraine (hemiplegic migraine)
Familial hemiplegic migraine (FHM) is an autosomal dominant classical migraine
subtype that typically includes hemiparesis (weakness of half the body) during the
aura phase. It can be accompanied by other symptoms, such as ataxia, coma and
epileptic seizures. - Wikipedia
•
Benign myoclonus (movement without any abnormalities in the EEG)
•
Gastro esophageal reflux disease (if it is accompanied by vomiting, the infant can
develop torticollis while vomiting which can be confused with a seizure)
Epileptic Syndrome
•
An epileptic syndrome consists of a complex of signs and symptoms that occur
together in a child with epilepsy more often than would be expected by chance
•
An epileptic syndrome is defined by:
–
Seizure type(s)
–
Natural history
–
EEG(ictal and inter ictal)
–
Response to AEDs
–
Etiology
Now let’s talk about a few Epileptic Syndromes:
Infantile Spasms
•
Peak onset : 4-6 mo ( 90 % before 12 mo)
•
Clinically characterized by spasms, which are mostly a mix between flexion and
extension (it is sometimes called “salam attack” as it mimics the Indian salute/salam.
When putting arms together like the Indian salute, your forearm will be flexed and
your hand will be extended)
•
Spasms occur in clusters (can occur up to 20-30 times)
•
West syndrome = infantile spasms +mental retardation + hypsarhythmia
Hypsarhythmia – abnormal EEG with characteristic wave patterns as if each limb has
its own electrical impulse.
Hypsarrhythmia is abnormal interictal high amplitude waves and a background of
irregular spikes seen in electroencephalogram, mostly in infant diagnosed with
infantile spasms. - Wikipedia
•
Treatment:
- Hormonal- ACTH, corticosteroids (if ACTH is not available) ,
- Anticonvulsants (the most effective for infantile spasms are the new AED
(Vigabatrin),
<Hormones and AED are used to treat idiopathic infantile spasm>
- Surgery (in symptomatic infantile spasm which has an underlying cause- we
perform surgery to remove the cause)
•
Prognosis: overall poor
Lennox- Gastaut Syndrome:
•
Age of onset:1-8 yrs ( 3-6 more common)
•
Clinically, A Triad:
1. Multiple seizure types (tonic most common)
2. Cognitive/ motor impairment
3. Slow spike and wave on EEG
•
Etiology: Usually symptomatic (surgery), could be idiopathic (medications)
–
30 % of patients with infantile spasms develop LGS.
LGS is one of the worst syndromes that could occur in adults and one of the most difficult to
treat.
•
Genetics: multiple loci: in the short and long arm in several locations 6p, 15q14,
8p,1p (the doctor did not read these locations)
•
EEG : Background is normal. Generalized 4-6 Hz polyspike and slow wave complexes;
Some have 3-4 Hz spike and slow wave complexes. (therefore it can mimic the
absence seizure on the EEG)
•
Treatment : Valproate, Lamotrigine,Topiramate
•
Prognosis:
–
Seizures are controlled in the majority of patients.
–
JME is one form of epilepsy in which discontinuation of pharmacotherapy
cannot be recommended. In most books the recommendation for treatment
in general is 2-4 years but this cannot be applied to this syndrome because
when therapy is stopped, the seizures will return.
–
90 % relapse after discontinuation of AED
Etiology of Epilepsy in Childhood: (Secondary Epilepsy)
•
Epilepsy not due to the above causes is termed idiopathic or caused by genetic factors.
To diagnose epilepsy we need to do the following:
•
Detailed History
•
Physical Examination
•
Supportive Investigations:
–
EEG/ Video EEG (as we mentioned earlier the video EEG is better than the
EEG because the EEG records for 20-30 minutes and there won’t necessarily
be an abnormal electrical discharge within this time period. The video EEG is
especially useful if the history is not very informative and you are not sure
about the diagnosis, so you attach the video EEG which keeps recording for
24-48 hours and then you can analyze this EEG to make a diagnosis)
–
Neuroimaging (CT scan, MRI)
–
Metabolic work up (if we suspect infection)
–
Lumbar puncture
Treatment:
•
1. Anticonvulsant medications
•
2. Nonpharmacologic treatments
–
Ketogenic diet (we increase the fat in the diet so that more ketones are
formed and studies showed that this decreased the frequency of seizures)
–
Vagus nerve stimulator (similar to the pacemaker which is put in the heart.
This device is attached to the vagus nerve sheath. Now any abnormal
impulses in the brain will be transferred to the cranial nerves. When an
abnormal impulse reaches the vagus nerve, the vagus nerve through various
mechanisms, will stop the impulse therefore aborting the seizure. This device
has been FDA approved and shown to decrease the frequency of seizures,
and it has even been done on several cases in Jordan.
<The Ketogenic diet and the Vagus nerve stimulator are only done under certain
indications – Cases which are resistant to Anticonvulsant Treatment (3 or more
drugs were used to control the seizure and there was no control)>
•
3. Epilepsy Surgery – if there is a clear focus we can remove it.
Also in certain extremely severe cases where the seizure manifests itself all the time,
we can do palliative surgery, for example temporal lobectomy. We could also cut the
corpus callosum in half so the right and left side will work independently therefore
we decrease the generalization of the seizure.
Let us talk briefly about the history of AED Therapy in the US:
They’ve been present for around a century and a half so we have old preparations
(conventional) and newer (since the 1990’s) preparations.
Some examples of the new preparations:
-
Levetiracetam (trade name Keppra)
Topiramate (Topamax)
Lamotrigine (Lamictal)
Gabapentin
Vigabatrin
Now we will talk briefly about some important medications:
Why have we added these preparations in addition to Valproate? Because they have fewer
side effects and they are less toxic on the liver (recall that valproate is an enzyme inhibitor)
What are the factors that affect our choice of AED?
•
Side effect profile (if a drug stopped the seizures yet caused idiosyncratic liver
failure, what did we gain?)
•
Titration schedule (any AED should never be given as a full dose immediately)
For example, if the maximum dose of valproate is 60 mg we should never start with
this amount. We start with 5 mg, and every 4-5 days we increase another 5 mg until
the seizures become controlled. Then we follow up the patient to observe the
frequency of seizures and the side effects experienced due to the given medication.
<some newer preparations do not need such a slow increase in the dose as in the
conventional way>
•
Other medications the patient is already on, we should know
–
Drug-drug interaction
–
Mechanism of action (we should not combine 2 medications that have the
same or similar mechanism of action. For example, if the drug the patient is
on is a Na inhibitor, we should look for a medication that acts on GABA or Ca
to increase efficacy)
•
Overall clinical experience
•
Physician’s personal experience
•
Cost
Alternatives to Anticonvulsant treatment:
Medically intractable seizures (pharmacoresistant epilepsy)
It is estimated that 20-30 % of patients with epilepsy have medically intractable seizures
(which is actually a large percentage)
We have already mentioned the alternatives to anticonvulsant treatment earlier.
Done By:
Zeina Yanbeiy
If it is not truthful and not helpful, don't say it.
If it is truthful and not helpful, don't say it.
If it is not truthful and helpful, don't say it.
If it is truthful and helpful, wait for the right time. - Buddha
Do not believe in anything simply because you have heard it. Do not believe in anything simply because it
is spoken and rumored by many. Do not believe in anything merely on the authority of your teachers and
elders. Do not believe in traditions because they have been handed down for many generations. But after
observation and analysis, when you find that anything agrees with reason and is conducive to the good
and benefit of one and all, then accept it and live up to it. – Buddha
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