Neurology Case Conference

NEUROLOGY CASE CONFERENCE

Case 2.1

Case 2.1

A 10 year-old girl was brought by her mother for a consult because of poor academic performance. School teachers often observed her to be absent minded described as recurrent but brief periods of blank staring and inattention. This was accompanied by eye blinking, reflex scratching of her head, lip smacking and chewing movements which all lasts for a few seconds. These would occur many times a day and after each attack, the patient would resume his usual activity.

Missing Data

1st episode or onset of symptoms Presence or absence of fever, loose

bowel movement, vomiting Previous school performance Family History

Salient Features

10 year old girl Poor academic performance Absent minded

Recurrent, brief periods of blank staring and inattention

Accompanied by eye blinking, reflex scratching of her head, lip smacking and chewing movements

Occurs many times a day

Differential Diagnosis

Differential Diagnosis

Probable Cause Type

Infants and Children(>1 month-<12yrs.)

Febrile seizureGenetic disorders (metanolic, degenerative, primary epilepsy syndromes)CNS infectionDevelopmental disordersTraumaIdiopathic

Complex partial SeizuresGeneralized Seizures: •Atonic Seizures•Absence (petit mal)Epilepsy Syndromes•JME•Lennox-Gastaut •MTLE

Types

Complex Partial

Ictal phase: sudden behavioral arrest or motionless stare

Automatisms:Chewing, lip smacking, swallowing, “picking” movements of hands

Seconds – an hourImpaired recollection or motionless stare

Atonic Briefly impaired consciousness

Quick head drop or nodding movement

1 to 2 secondsNo post ictal confusion

JME Bilateral myoclonic seizures;single or repetetiveConsciousness is preserved

Myoclonic seizures frequent in the morningProvoked by sleep deprivation

One-third have absence seizures

Lennox-Gastaut

•Multiple seizure types•Impaired cognitive function

Associated with CNS disease, devt. Abnormalities, perinatal hypoxia/ischemia, trauma, infection

Impaired cognitive syndrome

MTLE AuraBehavioral arrest/stare

Complex automatismsUnilateral posturing

Postictal disorientation, memory loss dysphasia

Absence (petit-mal)

Sudden, brief lapses of consciousness, “daydreaming”

No loss of postural controlRapid blinking, chewing movements.Can occur hundred times a day

Lasts for secondsNo postictal confusionDecline in school performance

Clinical Impression:Absence seizure

Absence Seizure

• A type of generalized seizure, lasting for several seconds to minutes and may occur several times a day

Segan, S. (2009). Absence Seizures. American Academy of Neurology and American Epilepsy Society

• Children with idiopathic generalized epilepsies may present with a history of staring spells, but infrequent absence seizures may not be diagnosed until a generalized tonic-clonic seizure has occurred.

Absence Seizure

• Other symptoms, such as behavioral problems may be the presenting complaint– Although the brief attacks are unrecognized, the

lapses of awareness interfere with attention

• Decline in school performance may be an indication of the onset or breakthrough of absence seizures

• In symptomatic generalized epilepsies, atypical absence seizures often occur in the setting of developmental delay or mental retardation.


Absence Seizure

On clinical examination, typical absence seizures appear as: Brief staring spells

Patients have no warning phase, and if engaged in gross motor activity, such as walking, they may stop and stand motionless or they may continue to walk

Unresponsive during the seizure Children have no memory of what happened

during the attack; they are generally unaware that a seizure has occurred


Pathophysiology

• The pathophysiology of absence seizures is not fully understood

• Abnormal oscillatory rhythms are believed to develop in thalamocortical pathways

– This involves GABA-B–mediated inhibition alternating with glutamate-mediated excitation

– GABA-B inhibition appears to be altered in absence seizures

– Enhanced burst firing in selected corticothalamic networks may increase GABA-B receptor activation in the thalamus, leading to generalized spike-wave activity


Absence Seizure vs Complex Partial Seizure

• An absence seizures can sometimes be confused with a complex partial seizure but each type has its own distinctive features:– Asence seizures :

• never preceded by an aura• are of briefer duration – seconds rather than minutes• begin frequently and end abruptly• the absence attack is always associated with the

strikingly typical EEG abnormality of spike and slow wave discharges, usually at a frequency of 3Hz which occur can occur interictally and ictally and are often provoked by hyperventilation

Diagnostic Work-up

Electroencephalography (EEG)

The only diagnostic test for absence seizures

Ambulatory EEG monitoring over 24 hours may be useful to quantitate the number of seizures per day and their most likely times of occurrence

EEG: Typical Absence

Findings in typical absence seizures include the following: Background activity is normal.

In syndromes with frequent absence seizures, such as childhood absence epilepsy, a routine awake recording is often pathognomonic.

In syndromes with less frequent absence seizures (juvenile absence epilepsy or juvenile myoclonic epilepsy), an awake recording may be normal; a sleep or sleep-deprived recording may be needed.

Typical absence seizures have generalized 3-Hz spike-and-wave complexes



The onset and ending of these seizures are abrupt; no postictal EEG slowing is noted.

Hyperventilation often provokes these seizures and should be a routine part of all EEGs in children.

EEG video monitoring demonstrates that clinical seizure manifestations may lag behind the start of ictal EEG activity; bursts lasting less than 3 seconds are usually clinically silent.

During the absence seizure, rhythmic eye blinks and mild clonic jerks may be present. As a seizure progresses, automatisms may be seen.

Clinical and EEG features may vary considerably in different children.

EEG: Atypical Absence

Findings in atypical absence seizures include the following: Background activity is often abnormal,

reflecting the diffuse or multifocal underlying encephalopathy of symptomatic generalized epilepsy.

Seizures are characterized by slow spike-and-wave paroxysms, classically 2.5 Hz.



• The onset may be difficult to discern, and postictal EEG slowing may be noted.

• The clinical correlation of generalized spike-and-wave complexes with clinical seizures is not as clear-cut as in typical absence seizures.

• EEG-video monitoring can show a more varied alteration of consciousness than in typical absence seizures. If the patient has underlying mental retardation, discerning changes in mental status also may be more difficult in atypical absence.

• Changes in postural tone, most noticeably head nods, are common.

Laboratory Studies

Laboratory tests for: Metabolic abnormalities Toxic or drug ingestion Blood levels of electrolytes, glucose,

calcium, magnesium Hepatic or renal disease

If a clear history of the episodic nature of the attacks is obtained, then the EEG can be diagnostic and laboratory tests may not be necessary.

Imaging Studies

Neuroimaging is not indicated if the typical clinical pattern is present.

Neuroimaging findings are normal in idiopathic epilepsies by definition

Often ordered if a child presents with a generalized tonic-clonic seizure, to rule out significant structural causes of seizures.

If imaging is performed, MRI is preferred to CT scanning. MRI is more sensitive for certain anatomic abnormalities.

Treatment

DEPENDS on the underlying cause

Metabolic : correctionStructural abnormality: seizure control

+ consider surgeryTumorVascular

Idiopathic : seizure control

Diagnosis and Classification of seizure disorder

choose Anti-epileptic drug of choice

Main Goal: Adequate seizure control

monitoring of response

(seizure-free) and side effects

therapeutic monitoring

drug interactions

Principles of Treatment

Individualized treatment Selection of specific drug for initial therapy is based on

specific clinical seizure type Monotherapy is preferred Dose is increased gradually Enough time for steady state to be reached must be allowed Prompt substitution when serious adverse reaction develops If poor seizure control-gradually withdraw first drug while

replacing with second drug of choice for seizure type (should not be stopped abruptly)

Treatment failures may be due to poor compliance or misdiagnosis

Continue treatment to achieve minimum seizure-free period of 3-5 years

Katzung Basic and Clinical Pharmacology, 9th ed.The Treatment of Epilepsy, 3rd ed.

Absence seizures

• Ethosuximide is the drug of choice for typical absence seizure

• Valproic Acid is the drug of choice for atypical absence seizure

• used only when treatment tolerance or failure appear with Ethosuximide

• Wide spectrum AEDKatzung Basic and Clinical Pharmacology, 9th ed.

The Treatment of Epilepsy, 3rd ed.

Anti Epileptic Drug Glutamate Antagonist

GABA agonist

Na channel blocker

Ca channel blocker

Phenobarbital *

Phenytoin *

Carbamazepine *

Valproic Acid * *

Gabapentin *

Topiramate * * * *

Oxcarbazepine * *

Ethosuximide *

Lamotrigine * *

Ethosuximide Primary indication: First-line or adjunctive therapy of generalized

absence seizures Mechanisms of action: Inhibition of neuronal T-type calcium

channels in the thalamus (Type III AED) Usual preparations: Capsules: 250 mg; syrup: 250 mg/5 mL Usual dosages: Initial: 250 mg (adults); 10–15 mg/kg/day

(children) Maintenance: 750–1500 mg/day (adults); 15–40 mg/kg/day

(children) Dosing frequency: 2–3 times/day Significant drug interactions:

Ethosuximide levels are reduced by co-medication with carbamazepine, phenytoin, phenobarbital and rifampicin.

Valproic acid may exert synergistic effects with ethosuximide in patients refractory to either drug given alone, and may have variable and inconsistent effects on ethosuximide levels. Serum valproic acid levels may be decreased by ethosuximide. Ethosuximide levels are increased by isoniazidKatzung Basic and Clinical Pharmacology, 9th ed.


Ethosuximide

Serum level monitoring: usually optimized based on clinical and EEG response.

Main advantages: Well-established treatment for absence epilepsy without the risk of hepatic toxicity carried by valproic acid

Main disadvantages: Adverse effects common. Unlike valproic acid, ethosuximide does not protect against generalized tonic–clonic seizures

Common/important adverse effects: Gastrointestinal symptoms, drowsiness, ataxia, diplopia, headache, dizziness, hiccoughs, sedation, behavioural disturbances, acute psychotic reactions, extrapyramidal symptoms, blood dyscrasias, rash, lupus-like syndrome, other severe idiosyncratic reactions

Katzung Basic and Clinical Pharmacology, 9th ed.The Treatment of Epilepsy, 3rd ed.

Valproic Acid

Primary indications: First line for atypical absence seizures. First-line therapy of idiopathic generalized epilepsies. First-line or adjunctive therapy of cryptogenic or symptomatic generalized epilepsies. Valuable but not generally first-line therapy for partialseizures

Mechanisms of action: Increases brain GABA activity by increasing activity of glutamic acid decarboxylase, inhibition of GABA transaminase, inhibition of succinic semialdehyde dehydrogenase

Usual dosages: Initial: 400–500 mg/day (adults); 15 mg/kg/day (children)

Maintenance: 500–2500 mg/day (adults); 20–40 mg/day (children under 20 kg); 20–30 mg/kg/day (children over 20 kg)

Dosing frequency: 2-3 times a day Serum level monitoring: Dosage usually can be adjusted on

the basis of clinical response, but monitoring serum valproic acid levels may be useful in selected cases Katzung Basic and Clinical Pharmacology, 9th ed.


Valproic Acid

Significant drug interactions : Enzyme-inducing drugs and imipenem antibiotics reduce serum valproic acid levels. Felbamate, stiripentol, isoniazid and other drugs may increase valproic acid levels. Valproic acid inhibits the metabolism of a number of drugs, most notably phenobarbital, lamotrigine and rufinamide. Valproic acid displaces phenytoin from plasma protein binding sites and may inhibit phenytoin metabolism at the same time

Common/important adverse effects: Tremor, sedation, asthenia, encephalopathy, extrapyramidal symptoms, nausea, vomiting, hyperammonaemia, weight gain, polycystic ovary syndrome, hair loss, platelet and coagulation disorders, liver toxicity, pancreatitis, teratogenic effects (including spina bifi da)

Main advantages: Unsurpassed effi cacy in most generalized epilepsy syndromes. Broadspectrum efficacy in different seizure types

Main disadvantages: Weight gain, severe liver toxicity (particularly in children), teratogenicity Katzung Basic and Clinical Pharmacology, 9th ed.


Other Modalities

• Surgical Management– surgical excision of epileptic foci in simple

and complex partial epilepsies that have not responded to intensive and prolonged medical therapy may be beneficial for some

• Regulation of Physical and Mental Activity– precipitating factors needs to be modified

and stressed to the patient – moderate amount of physical exercise can

also be advised– psychosocial difficulties needs to be

identified and addressed early The Treatment of Epilepsy, 3rd ed.

Other Modalities

• Ketogenic Diet– biochemical alteration both in the blood and

in the brain– possible GABA-mimetic effects of ketosis

given the structural similarities of GABA, -hydroybutyrate and acetoacetate

Vagal Nerve Stimulation– vagal stimulation produces its effects are

unclear and it is done through attachment of electrodes to the vagus nerve at the left carotid bifurcation


Management

American Academy of Neurology Guidelines on CESSATION OF TREATMENT

Stopping the treatment may be considered when:

The patient has been seizure-free for 2 to 5 years

The patient has a single type of seizure The patient has no abnormalities on neurologic

examination and has a normal IQ The patient’s electroencephalogram (EEG) has

become normal

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