1. Neurology Case Conference

2. 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.

3. Missing Data 1st episode or onset of symptoms
Presence or absence of fever, loose bowel movement, vomiting
Previous school performance
Family History

4. Steps in the diagnosis of Neurologic Disease
Anatomic diagnosis
By History
Interpretation of symptoms and signs in terms of physiology and anatomy
Syndromic formulation and localization of the lesion
Mode of onset and course
Elicitation of clinical facts
Other medical data
By neurologic examination
1. The symptoms and signs are secured by history and physical examination.
2. The symptoms and physical signs considered relevant to the problem at hand are interpreted in terms of physiology and anatomy that is, one identifies the disorder(s) of function and the anatomic structure(s) that are implicated.
3. These analyses permit the physician to localize the disease process, i.e., to name the part or parts of the nervous system involved. This step is called anatomic, or topographic, diagnosis. Often one recognizes a characteristic clustering of symptoms and signs, constituting a syndrome of anatomic, physiologic, or temporal type. The formulation of symptoms and signs in syndromic terms is particularly helpful in ascertaining the locus and nature of the disease. This step is called syndromic diagnosis and is often conducted in parallel with anatomic diagnosis.
4. From the anatomic diagnosis and other medical data particularly the mode and speed of onset, evolution, and course of the illness, the involvement of nonneurologic organ systems, the relevant past and family histories, and the laboratory findings one deduces the pathologic diagnosis and, when the mechanism and causation of the disease can be determined, the etiologic diagnosis. This may include the rapidly increasing number of molecular and genetic etiologies if they have been worked out for a particular process.
5. Finally, the physician should assess the degree of disability and determine whether it is temporary or permanent (functional diagnosis); this is important in managing the patient's illness and judging the potential for restoration of function
Appropriate lab tests II
III
Anatomic Diagnosis IV
Pathologic Diagnosis I
Adam and Victor’s Principles of Neurology”, 8th ed.

5. CLINICAL TYPE LOCALIZATION
Table 16-2 Common seizure patterns
CLINICAL TYPE
LOCALIZATION
Somatic motor
   Jacksonian (focal motor)
Prerolandic gyrus
   Masticatory, salivation, speech arrest
Amygdaloid nuclei, opercular
   Simple contraversive
Frontal
   Head and eye turning associated with arm movement or athetoid-dystonic postures
Supplementary motor cortex
Somatic and special sensory (auras)
   Somatosensory
Contralateral postrolandic
   Unformed images, lights, patterns
Occipital
   Auditory
Heschl's gyri
   Vertiginous
Superior temporal
   Olfactory
Mesial temporal
   Gustatory
Insula
   Visceral: autonomic
Insular-orbital-frontal cortex
Complex partial seizures
   Formed hallucinations
Temporal neocortex or amygdaloid-hippocampal complex
   Illusions
   Dyscognitive experiences (deja  vu, dreamy states, depersonalization)
   Affective states (fear, depression, or elation)
Temporal
   Automatism (ictal and postictal)
Temporal and frontal
Absence
Frontal cortex, amygdaloid-hippocampal complex, reticular-cortical system
Bilateral epileptic myoclonus
Reticulocortical, frontocentral
SOURCE: Modified by permission from Penfield and Jasper.
“Adam and Victor’s Principles of Neurology”, 8th ed.

7. 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

8. Differential Diagnosis
(<1month)
Neonates
(>1 month-<12yrs.)
Infants and Children
12-18yrs.
Adolescents
Young Adults
18-35yrs.

9. Table 16-4 Causes of recurrent seizures in different age groups
AGE OF ONSET
PROBABLE CAUSEa
Neonatal
Congenital maldevelopment, birth injury, anoxia, metabolic disorders (hypocalcemia, hypoglycemia, vitamin B6 deficiency, biotinidase deficiency, phenylketonuria, and others)
Infancy (1-6 months)
As above; infantile spasms; West syndrome
Early childhood
(6 months-3 years)
Infantile spasms, febrile convulsions, birth injury and anoxia, infections, trauma, metabolic disorders, cortical dysgenesis, accidental drug poisoning
Childhood
(3-10 years)
Perinatal anoxia, injury at birth or later, infections, thrombosis of cerebral arteries or veins, metabolic disorders, cortical malformations, Lennox-Gastaut syndrome, idiopathic, probably inherited, epilepsy (Rolandic epilepsy)
Adolescence
(10-18 years)
Idiopathic epilepsy, including genetically transmitted types, juvenile myoclonic epilepsy, trauma, drugs
Early adulthood
(18-25 years)
Idiopathic epilepsy, trauma, neoplasm, withdrawal from alcohol or other sedative drugs
Middle age
(35-60 years)
Trauma, neoplasm, vascular disease, alcohol or other drug withdrawal
Late life
(over 60 years)
Vascular disease (usually postinfarction), tumor, abscess, degenerative disease, trauma
a Meningitis or encephalitis and their complications may be a cause of seizures at any age. This is true also of severe metabolic disturbances. In tropical and subtropical countries, parasitic infection of the CNS is a common cause.
“Adam and Victor’s Principles of Neurology”, 8th ed.

10. Distribution of the main causes of seizures at different ages
Distribution of the main causes of seizures at different ages. Evident is the prevalence of congenital causes in childhood and the emergence of cerebrovascular disease in older patients.
Ropper, A. and Brown, R., “Adam and Victor’s Principles of Neurology”, 8th ed.

11. Differential Diagnosis
Probable Cause
Type
Infants and Children
(>1 month-<12yrs.)
Febrile seizure
Genetic disorders (metanolic, degenerative, primary epilepsy syndromes)
CNS infection
Developmental disorders
Trauma
Idiopathic
Complex partial Seizures
Generalized Seizures:
Atonic Seizures
Absence (petit mal)
Epilepsy Syndromes
JME
Lennox-Gastaut
MTLE

12. Complex Partial Atonic JME Lennox-Gastaut MTLE Absence (petit-mal)
Types
Complex Partial
Ictal phase: sudden behavioral arrest or motionless stare
Automatisms:
Chewing, lip smacking, swallowing, “picking” movements of hands
Seconds – an hour
Impaired recollection or motionless stare
Atonic
Briefly impaired consciousness
Quick head drop or nodding movement
1 to 2 seconds
No post ictal confusion
JME
Bilateral myoclonic seizures;single or repetetive
Consciousness is preserved
Myoclonic seizures frequent in the morning
Provoked 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
Aura
Behavioral arrest/stare
Complex automatisms
Unilateral posturing
Postictal disorientation, memory loss dysphasia
Absence
(petit-mal)
Sudden, brief lapses of consciousness,
“daydreaming”
No loss of postural control
Rapid blinking, chewing movements.
Can occur hundred times a day
Lasts for seconds
No postictal confusion
Decline in school performance

13. Clinical Impression: Absence seizure

14. Absence Seizure
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.
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

15. 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.
Segan, S. (2009). Absence Seizures. American Academy of Neurology and American Epilepsy Society

16. 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
Segan, S. (2009). Absence Seizures. American Academy of Neurology and American Epilepsy Society

17. 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
Segan, S. (2009). Absence Seizures. American Academy of Neurology and American Epilepsy Society

18. 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

19. Variants of Absence or Petit-Mal Seizure
Atypical petit mal
long runs of slow spike-and-wave activity, usually with no apparent loss of consciousness
External stimuli such as asking the patient to answer a question or to count will interrupt the run of abnormal EEG activity.

20. Variants of Absence or Petit-Mal Seizure
Lennox-Gastaut syndrome
Onset between 2-6years old
characterized by atonic, or astatic, seizures (i.e., falling attacks), often succeeded by various combinations of minor motor, tonic-clonic, and partial seizures and by progressive intellectual impairment
with a distinctive, slow (1- to 2-Hz) spike-and-wave EEG pattern
Triad of West Syndrome:
infantile spasms, a characteristic EEG picture (3-Hz hypsarrhythmia), and an arrest in mental development

22. Absence seizures

23. Absence seizures
In childhood absence epilepsy, seizures are frequent and brief, lasting just a few seconds (pyknoleptic). Some children can have many such seizures per day. In other epilepsies, particularly those with an older age of onset, the seizures can last several seconds to minutes and may occur only a few times a day (nonpyknoleptic or spanioleptic absence seizures).

24. The etiology of idiopathic epilepsies with age- related onset is genetic. About 15-40% of patients with these epilepsies have a family history of epilepsy; overall concordance in monozygotic twins is 74% with a 100% concordance during the peak age of phenotypic expression.  Family members may have other forms of idiopathic or genetic epilepsy (eg, febrile convulsions, generalized tonic- clonic seizures

25. Typical absence seizures
Sudden onset of impaired movements
staring episodes or "absence spells."
Accompanied by other motor, behavioral or autonomic phenomena
may interfere with school function and learning
Pediatric epilepsy: diagnosis and therapy: John M. Pellock,Blaise F. D. Bourgeois

26. Atypical absence Less abrupt onset and cessation
More pronounced changes in tone and longer duration
Usually begins before 5 years of age
Associated with other generalized seizure types and mental ratardation
Pediatric epilepsy: diagnosis and therapy: John M. Pellock,Blaise F. D. Bourgeois

27. Diagnostic Work-up

28. 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

29. 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

30. EEG: Typical Absence
The spike frequency is often faster at the onset, with a slight deceleration at the end. They can range from Hz, with the faster frequencies seen in syndromes with older age of onset.

31. EEG: Typical Absence
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.

32. 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.

33. EEG: Atypical Absence

34. EEG: Atypical Absence
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.

35. Clinical and EEG Findings in Typical and Atypical Absence Seizures
Segan, S. (2009). Absence Seizures. American Academy of Neurology and American Epilepsy Society

36. 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.

37. 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.

38. Treatment

39. DEPENDS on the underlying cause
Metabolic : correction
Structural abnormality: seizure control + consider surgery
Tumor
Vascular
Idiopathic : seizure control

40. 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

41. 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.

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

43. Anti Epileptic Drug
Glutamate Antagonist
GABA agonist
Na channel blocker
Ca channel blocker
Phenobarbital *
Phenytoin
Carbamazepine
Valproic Acid
Gabapentin
Topiramate
Oxcarbazepine
Ethosuximide
Lamotrigine

44. 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 isoniazid
2 ethyl 2 methylsuccinamide
Katzung Basic and Clinical Pharmacology, 9th ed.
The Treatment of Epilepsy, 3rd ed.

45. 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.

46. 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
Branched chain fatty acid structure
Lacks the nitrogen or aromatic moiety present in other AEDs
Antiepileptic activity greatest for carbon chain length of 5-8 atoms
Increasing to 9 atoms imparts sedative effects
Katzung Basic and Clinical Pharmacology, 9th ed.
The Treatment of Epilepsy, 3rd ed.

47. 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.
The Treatment of Epilepsy, 3rd ed.

48. 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.

49. Other Modalities Ketogenic Diet Vagal Nerve Stimulation
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
The Treatment of Epilepsy, 3rd ed.

50. 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