Therapeutics 250:
SEIZURE
Block 9
San Gabriel. Saniano. Santos J. Santos M. Sison.
Sorreda. Sotalbo. Sylim. Tabula. Taladtad.
Taleon. Tampo. Tanyu. Tiongson. Torio
Case
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M.D
60 year old
Male
Right-handed
Married
Works as a jeepney driver
Chief Complaint: “Ngalay”
History of Present Illness
• (+) tonic movements of the left hand for a few seconds
followed by tonic clonic movement of the left arm lasting
for a few minutes, occurring twice in the past month
• (-) loss of consciousness
• (-) consult
• Symptoms was ascribed to as “ngalay”
• (+) Third episode of tonic clonic movements of the left arm
which progressed to head turning to the left, followed by
loss of consciousness and generalized tonic-clonic
movements of the body and extremities lasting for a few
seconds. He regained consciousness after a few minutes
but was noted to be confused, unable to recognize friends
and family but later recovered.
Pertinent History
• 40-pack year cigarette smoking history
• Diagnosed to have carcinoma of the lung 3
months ago and is currently undergoing
treatment (Stage and type not specified)
• Heavy alcoholic drinker : 6- 10 bottles of beer
3x / week
• He stopped smoking cigarettes and drinking
alcoholic beverages 3 months ago
Neurologic Examination
• Mild motor weakness (4/5) of the left upper
and lower extremities
• Hypereflexic on the left extremities
• Left toe extension on Babinski
Diagnostic Tests
• Complete Blood Count : Normal
• Blood urea nitrogen, creatinine and
electrolytes : Normal
• Cranial CT Scan: 2 x 2 cm irregularly shaped,
contrast enhancing lesion at the right frontoparietal area
• Alanine aminotransferase : mildly elevated
• Aspartate transaminase : 4x elevated
DIAGNOSIS
Pertinent Data
This is the case of MD, a 60 year old, right-handed male, with 3 episodes of
tonic-clonic movements. The first two occurring in the past month and described as
tonic movements of the left hand for a few seconds followed by tonic-clonic
movement of the left arm lasting for a few minutes without associated loss of
consciousness. The third episode was tonic-clonic movements of the left arm which
progressed to head turning to the left, followed by loss of consciousness and
generalized tonic-clonic movements of the body and extremities lasting for a few
seconds. He regained consciousness after a few minutes but was noted to be
confused, unable to recognize friends and family but later recovered.
Patient is a diagnosed case of Lung Cancer 3 months ago and undergoing
treatment owing to a 40-pack year cigarette smoking history. He also was a heavy
alcoholic drinker drinking 6- 10 bottles of beer 3x / week.
Neurologic examination revealed mild motor weakness (4/5) of the left
upper and lower extremities, hypereflexia on the left extremities, and (+) Babinski.
Cranial CT Scan revealed 2 x 2 cm irregularly shaped, contrast enhancing
lesion at the right fronto-parietal area. CBC and electrolytes were normal , ALT was
mildly elevated, and AST was 4x elevated.
Other Important Things to Ask
• Staging and Type of Lung Cancer
• Medications currently used
– Drug interaction with contemplated
anticonvulsants
Brain abscess
• spectrum of organisms reflects the range of
underlying primary sources of infection.
• Approximately 60 percent are multimicrobial
• 10 to 60 percent of patients with a brain
abscess, no underlying source of infection is
found
Neoplasms
• primary or metastatic neoplasm
• aggressive primary brain tumors, such as
glioblastoma multiforme or anaplastic
astrocytoma, as well as metastases from lung and
breast cancer
• thin rim of low signal on T2 -weighted images,
which is thought to represent collagen, subtle
hemorrhage, or macrophages containing free
radicals, is more characteristic of an abscess than
of a neoplasm.
Differentials
Differentials
Rule IN
Brain Metastasis
Seizure episodes
Cannot be ruled out
Lung Cancer diagnosed 3
months ago, undergoing
treatment
CT Scan: 2 x 2 cm
irregularly shaped, contrast
enhancing lesion at the
right fronto-parietal area
Primary Brain Tumor
Seizure episodes
Less likely
CT Scan: 2 x 2 cm
irregularly shaped, contrast
enhancing lesion at the
right fronto-parietal area
Secondary Malignancy
Rule OUT
Less likely
Lung Cancer Metastases
• Metastases occur most commonly in the CNS,
vertebral bodies, bones, liver, adrenal glands,
lungs, and skin and soft tissues.
• At diagnosis, 10% of patients with lung cancer
have CNS metastases; another 10 to 15% will
develop CNS metastases. Symptoms are often
focal and include headache, nausea and vomiting,
seizures, hemiplegia, and speech difficulty.
• Distant metastases are found in about 40% of
patients with newly diagnosed lung cancer.
Schwartz, Principles of Surgery
Frequency of Nervous System Metastases
by Common Primary Tumors
Site of Primary
Tumor
Brain Metastases
Leptomeningeal
Spinal Cord
Compression
Lung
40%
24
18
Breast
19
41
24
Melanoma
10
12
4
Gastrointestinal
7
13
6
Genitourinary
7
10
18
Other
17
30
Extra (optional)
• Seizures may result from disruption of cortical
circuits. Tumors that invade or compress the
cerebral cortex, even small meningiomas, are
more likely to be associated with seizures than
subcortical neoplasms. Nonfocal neurologic
dysfunction usually reflects increased intracranial
pressure (ICP), hydrocephalus, or diffuse tumor
spread. Tumors in some areas of the brain may
produce behavioral disorders; for example,
frontal lobe tumors may present with personality
change, dementia, or depression.
About Seizures
Features that help to distinguish frontal lobe seizures from
nonepileptic events include:
> stereotyped semiology
> occurrence during sleep
> brief duration (often <30 seconds)
> rapid secondary generalization
> prominent motor manifestations
> complex automatisms
Despite this, the distinction remains difficult to make based
on history alone, and patients with frontal lobe epilepsy are
often directed first to psychiatrists rather than to
neurologists. Details obtained about the seizure semiology
may help to identify the specific frontal region of onset.
Prominent speech disturbances - May indicate dominant
hemisphere involvement
Supplementary motor area (SMA) - Typically involve
unilateral or asymmetric bilateral tonic posturing; may be
associated with facial grimacing, vocalization, or speech
arrest; seizures frequently preceded by a somatosensory
aura; complex automatisms such as kicking, laughing, or
pelvic thrusting may be present; responsiveness often
preserved
Primary motor cortex - Usually simple partial motor seizures
with clonic or myoclonic movements and preserved
consciousness; jacksonian spread to adjacent cortical areas
may occur, and secondary generalization is frequent; speech
arrest and contralateral adversive or dystonic posturing may
be present.
Medial frontal, cingulate gyrus, orbitofrontal, or frontopolar
regions - Complex behavioral events characterized by motor
agitation and gestural automatisms; viscerosensory
symptoms and strong emotional feelings often described;
motor activity repetitive and may involve pelvic thrusting,
pedaling, or thrashing, often accompanied by vocalizations or
laughter/crying; seizures often bizarre and may be diagnosed
incorrectly as psychogenic.
Dorsolateral cortex - Tonic posturing or clonic movements
often associated with either contralateral head and eye
deviation, or less commonly, ipsilateral head turn.
Operculum - Swallowing, salivation, mastication, epigastric
aura, fear, and speech arrest often associated with clonic
facial movements; gustatory hallucinations also may occur.
Nonlocalizable frontal seizures - Rare, manifesting as brief
staring spells accompanied by generalized spike/wave on
EEG, which may be difficult to distinguish from primarily
generalized absence seizures; may present as generalized
tonic-clonic seizures without obvious focal onset.
Nocturnal frontal lobe epilepsy - Autosomal dominant
inheritance; seizures occur mainly during sleep;
characterized by marked motor manifestations, including
dystonic posturing, jerking, bending, and rocking; difficult to
distinguish from parasomnias.
Therapeutic Objectives
Short Term Goals
• Control of symptoms
• Maintain high level of functionality
– Return to work
– Neurologic function
– Independent ADL’s
Long Term Goals
•
•
•
•
•
Minimize drug toxicity
Prevent recurrence of seizure episodes
Control progression of disease
Maximize survival
Achieve best possible quality of life
Guideline
Management of brain metastases: role of
radiotherapy alone or in combination with other
treatment modalities.
• Supportive Care Guidelines Group, Neuro-oncology Disease Site Group.
Tsao MN, Laetsch NS, Wong RKS, Laperriere N. Management of brain
metastases: role of radiotherapy alone or in combination with other
treatment modalities [full report]. Toronto (ON): Cancer Care Ontario
(CCO); 2004 Mar. 35 p. (Practice guideline report; no. 13-4). [36
references]
Major outcomes considered
• Outcomes of interest are survival, intracranial
progression-free duration, tumour response,
neurological function, quality of life, symptom
control, and toxicity.
MAJOR RECOMMENDATIONS
Radiotherapy and Surgery for Single Brain
Metastasis
• Surgical excision should be considered for
patients with good performance status, minimal
or no evidence of extracranial disease, and a
surgically accessible single brain metastasis
amenable to complete excision.
• Postoperative whole brain radiotherapy should
be considered to reduce the risk of tumour
recurrence for patients who have undergone
resection of a single brain metastasis.
Radiotherapy for Multiple Brain Metastases
• It is recommended that the whole brain be
irradiated for multiple brain metastases.
Commonly used dose fractionation schedules are
3,000 cGy in 10 fractions or 2,000 cGy in five
fractions.
• Altered dose fractionation whole brain
radiotherapy schedules have not demonstrated
any advantages in terms of overall survival or
neurologic function relative to more commonly
used fractionation schedules.
• The use of radiosensitizers is not recommended
outside research studies.
• The optimal use of radiosurgery in the treatment
of brain metastases remains to be defined. In
patients with one to three brain metastases (less
than 3 cm in size) and limited or controlled
extracranial disease, radiosurgery may be
considered to improve local tumour control
either as boost therapy with whole brain
radiation or at the time of relapse after whole
brain radiotherapy.
Chemotherapy and Whole Brain Radiotherapy
• The use of chemotherapy as primary therapy
for brain metastases (with whole brain
radiotherapy used for those whose
intracranial metastases fail to respond) or the
use of chemotherapy with whole brain
radiotherapy to treat brain metastases
remains experimental.
Supportive Care and Whole Brain Radiotherapy
• Supportive care alone without whole brain
radiotherapy is an option (for example, in
patients with poor performance status and
progressive extracranial disease). However, there
is a lack of Level 1 evidence to guide practitioners
as to which subsets of patients with brain
metastases should be managed with supportive
care alone without whole brain radiotherapy.
Anti-seizure Drugs
DRUG
DOSAGE
BRAND
PRICE (Php)
@
AR and SE
CARBAMAZEP
INE
Initial:
200mg
OD/BID
Maintenance
: 0.8-1.2g OD
Carbilepp,
Epazin,Epiko
r, Tegretol
10
PHENYTOIN
Initial:
100mg TID
Maintenance
: 300-400mg
OD
Dilantin,
Epilantin
24
Drowsiness,
dizziness,
imbalance,
nausea,
vomiting,
allergic
reactions
GI disturbance,
ataxia, slurred
speech,
diplopia,
nystagmus,
dizziness,
hirsutism,
hyperglycemia,
osteomalacia
contraind
ications
Hepatic
disease,
blood
disorders
Hypersensit
ivity to
hydantoins
DRUG
VALPROIC ACID
DOSAGE
BRAND
Initially: 10- Depakene,
15mg/kg OD Epival
Maintenance:
5-10mg/kg
per week
PRICE (Php)
@
39 per 500mg
AR and SE
contraindica
tions
Abdominal
Hepatic disease,
cramps, anorexia, hypersensitivity
diarrhea, nausea, to valproate
vomiting, weight
gain, drowsiness,
ataxia, irritability,
confusion,
restlessness,
hyperactivity,
headache,
malaise, alopecia,
erythema
multiforme,
hyperammonemi
a, pancreatitis,
thrombocytopeni
a, prolongation of
bleeding time,
transient
increased liver
enzymes, liver
failure, tremor,
nystagmus, spots
before eyes
DRUG
GABAPENTIN
DOSAGE
BRAND
900-3600mg/day Neurontin
PRICE (Php) @
AR and SE
51 per 100mg,
57 per 300mg,
72 per 400mg,
103 per 600mg
Agitation, Arachnoiditis,
Paralysis, Headache,
Intestinal Functional
Disorder, White Blood Cell
Count Increased, Blister,
Fluid Retention, Muscle
Spasms, Back Pain, Pain in
Extremity, Hypoaesthesia,
Anorexia, Dehydration,
Insomnia, Confusional
State, Nerve Injury, Drug
Ineffective, Abasia,
Impaired Work Ability, Pain,
Muscle Tightness,
Somnolence, Weight
Increased, Speech Disorder,
Nose Deformity, Blood
Cholesterol Increased,
Depression, Blood Pressure
Increased, Vomiting,
Nausea, Rhinorrhoea,
Hepatic Enzyme Increased,
Burning Sensation, Anxiety,
Visual Disturbance,
Dysuria, Spinal Disorder,
Face Injury
DRUG
LAMOTRIGINE
DOSAGE
25mg OD then
50mg OD
Maintenance:
100-200mg
OD/BID
BRAND
Lamictal
PRICE (Php) @
AR and SE
33 per 50mg, 66 Skin eruptions
usually
per 100mg
maculopapular in
nature, nausea,
headache,
tiredness,
dizziness, ataxia,
irritability/aggressi
on, tremor,
agitation,
confusion,
hallucination,
diplopia, blurred
vision.
Haematological
abnormalities e.g.
leucopenia and
thrombocytopenia
. Elevations of
LFTs. Arthralgia,
pain and back pain
DRUG
LEVETIRACETAM
DOSAGE
BRAND
500-1500mg BID Keppra
PRICE (Php) @
33 per 250mg,
66 per 500mg,
108 per 1g
AR and SE
Somnolence,
asthenia,
dizziness,
vertigo,
depression,
emotional
instability,
hostility,
nervousness,
ataxia, tremor,
amnesia,
headache,
nausea,
dyspepsia,
diarrhoea,
anorexia, rash,
diplopia.
DRUG
OXCARBAZEPINE
DOSAGE
BRAND
600-2400mg OD Trileptal
PRICE (Php) @
AR and SE
29 per 300mg,
51 per 600mg
Dizziness, somnolence,
headache, ataxia,
fatigue, vertigo,
nervousness, amnesia,
abnormal thinking,
insomnia, speech
disorder, agitation,
confusion; vomiting,
nausea, abdominal pain,
diarrhoea, dyspepsia,
constipation, gastritis, wt
gain; abnormal gait,
tremor, weakness, back
pain, abnormal
coordination, dysmetria,
sprains/strains, muscle
weakness; diplopia,
nystagmus, abnormal
vision and
accommodation;
hypotension, leg
oedema; rash, acne;
hyponatraemia; rhinitis,
chest infection, epistaxis,
sinusitis.
DRUG
TOPIRAMATE
DOSAGE
BRAND
Initially 25mg Topamax
OD
Maintenance:
100-500mg
OD
PRICE (Php)
@
AR and SE
36 per 25mg,
71 per 50mg,
143 per
100mg
Confusion, dizziness,
drowsiness, generalised
slowing of mental and
physical activity,
difficulty with
concentrations, ataxia,
paresthesia, anorexia,
weight loss, abnormal
vision, metabolic
acidosis, mood or
mental changes,
behavioural
disturbances,
depression, fatigue,
agitation, nervousness,
anxiety, oligohidrosis,
hyperthermia and
hyperammonaemic
encephalopathy.
contrai
ndicatio
ns
Hyperse
nsitivity
reaction
DRUG
DOSAGE
BRAND
ZONISAMIDE
Unavailable?
TIAGABINE
Unavailable?
PREGABALIN
Initially: 75mg
Bid
Maintenance:
150-300mg BID
Lyrica
PRICE (Php) @
AR and SE
66 per
75mgx14’s, 90
per 150mgx14’s
Dizziness, drowsiness,
visual disturbance
(including blurred vision,
diplopia), ataxia,
dysarthria, tremor,
lethargy, memory
impairment, euphoria, wt
gain, constipation, dry
mouth, peripheral edema,
depression, confusion,
agitation, hallucinations,
myoclonus, hypoaesthesia,
hyperaesthesia,
tachycardia, excessive
salivation, sweating,
flushing, rash, muscle
cramp, myalgia, arthralgia,
urinary incontinence,
dysuria, thrombocytopenia,
neutropenia, 1st ° heart
block, hypotension,
hypertension, pancreatitis,
dysphagia, oliguria,
rhabdomyolysis.
Should Patient Have Antiepileptic
treatment?
Tumor-induced seizures
• Usually have a focal onset then become
generalized
• Respond to standard anticonvulsant
medications
• Symptomatic epilepsy should be treated with
anticonvulsants, if possibly starting after the
first seizure. (Kaal et al, 2008)
• The use of the ‘classic’ anticonvulsants carbamazepine,
phenytoin and phenobarbital in patients receiving
concomitant chemotherapy or dexamethasone may lead to
insufficient tumour control.
– enzyme-inducing effects on isoenzymes of the hepatic
cytochrome P450 system
• Valproic Acid
– the preferred anticonvulsant in patients with epilepsy and brain
tumours because of effectiveness and relatively good
tolerability
– enzyme-inhibitor
– may cause enhanced toxicity due to impaired metabolism of
concomitant administered chemotherapeutic drugs. (Kaal et al,
2008)
Seizure Prophylaxis
• There was no difference between the
treatment interventions and the control
groups in preventing a first seizure in patients
with brain tumors.
• The risk of an adverse event was higher for
those on antiepileptic drugs than for
participants not on antiepileptic drugs (NNH 3;
RR 6.10, 95% CI 1.10 to 34.63; P = 0.046).
• (Tremont-Lukats et al, 2008)
• Tremont-Lukats IW, Ratilal BO, Armstrong T,
Gilbert MR. Antiepileptic drugs for preventing
seizures in people with brain tumors.
Cochrane Database of Systematic Reviews
2008, Issue 2.
• Kaal EC, Martin J.B. Taphoorn and Charles J.
VechtSymptomatic management and imaging
of brain metastases. Journal of NeuroOncology (2005) 75: 15–20