Therapeutics 250:SEIZURE

Block 9San Gabriel. Saniano. Santos J. Santos M. Sison.

Sorreda. Sotalbo. Sylim. Tabula. Taladtad. Taleon. Tampo. Tanyu. Tiongson. Torio

Case

• 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 fronto-parietal area

• Alanine aminotransferase : mildly elevated • Aspartate transaminase : 4x elevated

DIAGNOSIS

Pertinent DataThis 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.

DifferentialsDifferentials Rule IN Rule OUT

Brain Metastasis Seizure episodesLung Cancer diagnosed 3 months ago, undergoing treatmentCT Scan: 2 x 2 cm irregularly shaped, contrast enhancing lesion at the right fronto-parietal area

Cannot be ruled out

Primary Brain Tumor Seizure episodesCT Scan: 2 x 2 cm irregularly shaped, contrast enhancing lesion at the right fronto-parietal area

Less likely

Secondary Malignancy 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 automatismsDespite 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 contraindications

CARBAMAZEPINE

Initial: 200mg OD/BID

Maintenance: 0.8-1.2g OD

Carbilepp, Epazin,Epikor, Tegretol

10 Drowsiness, dizziness, imbalance, nausea, vomiting, allergic reactions

Hepatic disease, blood disorders

PHENYTOIN Initial: 100mg TID

Maintenance: 300-400mg

OD

Dilantin, Epilantin

24 GI disturbance, ataxia, slurred speech, diplopia, nystagmus, dizziness, hirsutism, hyperglycemia, osteomalacia

Hypersensitivity to hydantoins

DRUG DOSAGE BRAND PRICE (Php) @

AR and SE contraindications

VALPROIC ACID

Initially: 10-15mg/kg OD

Maintenance: 5-10mg/kg per week

Depakene, Epival

39 per 500mg Abdominal cramps, anorexia, diarrhea, nausea, vomiting, weight gain, drowsiness, ataxia, irritability, confusion, restlessness, hyperactivity, headache, malaise, alopecia, erythema multiforme, hyperammonemia, pancreatitis, thrombocytopenia, prolongation of bleeding time, transient increased liver enzymes, liver failure, tremor, nystagmus, spots before eyes

Hepatic disease, hypersensitivity to valproate

DRUG DOSAGE BRAND PRICE (Php) @ AR and SE

GABAPENTIN 900-3600mg/day Neurontin 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 DOSAGE BRAND PRICE (Php) @ AR and SE

LAMOTRIGINE 25mg OD then 50mg OD

Maintenance: 100-200mg

OD/BID

Lamictal 33 per 50mg, 66 per 100mg

Skin eruptions usually maculopapular in nature, nausea, headache, tiredness, dizziness, ataxia, irritability/aggression, tremor, agitation, confusion, hallucination, diplopia, blurred vision. Haematological abnormalities e.g. leucopenia and thrombocytopenia. Elevations of LFTs. Arthralgia, pain and back pain

DRUG DOSAGE BRAND PRICE (Php) @ AR and SE

LEVETIRACETAM 500-1500mg BID Keppra 33 per 250mg, 66 per 500mg,

108 per 1g

Somnolence, asthenia, dizziness, vertigo, depression, emotional instability, hostility, nervousness, ataxia, tremor, amnesia, headache, nausea, dyspepsia, diarrhoea, anorexia, rash, diplopia.

DRUG DOSAGE BRAND PRICE (Php) @ AR and SE

OXCARBAZEPINE 600-2400mg OD Trileptal 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 DOSAGE BRAND PRICE (Php) @

AR and SE contraindicatio

nsTOPIRAMATE Initially 25mg

ODMaintenance:

100-500mg OD

Topamax 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.

Hypersensitivity reaction

DRUG DOSAGE BRAND PRICE (Php) @ AR and SEZONISAMIDE Unavailable?

TIAGABINE Unavailable?

PREGABALIN Initially: 75mg Bid

Maintenance: 150-300mg BID

Lyrica 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 Neuro-Oncology (2005) 75: 15–20