Differential Diagnosis in Neurology

Topic 2. Epilepsy

2.2. Generalized Seizures

Generalized Tonic-Clonic Seizures (GTCS)

Different cortical areas are more likely to initiate the paroxysmal depolarization shift (PDS) that initiates a generalized tonic clonic seizure (GTCS) than others. Approximately 85% of GTCS are secondarily generalized. The usual cortical area that initiates the generalized seizure is the temporal lobe followed by the frontal lobe. Frontopolar and occipital areas of the cortex are less likely to initiate a major motor seizure. The primary motor and sensory area (MI and SI) are very seizurogenic and propagate to the basal ganglia and thalamus quickly. The bilateral projections from the reticular nuclei of the thalamus to the motor cortex initiates the tonic phase of the seizure. Inhibitory interneurons in the cortex and reticular formation and cerebellar volleys terminate the tonic phase and initiate the clonic phase. Oscillatory activity between the cortex and the thalamus sustain the GTCS.

  • Clinical characteristics of generalized tonic-clonic seizures
    • Prodrome:
      • Extreme fatigue several days to a week prior to seizure onset
      • Increase of nocturnal myoclonic jerks
      • Mood change
      • Increased irritability and headache
    • Pretonic-clonic phase (at the initiation of the seizure):
      • Myoclonic jerks
      • Brief clonic seizures
      • Deviation of the head and eyes (frontal and rarely occipital cortical focus)
    • Tonic phase:
      • Tonic contraction of the axial musculature
      • Upward eye deviation
      • Pupillary dilatation
      • Tonic limb contraction
      • "Epileptic cry"
        • Sudden contraction of intercostal muscles forcing air through the larynx
      • Tongue and jaw contraction
        • Tongue biting (side opposite a focal lesion)
      • Cyanosis
    • Clonic phase:
      • Gradual onset
      • Low amplitudes of clonic activity
      • Frequency of eight jerks per second
      • Progressive increase in amplitude that then decreases in frequency to four jerks per second
      • Atonic inhibition supervenes:
        • Loss of continence
        • Atonia of somatic muscles
      • Seizures usually last 30 seconds to 1 1/2 minutes
    • Post ictally:
      • Post ictal sleep (30 minutes to one hour)
      • Confusion on awakening (minutes to one hour) is usual; may last for 1–2 hours
      • Dull pounding headache (occipital predominance)
      • Todd's paralysis (if there is underlying structural lesion)
      • Tongue biting (more severe the side opposite a focal onset)
      • Soreness of the paraspinal muscles and large leg extensor muscles
      • Rarely bilateral posterior dislocation of the shoulders (younger patients)
      • Fracture of a thoracic vertebrae (older patients)
      • Increased blood pressure (during a seizure)
      • Severe hyperhydrosis for minutes to hours
      • Temperature to 101° F (sustained seizure)
      • Cerebral spinal fluid (cells up to 100 neutrophils per mm3
      • Post ictal psychosis (fighting constraint)
      • Myoglobinuria and renal failure (prolonged seizure)
      • May briefly awaken and then fall back asleep
      • Rarely trismus or opisthotonos is maintained
      • Tonic seizure more common with secondary generalized epilepsy
      • Tonic seizures of adults usually a variant of GTCS
      • Increased prolactin levels (temporal lobe focus)
    • Some generalized seizures are just tonic or clonic. Sudden death may occur during sleep
  • Rare Sequelae:
    • Neurogenic pulmonary edema
    • Cardiac arrhythmias with EKG abnormalities
    • Bleeding from the first portion of the duodenum (through and through penetrating ulcer)
    • Myoglobinuria with renal failure
    • Severe acidosis pH < 7.0
    • Posterior shoulder dislocation
    • Sudden unexplained epileptic death (SUDEP)
      • Tonic clonic seizures are important proximate cause
      • Incidence is 0.7–1.3/10,000 patient years
      • Disease severity is the primary determining factor for sudden death
      • Independent risk factors:
        • Mental retardation
        • Number of anticonvulsant drugs used
        • Increased seizure frequency

Differential Diagnosis of Causes of GTCS

  • Generalized Epilepsy with Febrile Convulsions
    • Genetics:
      • Reported loci for febrile convulsions with GTCS
        • Chromosome 5 q 14–15
        • Chromosome 8 q 13–21
        • Chromosome 19 p 13.3 (SCN 1B)
        • Chromosome 2 (SCNIA/2A genes)
    • SCN 1B and SCN 2B genes
      • Modulate the expressions of Na channel alpha-subunits
    • Clinical Features:
      • Benign childhood onset
      • Tonic-clonic seizure without fever
      • 1/3 of patients have:
        • Atonic; myoclonic; astatic seizures
      • Seizures with fever after six years of age
      • Simple febrile seizure (FS)
        • Followed more frequently by GTCS
      • Complex FS
        • Prolonged duration
        • Followed by TLE in 25% of patients
      • AD febrile seizures
        • Occur after six years of age (noted above)
  • Generalized Epilepsy with Focal Seizures Plus (GEFS+)
    • Genetics: chromosome 19q 13.1
      • Codes for a voltage gated sodium channel (subunit B1)
      • Na channel mutation cause febrile convulsions
    • Associated with afebrile seizures

Metabolic Disease

  • Hypoglycemia: cerebral spinal fluid sugar is approximately 2/3 of blood sugar. Patients will have seizures when the cerebral spinal fluid sugar is less than 30 mg/dl. This occurs between 40–60 mg/dl of peripheral blood sugar. The rate at which the sugar falls may also be a determinant if a seizure will be provoked. As the blood sugar starts to fall, a nonadrenergic response causes hunger, piloerection, hyperhidrosis and abnormal behavior. Parasympathetic discharge occurs frequently when the peripheral sugar is 30 mg/dl. The temperature of the patient may drop to 97° Fahrenheit.
  • Hypocalcemia:
    • The usual setting is renal failure
    • Fasciculation of muscle may occur spontaneously or with mechanical stimuli
    • Peripheral nerves may discharge to mechanical stimuli (Chvostek's sign VIIth nerve) or to ischemia (Trousseau's sign)
    • Long QT interval; non-specific T wave change on EKG
  • Hypomagnesemia:
    • Often occurs concomitantly with hypocalcemia
    • Secondary to prolonged enteral feeding
    • Burn patients
    • Clinically similar to hypocalcemic seizures
    • Increased neuro excitability; increased reflexes throughout
    • EKG changes similar to hypomagnesemia; often both electrolyte abnormalities occur concomitantly.
  • Uremia:
    • BUN usually between 90–120 dl% when seizures occur
    • Following rapid osmotic shifts (post dialysis)
    • Need to rule out intracranial blood:
      • Uremic platelet dysfunction
      • Hypertensive hemorrhage from the uremic state
      • Incomplete reversal of anticoagulation (following hemodialysis)
      • Subarachnoid hemorrhage (platelet dysfunction; combination of pathologies)
    • Infection (gram bacilli negative, fungus, HIV) as cause of seizures
    • Seizures are often short
    • Pupillary abnormalities may occur; (usually dilated) and are often associated with uremic optic neuritis (pallor, loss of the cup) which may complicate the exam
    • Rare central pontine myelinolysis occurs (if low sodium corrected too rapidly); which may be seen in ectopic areas: midbrain, thalamus, periventricularly; and is rarely associated with seizures
  • Hepatic encephalopathy:
    • May occur with anticonvulsant medications (valproic acid and phenobarbital)
    • Dilantin (Steven Johnson's syndrome, severe arteritis with lobar hepatic infarction)
    • Carbamazepine:
      • Hepatotoxicity
      • Seizures also caused by inappropriate antidiuretic hormone secretion
    • Valproic acid (VPA)
      • May have hyperammonia without hepatic failure; accompanied by seizures and worsening EEG
      • Phenobarbital, phenytoin valproic acid induced encephalopathy occur with combined use
      • Vigabatrin, gabapentin and topiramate all can contribute to Valproic acid encephalopathy
      • VPA and topiramate cause hyperammonemic encephalopathy
      • Clinical features of VPA induced encephalopathy:
        • Acute onset of impaired consciousness
        • Focal neurological signs
        • increased seizure frequency
        • EEG; pronounced slowing and increased epileptiform discharges
        • Patients at most risk: those with liver disease, congenital enzyme deficiencies
      • Cirrhosis
  • Hyponatremia
    • Frequently seizures are dependent on the rate at which the sodium falls
    • Seizures usually occur at levels less than 110 mEq/ml
    • Hyporeflexia: severe weakness are concomitant features
  • Acute intermitted porphyria:
    • Major motor seizures occur due to porphyrins themselves (mechanisms not certain)
    • Inappropriate ADH
    • May cause status epilepticus
    • Usually associated with abdominal pain and severe motor neuropathy
  • Inappropriate ADH:
    • Usually serum sodium is between 120–130 mEq/dl
    • Initiated by:
      • Head trauma
      • Metabolic abnormalities
      • Drugs (carbamazepine)
      • Paraneoplastic (rare)
      • Intracranial surgery
    • May cause status epilepticus
  • Hyperosmotic states:
    • Nonketotic-diabetic coma (blood sugar often between 2000–3000 mg/dl)
    • Renal failure
    • Hyperlipidemia
    • Insufficient free water with PEG feedings
    • Clinical manifestations:
      • Multiple movement disorders; often segmental myoclonus
      • Asterixis
      • Focal and generalized seizures
  • Pulmonary failure:
    • pCO2>70 torr; pO2 < 80 torr
    • Clinical manifestations:
      • Suffused optic disease; dilated veins; papilledema
      • Asterixis
      • Fasciculations, muscle hyperexcitability
      • Generalized seizures
  • Drugs/Toxin-associated features with GTCS:
    • Often osmotic gap noted on electrolyte evaluation (with toxin)
    • Specific features of different drugs and toxins:
      • Methanol: hemorrhagic optic neuritis
      • INH: hyperthermia: hyperglycemia
      • Phenothiazine: hypo or hyperthermia
      • Insulin: severe hypoglycemia
      • Anesthetics
        • Propofol
        • Halothane
        • Enflurane
        • Sevoflurane
      • Theophylline (jitteriness)
      • Disopyramide
      • Amphetamine (psychosis)
      • Tricyclic anti-depressants (parasympathomimetic effects
      • Lithium (tremor)
      • Antimalarials (muscle and macular degeneration)
      • Cocaine:
        • Hypertension with cerebral hemorrhage
        • Severe cortical and coronary artery vasospasm
        • Hemorrhage if underlying vascular abnormality is present
      • Heroin: pulmonary edema, transverse myelitis
      • PCP: hallucinations, self-destructive behavior, changing nystagmus
      • Anticonvulsants: liver failure, ophthalmoplegia (phenytoin; rarely carbamazepine)
      • Penicillin: large IV doses; setting of renal failure
      • Alcohol withdrawal: hypothalamic disinhibition, delirium, tremens

Infections Associated with GTCS

  • The cortex must be involved to initiate a major motor GTCS
    • Diffuse inflammation of the meninges occurs with infections that spread to the arachnoid and pia mater
    • Cortical stroke is caused by:
      • Tuberculosis (endarteritis, meningeal involvement)
      • Cryptococcosis (meningeal)
      • Mucormycosis (sinus spread)
      • Aspergillus (venous spread); often lung abscess is the source
      • HIV (blood vessel involvement directly; endothelial cell damage)
      • Syphilis (proliferative endarteritis); often brainstem
      • Subacute bacterial endocarditis (aneurysms; late focal hemorrhage)
      • Cysticercosis (calcification with adjacent cysts)
      • Toxicants (toxocana canis); primarily children
  • Direct cortical involvement:
    • SBE (gram negative or positive)
    • HIV
    • Toxoplasmosis
    • Opportunistic infections in an HIV infected patient
    • Parasitic infections (tropical) (setting of metabolic dysfunction)
  • Other causes of GTCS:
    • Venous infarction (often postpartum)
    • Vascular (infarction, hemorrhagic, malformation)
    • Tumor (primary and metastatic)
    • Head injury (acute or distant past)
    • Prior cortical scar (setting of metabolic dysfunction)
    • Prior stroke (at least 10% of stroke patients)
    • Anticonvulsant withdrawal
    • Alcohol withdrawal
  • Precipitating factors for GTCS:
    • Failure of drug compliance
    • Alcohol withdrawal
    • Specific drugs that cause seizures:
      • Cocaine
      • Antihistamines
      • High doses of penicillin (renal failure)
      • Phenothiazine (particularly if there is a preexisting structural lesion)
      • Phosphodiesterase inhibitors (asthma)
    • Hypoglycemia (missing breakfast then administering insulin in a diabetic)
    • Stress
    • Lack of sleep

Differential Diagnosis of GTCS by Age

  • Adolescent:
    • Idiopathic
    • Noncompliance with drug therapy
    • Drugs (cocaine, PCP, barbiturate, and alcohol withdrawal)
    • Metabolic (hypoglycemia)
    • Vascular (infarction embolus, hemorrhage malformations)
    • Tumor (rare)
    • Encephalitis
    • Head injury
    • Migrational disorders (nodular and band heterotopia; microdysgenesis)
    • Hippocampal sclerosis with secondary generalization
    • Syndromic (tuberous sclerosis); Chromosal defects
    • Mitochondrial disease
  • Adults under 40 years of age
    • Lack of AED drug compliance
    • Drugs (cocaine)
    • Vascular (embolus, hemorrhage, infarction)
    • Tumor (primary greater than secondary)
    • Infection (HIV associated)
    • Head injury
    • Cardiac arrhythmia (global cerebral ischemia)
    • Metabolic causes
    • Migrational disorders
  • Adults over 40 years of age
    • Vascular; embolus > infarction > hemorrhage
    • Lack of drug compliance (AED's)
    • Cardiac arrhythmia
    • Tumor (metastatic > primary)
    • Metabolic causes
    • Drugs (hypnotic sedative withdrawal; elicit)
    • HIV (associated opportunistic infection)
    • Herpes simplex infection (TLE with secondary generalization)
    • Migrational disorders
  • Adults over 60 years of age
    • Cardiac arrhythmia
    • Cerebrovascular disease (infarction > embolus >hemorrhage)
    • Metabolic dysfunction
    • Prior CNS structural lesion
    • Tumor (metastatic >meningioma > lymphoma)
    • Herpes simplex infection (bitemporal and frontal lobe involvement)
    • Rarely migrational disorder

Absence Seizures

  • General features:
    • Onset between 3–6 years of age
    • Most prevalent in first 10 years of life
    • Rarely persist into adulthood
    • Petit mal status is rare in adults
    • Seizures are short, less than 30 seconds
    • Never associated with an aura or post ictal confusion
  • Clinical types:
    • Simple typical absence:
      • Sudden onset of impaired consciousness associated with absence of facial expression and without motor or behavioral manifestations
      • Approximately 10% of absence seizure patients have this type
    • Complex typical absence seizure:
      • Accompanied by motor, behavioral or autonomic features
  • Clinical features:
    • Sudden onset of a blank stare
    • Arrest of motor activity
    • Clonic components: eye blinking, nystagmus, rapid jerking of the arms
    • Tonic postural contraction causing flexion or hypertonic extension postures
    • Loss of tone causes head nodding or dropping of objects
    • Patients rarely fall
    • Automatisms:
      • Occur in approximately 40% of typical absence seizures
      • Automatisms are semi-purposeful movements and behaviors which the patient cannot recall. They are perseverative or de novo:
        • De novo: simple acts such as hand rubbing, licking the lips, chewing, scratching, picking at clothes
        • Perseverative: dealing cards, handling an object or playing a hand game
        • Speech is usually dysarthric, it may be normal or perseverative
    • Autonomic manifestations:
      • Pupillary dilation
      • Hyperhidrosis
      • Salivation
      • Piloerection
      • Urinary incontinence
  • Atypical Absence Seizure (AAS):
    • Onset prior to age 5
    • Associated with other generalized seizure types and mental retardation EEG: 1.5–2.5 Hz spike-and-wave discharges or multiple spike-and-waves that are irregular or asymmetrical; interictal EEG is unusually slow and demonstrates multifocal epileptiform features.
    • Average seizure is longer than typical absence; onset is less abrupt
    • Diminished postural tone; tonic or myoclonic activity is more frequent than in typical absence seizures:
      • Automatisms are more perservative in atypical absence seizures than in typical absence seizures (AS)
      • Postural tone changes are more frequent in atypical absence seizures (AAS) than typical absence seizures (TAS)
      • A blank stare or change in facial expression > AAS than TAS
      • Smiling automatism common in AAS
      • Hyperventilation may induce absence seizures; this rarely occurs in CPS or GTCS
      • Photic stimulation may induce GTCS, absence, atypical absence or CPS
    • Adult petit-mal status occurs rarely and usually presents as confusion or stupor
    • Between 40–60% of patients with TAS have GTCS
      • First absence to first CTS: 1 to 16 years
      • AAS: almost always have GTCS's, myoclonic, tonic and TAS seizures concomitantly
      • Partial seizures are uncommon in AAS and TAS
  • Absence Syndromes:
    • Generalized idiopathic epilepsies:
      • Childhood absence
      • Juvenile absence
      • Juvenile myoclonic
    • Generalized symptomatic epilepsies:
      • Lennox–Gastaut Syndrome
      • Epilepsy with myoclonic astatic seizures
      • Epilepsy with myoclonic absences
  • Generalized idiopathic epilepsies:
    • Childhood absence:
      • Typical absence (simple and complex)
      • Onset: 3–5 years and puberty
      • Genetic predisposition
      • Girls more frequently affected
      • Frequent: up to several hundred per day and may cluster
      • EEG: bilateral symmetrical synchronous 3 Hz spikes and wave discharges; normal interictally
      • Absences may remit during adolescence: 25–30% develop GTCS
    • Juvenile absence Epilepsy:
      • starts around puberty
      • seizures are more sporadic
      • fewer retropulsive movements
      • generalized tonic-clonic and myoclonic seizures occur upon awakening
      • males equally affected
      • EEG: spike-and-wave is faster than 3 Hz

Juvenile Myoclonic Epilepsy of Jansen:

  • Starts 12–18 years of age (few patients start in the late 20's) approximately 4–10% of epilepsy
  • Genetics:
    • AD
    • Chromosome 6q; 15q
  • Early morning: mild to moderate myoclonic jerks of the neck, shoulders and arms
  • Patients may just notice shakiness or nervousness upon awakening or drop or throw objects (hair brush)
  • GTCS occur in 90% of patients: 1/3 suffer absence seizures
  • Myoclonic jerks may culminate in GTCS
  • Seizures precipitated or increased by awakening, fatigue, alcohol or by recreational drugs; 30–35% of patients suffer absence attacks
  • EEG: interictal 3.5 to 6 Hz, irregular spike and wave and multiple spike and wave complexes
  • Rapid 10–16 Hz spikes followed by irregular slow waves are noted during the myoclonic seizures
  • EEG activated by sleep deprivation and photic stimulation
  • JME persists for life
  • Drinking on the weekend in adults may initiate myoclonic seizures with GTCS on Monday morning

Epilepsy with Generalized Tonic-Clonic Seizures on Awakening

  • General features:
    • Onset occurs in the second decade
    • 90% of seizures occur on awakening at any time of the day
    • May occur with relaxation in the evening
    • Associated with absence and myoclonic seizures

Generalized Symptomatic Epilepsies Lennox–Gastaut Syndrome

  • Onset usually prior to age 5 (may start as late as age 8)
  • Tonic, atonic and absence seizures are most typical. May also have myoclonic, GTCS or partial seizures
  • EEG: slow spike-and-wave less than 3 Hz; abnormal background multifocal abnormalities
  • Pathology: both structural and metabolic
  • Seizures are refractory
  • Developmental outcome guarded

Epilepsy with Myoclonic-Astatic Seizures

  • Onset between the ages of 7 months to 6 years (usually between 2–5 years)
  • Normal developmental background
  • Hereditary predisposition
  • Boys are affected twice as often as girls (unless onset is within the first year)
    • Seizures: myoclonic, astatic; myoclonic-astatic, absence or tonic-clonic, frequent status epilepticus
  • EEG: initially normal, but with 4–7 Hz theta/rhythms; evolves into irregular fast spike-or-multiple spike-and-wave complexes

Epilepsy with Myoclonic Absences

  • Onset usually at 7 years of age
  • Boys more affected than girls
  • EEG: similar to absence seizures
  • Seizures are frequent and less responsive to medication than with childhood absence seizures
  • Mental deterioration and evolution to Lennox–Gastaut occurs

Landau–Kleffner Syndrome

  • General features:
    • Presents between 3–9 years
    • An acquired aphasia associated with seizures
    • Seizures may be GTCS, myoclonic or partial
    • Word deafness with normal hearing is the seminal feature
  • EEG:
    • Spike activity over the central temporal regions
    • Multifocal spike and slow wave patterns may occur

Absence Status Epilepticus

  • Clinical features:
    • Sustained impairment of consciousness
    • Patients are confused
    • Partially responsive and able to perform activities of daily living
    • Facial twitching
    • Eye blinking
    • Staring
    • Automatisms
    • EEG: generalized irregular approximately 3 per second spike-and-wave discharges; prolonged generalized bursts of spike-and-wave discharges or irregular slow spike-and-wave discharges
    • Ictal stupor in adolescents with history of childhood absences after seizure free interval
    • Most commonly arms, neck and facial muscles are involved
    • More common in children than adults

Electrical Status Epilepticus During Slow Wave Sleep

  • General features:
    • Present between 1–12 years of age
    • Cognitive regression
    • Patient may not have clinical seizures
  • EEG:
    • Seizures are commonly nocturnal
    • Continuous spike and slow wave during NREM sleep
    • Seizures and EEG changes may disappear during the second decade
    • Continued cognitive and language deficits
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