ENCEPHELOPATHY & STATUS EPILEPTICUS

Dr. Amish Bhutani

Encephelopathy

- a general alteration in brain function manifesting as an attentionaldisorder - between a hyperalert agitated state and coma, and typically refers to the commonly encountered clinical scenario of diffuse brain dysfunction felt to be due to a systemic, metabolic, or toxic derangement.

Global encephalopathy Delirium Sepsis Organ failure- hepatic, renal Medication related - sedatives, hypnotics, analgesics, H2 blockers, antihypertensives Drug overdose Electrolyte disturbance - hyponatremia, hypernatraemia,

hypoglycemia, hypocalcaemia Hypotension/hypoperfusion

Hypoxia Meningitis – bacterial, viral, fungal Encephalitis Subarachnoid hemorrhage ( SAH ) Wernicke's disease Seizure - postictal or nonconvulsive status Hypertensive encephalopathy Hypothyroidism- myxedema

Status Epilepticus Refers to continuous seizures or repititive, discrete seizures with impaired consciousness in the interictal period.Duration of seizure activity is 15 - 30 minutes. Consider status epilepticus as a situation in which the duration of seizures prompts the acute use of anticonvulsant therapy.

Can be – > Generalised Convulsive status epilepticus ( GCSE)

- persistent, generalised electrographic seizures, come and tonic-clonic movements

> Non-convulsive status epilepticus - persistent absence seizures or focal siezures, confusion or partially impaired consciousness and minimal motor abnormalities

Why should it draw your attention ?

Consequences of status epilepticus – > cardiorespiratory dysfunction,> hyperthermia,> metabolic derangements, and > irreversible neuronal injury

“ If appropriate therapy is delayed, SE can cause permanent neurologic sequelae or death …”

* CNS injury can occur even when the patient is paralyzed with neuromuscular blockade but continues to have electrographic seizures

Precipitating event ?

Anticonvulsant withdrawal or noncompliance ? Metabolic disturbances ?Drug toxicity ?CNS infection ? CNS tumors ?Refractory epilepsy ?Head trauma ?

Drugs which can cause seizures

• Antibiotics– Penicillins– Isoniazid– Metronidazole

• Anesthetics, narcotics– Halothane, enflurane– Cocaine, fentanyl– Ketamine

• Psychopharmaceuticals– Antihistamines– Antidepressants– Antipsychotics– Phencyclidine– Tricyclic antidepressants

Importance of EEG ?

After 30 - 45 minutes of uninterrupted seizures, the signs may become increasingly subtle. For example – Mild clonic movements of only the fingers or fine, rapid

movements of the eyes. Paroxysmal episodes of tachycardia, hypertension, and pupillary

dilation. In such cases, the EEG may be the only method of establishing the diagnosis. Perform EEG :- if the patient stops having overt seizures, yet remains comatose patient with GCSE has been paralyzed with neuromuscular

blockade in the process of protecting the airway.

Prolonged seizures

Duration of seizure

Life threatening

systemicchanges

DeathTemporary

systemicchanges

Respiratory

• Hypoxia and hypercarbia

- ß ventilation (chest rigidity from muscle spasm)- Hypermetabolism (Ý O2 consumption, Ý CO2

production)- Poor handling of secretions- Neurogenic pulmonary edema?

11

Hypoxia

• Hypoxia/anoxia markedly increase the risk of mortality in SE

• Seizures (without hypoxia) are much less dangerous than seizures and hypoxia

Neurogenic pulmonary edema

• Marked increase of pulmonary vascular pressure

Acidosis

• Respiratory• Lactic

– Impaired tissue oxygenation– Increased energy expenditure

Hemodynamics

• Sympathetic overdrive – Massive catecholamine /

autonomic discharge– Hypertension– Tachycardia– High CVP

Exhaustion Hypotension Hypoperfusion

0 min 60 min

GlucoseG

luco

se

Seizure duration

30 min

SE

SE + hypoxia

• Hyperdynamic phase – Hyperglycemia

• Exhaustion phase– Hypoglycemia

develops– Hypoglycemia

appears earlier in presence of hypoxia

– Neuronal damage ensues

Hyperpyrexia

• Hyperpyrexia may develop during protracted SE, and aggravate possible mismatch of cerebral metabolic requirement and substrate delivery

• Treat hyperpyrexia aggressively– Antipyretics, external cooling– Consider intubation, relaxation, ventilation

Other alterations

• Blood leukocytosis (50% of children)• Spinal fluid leukocytosis (15% of children)• Ý K+

• Ý creatine kinase• Myoglobinuria

Management• Attend to any acute cardiorespiratory problems or

hyperthermia• Perform a brief medical and neurologic examination• Establish venous access• Send blood samples for laboratory studies to identify

metabolic abnormalities• Anticonvulsant therapy

Oxygen, oral airway. Avoid hypoxia!

Consider bag-valve mask ventilation. Consider intubation

IV/IO access. Treat hypotension, but NOT hypertension

A

B

C

Management

• Secure the Airway– It may be difficult to intubate the actively seizing

patient– Stop or slow seizures first, give O2, consider BVM

ventilation– If using paralytic agent to intubate, assume that SE

continues

Initial investigations

• Labs– Na, Ca, Mg, PO4 , glucose– CBC– Liver function tests, ammonia– Anticonvulsant level– Toxicology

Initial investigations

• Lumbar puncture– Always defer LP in unstable patient, but never delay

antibiotic/antiviral rx if indicated• CT scan

– Indicated for focal seizures or deficit, history of trauma or bleeding d/o

Correct Metabolic factors

• Hypoglycaemia – If RBS < 60mg %, use 25 % Dextrose iv fast– Monitor hourly Sugar levels

- Hyperglycemia has no negative effect in SE (as long as significant hyperosmolality is being avoided)

• Hyponatraemia :– Use 0.9 % NS, 3 % NS according to the severity of

hyponatraemia

• Hypocalcaemia :– Calcium gluconate or Calcium Chloride can be used

Anti-epileptic Drugs ( AED )

• The longer you wait with anticonvulsant, the more anticonvulsant you will need to stop SE

• Most common mistake is ineffective dose

Phenytoin or Diphenylhydantoin

• MOA-– Stablizing influence on neuronal membrane– prolongs the inactivated state of voltage sensitive

neuronal Na channel– high frequency discharges are inhibited

• Not a CNS depressant• T ½ = 12-24 hrs• Metabolized by hepatic ER by hydroxylation. Chance for

drug interactions.• Shift from first to zero order elimination within therapeutic

concentration range.

Adverse effects At therapeutic levels

• Gum hypertrophy – commonest– More in young– d/t gingival collagen overgrowth– Maintain oral hygiene

• Hirsutism, coarsening of facial features

• Megaloblastic anaemia – decrease folate absorbtion

• Osteomalacia- desensitizes target tissue to vit d

• Inhibit insulin release- hyperglycaemia

• Hypersensitivity rxns

At toxic doses

• Cerebellar & vestibular manifestations- ataxia, vertigo, diplopia, nystagmus

• Drowsiness, behavioral alterations, hallucinations, rigidity

• Nausea, vomiting• i.v. injection

– thrombosis of the vein – Cardiac arrythmias

Gingival Hyperplasia Induced by Phenytoin

Fetal Hydantoin Syndrome

When used during pregnancy

Hypoplastic phalanges

Hare lipCleft palatemicrocephaly

Interactions of phenytoin

• Levels are increased by – isoniazid, sulfonamides • Levels decreased by – enzyme inducing drugs

- phenobarbitone • Competitively inhibits warfarin metabolism

Fosphenytoin

• A Prodrug. Given i.v. or i.m. and rapidly converted to phenytoin in the body.

• Avoids local complications associated with phenytoin: vein irritation, tissue damage, pain and burning at site, muscle necrosis with i.m. injection, need for large fluid volumes.

• Otherwise similar toxicities to phenytoin.

Stevens-Johnson Syndrome

Valproic Acid / Sodium Valproate

• Effective in multiple seizure types.• MOA-

– Phenytoin like frequency dependent prolongation of Na channel inactivation

– Ethosuximide like Weak attenuation of Ca mediated ‘T’ current

– Augmentation of GABA by inhbiting breakdown and increasing synthesis

Adverse effects

• Fulminant hepatitis– Occurs in children < 3 yrs of age– High risk patients with preexisting hepatic diseases or

who receive other anticonvulsant drug

• Polycystic ovarian disease & menstrual iregularities• During pregnancy- spina bifida & other neural tube defects• Anorexia, vomiting• Alopecia, curling of hair, increased bleeding tendency• Drowsiness, ataxia – dose related S/E

uses

• DOC for absence sz• Alternative/ adjunct drug for GTCS, SPS, CPS• Migraine- prophylactic efficacy• Mania and bipolar illness

Interactions

• Displaces phenytoin from protein binding site and causes phenytoin toxicity

• Concurrent administration of clonazepam and valproate is contraindicated – absence sz precipitated

• Fetal abnormalities are common when valrpoate & carbamazepine used together

• Sedative - hypnotic- anxiolytic drugs.• MOA

– GABA facilitatory action – Bind to another site on GABA receptor, enhances

presynaptic/ postsynaptic inhibition and ↑ frequency of opening of Cl channel

• Metabolized by liver• Diazepam undergo enterohepatic circulation

Benzodiazepines

Adverse effects of BZD

• Dizziness, vertigo, disorientation, amnesia, prolongation of reaction time

• Weakness, blurring of vision, dry mouth, urinary incontinence

• Aggravate sleep apnoea• Dependence liability is low

Interaction• Synergise with alcohol & other CNS depressants• Concurrent use with valproate- psychotic symptoms

Ethosuximide

• Raises sz threshold • Blocks Ca++ currents (T-currents) in the

thalamus.• Not effective in other seizure types

Adverse effects- • GI complaints most common• CNS effects: drowsiness lethargy• Hypersensitivity rxns are rare

Phenobarbital

• The only barbiturate with selective anticonvulsant effect.

• MOA-– Bind at allosteric site on GABA receptor and ↑ duration of

opening of Cl channel.– ↓ Ca-dependent release of neurotransmitters at high doses.– raises sz threshold

Adverse Effects-• Behavioral abnormalities• Diminution of intelligence• Impairment of learning and memory • Rashes, megaloblastic anaemia, osteomalcia

Interactions

• Induce metabolism of steroids – contraception failure, warfarin

• Synergistic effect wit alcohol and other CNS depressant

• Valproate increases concentration of phenobarbitone

• Gabapentin: Developed as GABA analogue. Mechanism: Increases release of GABA by unknown mechanism.

• Vigabatrin: Irreversible inhibitor of GABA transaminase. Potential to cause psychiatric disorders (depression and psychosis).

• Tiagabine: decreases GABA uptake by neuronal and extraneuronal tissues.

Enhancers of GABA Transmission

Other Na Channel Blockers

• Carbamazepine: may have adrenergic mechanism as well. Serious hematological toxicity: aplastic anemia. Antidiuretic effect (anti ADH).

• Also for trigeminal neuralgia• Lamotrigine: possible other mechanisms.

Effective in Absence seizures and has antidepressant effects in bipolar depression. No chronic associated effects.

Other Drugs

• Topiramate; multiple mechanisms of action (Na channel, GABA enhancement like BZD, antagonist at AMPA subtype of glutamate receptors (not NMDA).

• Felbamate: multiple mechanisms: Na channel block; modulates glutamate transmission interacts with glycine site. Serious hematological and hepatic toxicities.

Non - convulsive status epilepticus

• How do you tell that patient’s seizures have stopped?

Non - convulsive SE ?

• Neurologic signs after termination of SE are common:– Pupillary changes– Abnormal tone– Babinski– Posturing– Clonus– May be asymmetrical

Non - convulsive SE ?

• If patient does not begin to respond to painful stimuli within 20 - 30 minutes after tonic - clonic SE, suspect non - convulsive SE– Urgent EEG

Conditions mimicking seizures

• Syncope• Hypoglycemic attacks• TIA• Panic attacks• Physiological jerks during sleep• Breath holding spells in children• Psycogenic ( hysterical) episodes

Syncope v/s seizures

Features syncope seizuresPrecipitating factors common rare

occurence Awake, mostly when upright Awake or sleep

Premonition( nausea,sweating, light Headedness)

Common Uncommon

Onset Less abrupt Abrupt

Jerking of limbs Occasional Frequent

Incontinence Rare Common

Post-ictal recovery Rapid Slow

Post-ictal confusion Uncommon Common

EEG Usually normal May be abnormal

Psychogenic episodes v/s seizures

features Psychogenic episode seizures

Age and gender Young, more in women Any age

Precipitating factors Emotional disturbances Lack of sleep, poor drug compliance

Occurs in sleep No Yes

Duration Minutes to hours Seconds to minutes

movements Vocalization, pelvic thrust, bizzare flinging of limbs

Tonic or tonic clonic jerks

eyes Forcibly close, resistance to opening open

Injuries, including tongue infrequent frequent

Post-ictal confusion, headache,sleep

Uncommon Common

Patterns of attacks Variable stereotyped