PERIODIC LIMB MOVEMENTS/RESTLESS LIMB SYNDROME: + Not primary sleep disorders, but involuntary movements interfere with sleep + Seen in > 20% of those over 60 SLEEP APNEA: + Often seen in rapid weight gain, high blood pressure + Involves heavy snoring, prolonged gaps in breathing TREATMENT OF SLEEP DISORDERS: CHRONIC DRUG USE USUALLY EXACERBATES PROBLEM! For example, virtually all such drugs interfere with REM and circadian sleep cycles + And many are addictive, with serious withdrawal problems Melatonin is a possible exception Despite this, over the last 40 years, hypnotics have comprised 15% of ALL drug prescriptions COMMONLY-PRESCRIBED DRUGS INCLUDE: Drugs with antihistaminergic properties: + Tricyclics, especially amitriptyline + Over-the-counter sleep preparations are classic antihistamines Drugs which act at the GABA-A receptor: + Sedatives such as barbiturates or chloral hydrate + Alcohol + Benzodiazepines Melatonin THE EPILEPSIES EPILEPSY: A DISORDER OF THE BRAIN CHARACTERIZED BY PERIODIC AND UNPREDICTABLE SEIZURES SEIZURES: CAN BE EPILEPTIC OR NON-EPILEPTIC Epileptic when they occur without evident provocation RESULT FROM RUN-AWAY ACTIVITY IN SOME PART OF THE CEREBRAL CORTEX OR LIMBIC SYSTEM Hence clearly visualized by EEG STATUS EPILEPTICUS: Any seizure lasting for more than an hour SEIZURE CLASSIFICATION: There are at least two different ways of classifying the epilepsies: 1. Epileptic Syndromes: There are over 40 known epileptic syndromes, differing by area of brain affected, etiology, etc: + For example, temporal lobe epilepsy, or epilepsy triggered by visual stimuli 2. Classification by TYPE of seizure There are two major types of seizure, each with numerous sub-types. 1. Partial Seizures: Those localized to one region of the brain, hence limited behavioral effects; "focal" seizures + SIMPLE Partial Seizures: Key feature is preservation of consciousness Diverse manifestations: if motor cortex for left thumb is involved, left thumb shows involuntary jerking, called CLONIC seizures. If somatosensory area for left thumb is involved, one gets numbness or PARATHESIS of the left thumb. + COMPLEX Partial Seizures: Impaired consciousness lasting 30 seconds to 2 minutes often accompanied by purposeless movements such as hand wringing or lip smacking + PARTIAL with secondary general seizures: Begins as Simple or Complex partial seizures Evolves into generalized seizures Typically involve loss of consciousness Accompanied by generalized TONIC seizures (rigidity), OR CLONIC seizures (jerking, rigidity followed by relaxation) or TONIC-CLONIC seizures 2. Generalized Seizures: Involve virtually all cortex, in both hemispheres + ABSENCE Seizures: Abrupt onset of impaired consciousness Associated with staring, cessation of on- going activity Typically last less than 30 secs + MYOCLONIC Seizures: A brief, violent, shock-like muscular contraction Localized or generalized Contractions are brief (~ 1 sec) + TONIC-CLONIC Seizures: As above, but not preceded by a partial seizure EPIDEMIOLOGY: EPILEPSY IS MORE COMMON IN THE YOUNG PARTIAL SEIZURES: Account for some 60% of all epilepsies Etiology usually some form of focal brain damage GENERAL SEIZURES: Account for some 40% of all epilepsies Etiology usually GENETIC Most common single type is Juvenile Myoclonic Epilepsy: + 10% of all epilepsies + Onset in early teens + Involves all major sub-types of general seizures + Cause appears to be genetic, but involving multiple genes, hence non-Mendellian EPILEPTIC MECHANISMS ONE THING IS CLEAR: EPILEPSY INVOLVES ABNORMAL EXCITABILITY OF NEURONAL ASSEMBLAGES It is less certain whether increased excitability is due to over-excitation, under-inhibition, or both THE ELECTROPHYSIOLOGY OF EPILEPSY: EEG Level: + "Interictal" (inter-seizure) spikes: Identify the epileptic focus in brain Are NOT a seizure, but reliably precede seizures Are followed by a silent period Then a storm of seizure activity Single Neurons: A firing burst occurs during the interictal spike Followed by a silent period, characterized by a long-term DEPOLARIZATION SHIFT, increasing the potential excitability of the neuron Following which the neuron fires at very high frequencies during the actual seizure (SEE FIGURE) THE NEUROCHEMISTRY OF THE EPILEPSIES Glutaminergic over-excitation: + Glutamate is the primary excitatory neurotrans- mitter + Kindling: Common animal model Repeated low-level electrical stimulation of the amygdala (levels initially too low to cause epilepsy) eventually leads to general seizures - This is a kind of "learning" that lasts a lifetime - Involves NMDA receptor changes + Excitotoxicity: Epileptic over-release of glutamate KILLS target neurons This cell death apparently impacts inhibitory mechanisms GABA-A Inhibition: + Small reductions in GABA, or GABA-A antagonists, cause epileptic seizures + Increases in GABA, or GABA-A agonists, protect against epilepsy Enhancement of Na+ channel inactivation + High frequency firing during seizures requires rapid opening and closing of voltage-gated sodium channels + The inactivation is caused by a sort of molecular plug, the INACTIVATION GATE + Some drugs can prolong the closure of the Na+ channel by the inactivation gate, hence slowing firing rate and epileptic high- frequency firing Thalamic Calcium channels: + Absence seizures involve rhythmic firing of thalamic neurons, and a corresponding firing of cortical cells + This thalamic 3 cps rhythm involves calcium channels (T-type calcium channels) + Thus blocking such channels can block absence seizures THE PHARMACOLOGY OF ANTIEPILEPTIC MEDICATION CHARACTERISTIC OF MOST ANTIEPILEPTICS IS THE ABILITY TO POTENTLY INDUCE P450 ENZYMES Causing complex drug interactions And tolerance ALSO CHARACTERISTIC ARE A VARIETY OF SIDE EFFECTS: SEDATION ALLERGIC REACTIONS BIRTH DEFECTS THE BARBITURATES: PHENOBARBITAL: The oldest antiepileptic (ca. 1912) Mechanism: An agonist of the GABA-A receptor Side Effects: Sedation is the universal side-effect but tolerance does occur Low toxicity, low cost keep this a popular drug, despite the sedative effects Related compounds include Mephobarbital and Primidone THE HYDANTOINS: PHENYTOIN (Dilantin, diphenylhydantoin) Chemically related to the barbiturates Product of a deliberate search using animal models Mechanism: increased refractory period in sodium channels due to prolongation of blockade by the inactivation gate Lacks strong sedative properties of the barbiturates But has LOTS of potential side-effects, including: + Cerebellar signs or even damage + A variety of eye-movement problems, some associated with cerebellar dysfunction + Hirsutism + digestive problems + Gingival overgrowth + Bone problems + Common allergic reactions, including severe rashes CARBAMAZEPINE: (Tegretol) Chemically related to the TCAs Mechanism: same as phenytoin Side effects: rather like phenytoin Other uses include: + Treatment of trigeminal neuralgia + Bipolar depression ETHOSUXIMIDE: Efficacious against absence seizures By blocking thalamic calcium T currents Side effects: Nausea, vomiting Sedation Hiccups Blood disorders VALPROIC ACID: Very broad efficacy against all forms of seizure Blocks both sodium channel recovery AND T current PLUS having a positive effect on GABA synthesis Side-effects are limited, and include: Nausea and vomiting Infrequent sedation rashes Rare but fatal hepatotoxicity BENZODIAZEPINES: Treatment of choice for acute, emergency cessation of status epilepticus Only Cloneazepam and Clorazepate used for longer-term treatment And permanent resistance to antiepileptic effects often develops Mechanism: GABA-A agonists GABAPENTIN: One of the newest compounds Increases GABA release Can be used with other antiepileptics without drug interactions Side-effects are rather limited But so is information! TREATMENT CONSIDERATIONS: PRIMARY DISTINCTION: Drugs effective against absence seizures: Clonazepam, ethosuximide, valproate Drugs effective against all other forms of seizure PRIMARY CLINICAL CONSIDERATION: Identify a drug with minimal side effects for a given patient!