L. Jarrett Barnhill, M.D.
The relationship between seizure disorders and mental retardation is a complex one. When considered across the spectrum of mental retardation, the frequency and severity of epilepsy varies inversely with the level of mental retardation (Roberts, 1986). Among individuals with mild retardation, the distribution of various subtypes of seizures approximates the general population. This observation probably relates to lower rates of neuroanatomical abnormalities or metabolic disorders. The clinical response to anticonvulsant is also comparable to the general population. Among individuals with severe/profound retardation, increased rates of underlying neurological abnormalities are manifested by a higher frequency of mixed seizure disorders, and an onset of seizures in infancy or early childhood (Ratey & Dynek, 1996; Roberts, 1986). This factor contributes to higher rates of uncontrollable seizures and neuropsychiatric complications. These clients may also require multiple anticonvulsants (AEDs), increasing the risk for medication side effects and pharmacokinetics interactions (Reynolds, 1985). Even with AED combinations, many clients continue to experience frequent seizures and risk further cognitive or behavioral deterioration. The degree of clinical deterioration relates to frequent seizures; early age of onset, level of seizure control and time required to establish control, and the presence of underlying neuroanatomical lesions (Dodrill, 1992; Trimble et al, 1996).
The type of seizure disorder is also influential in assessing outcome. Primary tonic-clonic generalized (TCGS) and absence seizures are often the easiest to control with conventional AEDs. Partial seizures may be less dramatic in presentation, but pose special management problems. Complex partial seizures (CPS) are characterized by an intrusive abrupt onset behavioral arrest; automatism; and post ictal confusion, somnolence, aphasia or behavioral changes (Kotagal, 1996). Previously called psychomotor or temporal lobe seizures, CPSs involve subtle changes in consciousness, as well as alterations in affective state, sensory perception; hallucinations; and motor activity (Mikita & Holmes, 1997). In the general population, complex partial seizures (CPS) are the most common presentation of adult epilepsy (Cascino, 1992) and are associated with the greatest risk for psychopathology (Hauser & Hesdorffer, 1996). This risk is related to disruption of the limbic system and resultant neurochemical changes (Stagno, 1996). In particular, ictal fear and autonomic changes may be markers for increased risk for subsequent psychopathology. Affective and anxiety disorders are the most common type of neuropsychiatric complaints, while psychosis effects nearly 7% of clients with CPS (Perrine, 1991). CPS with an early onset, inadequate seizure control, and underlying disorders of language development may increase risk for aggressive behaviors (Pincus & Lewis, 1991).
Among individuals with severe/profound retardation, mixed seizure disorders are frequent problems. Poorly controlled, infantile spasms are frequently associated with mental retardation and an autistic-like syndrome (Dulac, Plouin, & Schlumberger, 1996). Lennox Gastaut Syndrome occurs in clients with developmental disorders and includes tonic-clonic, clonic, atypical absence, various drop attacks, and other generalized seizures (Farrell, 1996). Seizures may also result from focal brain lesions and increase the risk for neuropsychiatric disorders and further compromises in adaptability.
Due to treatment refractoriness, there is a frequent need for high serum levels or multiple AEDs. As a result, neurobehavioral and negative cognitive side effects are commonplace (Brown, 1991). Several anticonvulsants have behavioral toxicity. For example, phenobarbital can produce increased irritability, SIB, and hyperactivity. (Uthman & Beydoun, 1997). Dilantin may produce metabolic changes related to folate metabolism (Graves & Ramsay, 1996). Valproic acid has been associated with carnitive mediated deficits in short chain fatty acid transport and metabolism by the mitochondria (Dean, 1996). The side effect of these anticonvulsant on cognition, and neurobehavioral status must be weighed in against the risk of continued seizure activity.
The introduction of lamotrigine (Messenheimer, 1996), topiramate (Fisher, 1996), gabapentin (McLean, 1996), gabatril (Fisher, 1996), vigabatrin (Ben-Menachem, 1996), tiagabine (Fisher, 1996), and felbamate (Faught, 1996) have been helpful in the management of focal and partial seizure disorders. These drugs have more refined mechanisms of action, but have limitations. For example, the use of felbamate has been limited by the risk of aplastic anemia (Faught, 1996). Many clients with mixed seizure types or CPS remain treatment resistant to these new AEDs. Interestingly, lamotrigine, gabapentin, topiramate have joined carbamazepine and valproic acid in the treatment of mood disorders (Pollack & Scott, 1997) and aggressive behavior (Sovner & Fogelman, 1996; Fava, 1997).
Mental Retardation and Psychopathology
Population studies indicate that rates of psychiatric disorders approach 40% of the population of individuals with mental retardation (Parsons et al, 1984). The categories of psychopathology vary depending on the level of mental retardation and deficits in adaptive behavior, and genetic vulnerability to disorders such as affective illness, anxiety disorders, and schizophrenia (Ruedrich & Menolascino, 1984). Nonspecific behavior problems in individuals with mild retardation may relate to either the presence of seizures, language disorder, or neurological complications. Aggressive behavior in clients with mild retardation may relate to past history of abuse, neglect; delayed language development; seizure disorder or brain dysfunction; and dissociative episodes (Pincus and Lewis, 1991).
Among individuals with profound retardation, impaired adaptive behaviors, excitability, explosiveness, hyperactivity, agitation and pacing, irritability and aggression, stereotypic behaviors and self-injurious behaviors generate psychiatric referrals (Feinstein & Reiss, 1996). Mood disorders frequently produce a baseline exaggeration in irritability, self-injury, agitation and aggression (Sovner, 1996). Bipolar illness, especially cyclical episodes of mania, may produce periods of extreme hyperactivity, sleep and appetite disturbance, and marked increases in externally related aggression (Goodwin & Jamison, 1990).
Anxiety disorders or posttraumatic stress disorder may present with some SIB in response to frustration or threatening situations; fearfulness and avoidant behaviors. Panic attacks may resemble rage outbursts, and result in aggression or self-injury (Sovner, 1996).
Psychoses must be distinguished from delirium, or cognitive disintegration due to overwhelming environmental stresses or psychotic mood disorders. Delirium is a state of brain failure associated with disorientation, and often is associated with either medical conditions, or reactions to medication regimens (Pincus & Tucker, 1985). Organic causes of delusions and hallucinations frequently involve damage to the temporal lobes or limbic structures (Hurley, 1996). The diagnosis of schizophrenia requires a careful differentiation of these organic hallucinations, delusions and thought disorganization. Clients with profound mental retardation who are nonverbal pose significant problems in the diagnosis of schizophrenia and the diagnosis of nonspecific psychosis is more accurate (Parsons et al., 1984 & Bregman, 1996).
The mental health clinician should take a systematic approach towards the client with mental retardation and epilepsy. Information is needed regarding past psychiatric, family, and developmental history, as well as the seizure disorder. Paroxysmal changes in mental status are frequently referred to as a fit, spell, orseizure. Careful history often fails to support the diagnosis of epilepsy. Many seizures are ambiguous and may require repeated EEGs, neuroimaging, and occasional telemetry and monitoring.
A detailed history should focus on the following: abruptness of onset, duration of the event, a concise description of level of consciousness, behaviors, and post ictal changes. A complex partial seizure will have an abrupt onset, behavioral arrest followed by highly stereotyped automatism that last approximately 60 seconds. Post ictally the client is slowly returning to conscious awareness while the risk of post ictal aggression is highest (Devinsky & Luciano, 1991; Cascino, 1992).
Among patients with established epilepsy, psychopathology can emerge at any point during cycle of a seizure. Prior to a seizure, a prodromal state or build-up may present with irritability, anxiety, intense dysphoria, poor concentration and sleep disturbance. These psychiatric symptoms may remain for several days and be relieved by a seizure (Perrine, 1991; Pincus & Tucker, 1985).
Some patients will experience a continuous aura, and present with catatonia, confusional episodes, or psychosis (So, 1996). Other patients with simple partial seizures may present with brief, stereotyped events, and minimal confusion or changes in awareness (Devinsky & Luciano, 1996).
Post ictally, clients are confused, disoriented, psychotic, agitated, or affectively labile (Neppe & Tucker, 1992). Some clients develop prolonged periods of psychiatric impairment, apparently triggered by the seizure. These symptoms may emerge after lucid interval where orientation and memory are in tact. In either case, frequent seizures worsen rather than improve the clients mental status (Stagno, 1996).
Interictally, psychopathology has been closely linked to complex partial seizures. The interictal personality is characterized by changes in personality associated with complex partial seizures. Hypergraphia, hyper-religiosity, irritability, viscosity, and hyposexuality are the primary symptoms. The symptoms are infrequent in patients with uncomplicated CPS (Fedio, 1986; Benson, 1986), but have not been studied in individuals with the developmental disabilities. Other forms of interictal psychopathology may differ from primary psychiatric disorders and present with atypical clinical features (Trimble, 1991; Trimble et al, 1996). Epilepsy associated mood disorders may manifest intense, episodic dysphoria or euphoria and increased irritability, suggestive of resemble rapid cycling or mixed bipolar states (Blumer 1991b; Robertson, 1991). Interictal psychosis may present with brief periods of positive symptoms in conjunction with preserved affective flexibility and social relatedness. Psychoses often appear as seizure frequency is declining, and often after 10-15 years of seizure activity. Factors may relate to the long-term risk for psychosis include: onset of seizures in adolescence, difficulty with control, alien tissue or hamartomas, handedness, and female sex (Trimble, 1991).
The treatment of psychopathology in clients with mental retardation and epilepsy requires a thorough assessment of psychosocial, environmental/ecological, as well as cognitive risk factors. In general, lower functioning clients have severe forms of uncontrollable epilepsy and brain dysfunction. The treatment of epilepsy-related psychotic disorders often require combinations of anticonvulsants and antipsychotics (Trimble, 1991). When drug combinations are used, the potential for pharmacokinetics interactions is likely. The phenothiazines may affect seizure threshold in poorly controlled patients. The atypical neuroleptics may be helpful treatment resistant psychosis, but clozapine (serum levels > 450 mcg/dl) may increase EEG abnormalities and risk for seizure activity (Sajatovic, 1995). Other atypical neuroleptics such as risperidone, olanzapine, and quetiapine may have significant drug interactions with several anticonvulsants (Casey, 1996; Ereshevsky, 1996). Two newer AEDs, gabapentin (McLean, 1996) and topiramate (Fisher, 1996) are excreted by the kidneys and are less likely to interact with antipsychotic drugs. These new generation AEDs are also used with increasing frequency in psychiatric patients with schizo affective and mood disorders (Pollack & Scott, 1997).
In clients with epilepsy, mood and anxiety disorders are the most common form of psychopathology. Clients with mood disorder and CPS report increased frequencies of hallucinations; prolonged depression interrupted with brief periods of euphoria or intense dysphoria (Blumer, 1991a). Premenstrual changes or increased irritability are also more commonly associated with mood disorder in the context of epilepsy (Blumer, 1991b).
The treatment of mood disorders involves several steps. The first step involves an assessment of current AEDs and a review of potential adverse behavioral side effects. Occasionally, dilantin may contribute to depression through disruption of folic acid metabolism (Reynolds, 1985). Valproic acid may also affect mood, possibly related to carnitive deficiencies (Dean, 1996). Phenobarbital has been closely linked to depression and suicidal behavior in patients with complex partial seizures (Stagno, 1996). Alternative anticonvulsant may be a reasonable step. Lamotrigine, and possibly gabapentin have some mood elevating properties (Pollack & Scott, 1997). Step two involves selection of antidepressant treatments. Tricyclic antidepressants have been the mainstay of treatment. The rapid escalation of (TCAs) doses may lower seizure threshold in inadequately controlled clients (Robertson, 1991). The SSRIs have fewer side effects but fluoxetine, paroxetine, and fluvoxamine may increase the blood levels of several AEDs and increase the risk of side effects (Stagno, 1996). Venlafaxine has been helpful in several patients with established epilepsy. The drug works rapidly, and has not been associated with significant changes in anticonvulsant blood levels (Stagno, 1996). Lithium may be of limited use, especially since the risk of organic mental changes is increased in patients with both epilepsy and brain dysfunction (Gadow & Poling, 1988).
Mania is uncommon in clients with seizure disorders often requiring right hemisphere onset as well as a genetic vulnerability to bipolar illness (Blumer, 1991b). In some individuals, brief periods of mania may be triggered by a seizure. The reason for lower rates of bipolar illness may relate to the mood stabilizing properties of most AEDs (Stagno, 1996).
Comorbid anxiety disorders are a heterogeneous group of affective disturbances. Panic disorder may be confused with CPSs that involve ictal fear (Pollack & Scott, 1997). In addition, nonepileptiform seizures (pseudoseizures) may add to the confusion since many clients will have an anxiety disorder or history of abuse (Cascino, 1992; Stagno, 1996). Treatment is similar to mood disorders, but starting doses of antidepressants need to be lowered. High potency benzodiazepines, like clonazepam, are also used in the treatment of seizures, and seem a logical choice (Neppe & Tucker, 1992). Clonazepam has been associated with increased irritability and aggression, and this form of disinhibition needs careful consideration (Perrine, 1991).
The rates of psychopathology vary inversely with level of mental retardation. Among individuals with severe/profound retardation, the clarity of psychiatric diagnosis is lacking. Patients may present with nonspecific behavior disorders that are impacted by associated brain dysfunction and epilepsy. The types of epilepsy may contribute to cognitive impairment. Among the clients with mild retardation, seizure type and psychopathology more closely resemble the general population. Among individuals with severe/profound retardation, developmental forms of epilepsy are commonly associated with progressive medical refractoriness, or severe cognitive impairments.
Psychiatric diagnosis is a complex process that requires the clinician to weigh the risk benefits of anticonvulsants with traditional psychotropic medications. A good working knowledge of pharmacokinetics helps in understanding potential iatrogenic psychopathology. Comfort with newer anticonvulsants may also be helpful since these drugs have fewer side effects, mood stabilizing properties and treatment benefits for difficult to control seizure disorders.
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For further information contact:
Jarret Barnhill, MD
The University of NC at Chapel Hill
Campus Box # 7160
Chapel Hill, NC 27599-7160