The potential importance of excitotoxic mechanisms in understanding lithium neurotoxicity is underscored by clinical and laboratory data which are reviewed here. A variety of different animal models of neurotoxicity are discussed as potential strategies for exploring excitotoxic aspects of lithium. Clinical research strategies suggested by the excitotoxic concept are also discussed, including use of neuroprotective drug treatment to prevent lithium induced irreversible brain damage.
1. In recent years, there has been an exponential growth of basic and clinical research directed towards understanding pathophysiological aspects of the brain's own excitatory amino acid (EAA) neurotransmitter systems. Excessive excitatory neurotransmission appears capable of producing a variety of serious acute or chronic derangements of neuronal metabolism. These include increased levels of intracellular calcium, increased free radical formation, depletion of neuronal energy metabolism as well as breakdown of cellular defenses leading at times to lipid peroxidation and neuronal injury and death (Olney, 1989; Jesberger and Richardson, 1991; Dutka and Hallenbeck, 1991).
2. Clinical models of excitotoxic neural disease include acute fulminant illness leading to sudden neurological deficits as well as chronic insidious neurotoxic processes. Excessive concentrations of EAA are most likely to be a causative factor in acute fulminant forms of disease as typified by the neurological sequelae of severe hypoxia, ischemia, and status epilepticus (Olney, 1989). Also, acute excitotoxic lesions are produced in cerebellum by drugs such as harmaline and ibogaine which may act in part at a post receptor level (i.e., neuronal sodium channels) (Deecher et al., 1992).
3. In more chronic insidious forms of disease (such as Huntington's, Alzheimer's and Creutzfelt Jakob syndrome) it appears more likely that EAA produce neuronal injury through an interaction with other risk factors. Risk factors may include increased sensitivity of EAA receptors (Cotman et al., 1992), compromised neuronal defenses against oxidative stress (Coyle and Puttfarken, 1993) or impairments in neuronal energy metabolism secondary to mitochondrial disease (Albin and Greenamyre, 1992) or glucocorticoids exposure (Stein-Behrens et al., 1994). Neurotoxicity caused by glucocorticoid exposure (whether stress or drug induced) is especially likely to occur in hippocampus and may be caused by a combination of factors including increased levels of excitatory amino acids (EAA) as well as disturbances in energy metabolism (Sapolsky, 1990; Stein-Behrens et al., 1994).
4. The excitotoxic aspects of lithium are most clearly illustrated by the now well documented observation that modest doses of lithium dramatically increase the seizure activity and brain damage produced by cholinergic agonists (Honchar et al., 1983; Persinger et al., 1988). One possibility reviewed by Williams and Jope (1994) is that lithium potentiates the excitotoxic aspects of cholinergic agonists by increasing cholinergic activity in the brain. It appears that seizures induced by combined lithium pilocarpine treatment are associated with brain acetylcholine levels considerably higher than observed when seizures are induced by other epileptogenic agents (Jope and Williams, 1994).
5. However, a number of kinds of evidence suggest that lithium may also have a direct effect on the presynaptic side of the excitatory amino acid (EAA) synapse. Evans et al. (1990) present electrophysiological data from the hippocampal slice preparation showing that lithium potentiates measures of presynaptic excitatory responses. Evans et al. (1990) found that lithium increased both intracellular and extracellular evoked post synaptic potentials (EPSP) as measured in the mid portion of the stratum radiatum of region CA1 of hippocampus. While cholinergic agonists produced opposite (decremental) effects on these same evoked potential measures, lithium prevented the cholinergic effects (Evans et al., 1990). Excitatory effects of cholinergic agonists in brain depend primarily on inhibition of potassium currents in postsynaptic neurons (Krnjevic, 1993). Thus, the fact that lithium potentiates the epileptogenic effects of cholinergic agonists may be explained by its presynaptic effects.
6. Other evidence also points to presynaptic action of lithium at the EAA synapse. Dixon et al. (1994) found in the monkey cortical slice preparation that lithium increases release of glutamate. Harvey et al. (1994) report that lithium increases cGMP levels in rat cortex in a manner consistent with a potentiation of excitatory amino acid (EAA) responses. Furthermore, much interest has centered on the observation that lithium interferes with the glutamate transporter in glial cells (Mennerick and Zorzumski, 1994) and the possibility that this effect may delay clearance of glutamate from brain extracelluar space and potentiate excitatory responses (Tong and Jahr, 1994).
7. It is also possible that lithium potentiates excitatory responses through a post synaptic action. For example, Ponzer and Crews (1992) found in the cortical slice preparation that lithium appeared to simultaneously block inositol triphosphate formation and to block the process by which neurons desensitize their excitatory responses to cholinergic agonists. Thus lithium had the effect of gradually increasing the rate of neuronal firing in cholinergically stimulated cortical slices while this effect was reversed by inositol supplementation.
8. The observations of Ponzer and Crews (1992) are consistent with the inositol depletion theory of lithium action as is the observation that inositol supplementation can block seizures produced by combined administration of pilocarpine and lithium (Tricklebank et al., 1991). However, biochemical studies have generally failed to convincingly document that lithium depletes whole brain inositol (Jope and Williams, 1994). The possibility remains that lithium depletion of inositol is selective to particular neuronal compartments or to particular regions of the brain. Alternatively, lithium may block PI hydrolysis through effects on G proteins rather than by inositol depletion (Jope and Williams, 1994). Since PI hydrolysis is implicated in desensitizing neuronal responses to cholinergic agonists (Ponzer and Crews, 1992), any mechanism by which lithium reduces PI hydrolysis might potentiate excitatory neuronal responses.
9. Phenomenological evidence suggests that neurotoxicity from lithium involves elements of both CNS (central nervous system) depression and CNS excitation. CNS depression is, of course, seen in the dose related progressive impairment in consciousness which may vary from simple drowsiness to frank coma. CNS excitation is seen most clearly in seizure activity which may be a part of neurotoxicity with lithium (Sheean, 1991).
10. A number of different kinds of seizure like EEG activity have been reported in patients with lithium induced encephalopathy. These include "runs of periodic sharp waves ... triphasic complexes ... widespread slow activity alternating with runs of periodic sharp waves" (Smith and Kocen, 1988); "increased slow waves, sharp waves and high voltage activity ... sudden appearance of high voltage paroxysmal groups with sharp waves and spike wave like activity" (Itil et al., 1971); "pseudo periodic discharges" (Prima Vera et al., 1989); "increased theta and delta especially in frontal areas with triphasic waves and sharp waves in frontal areas" (Broussolle et al., 1989). The possibility that lithium induced seizure activity may contribute to the encephalopathic syndrome observed in lithium neurotoxicity is suggested by some observations on mental status changes in a series of patients with non convulsive status epilepsy. (Lee, 1985).
11. Ellis and Lee (1978) and Lee (1985) described a subacute encephalopathy in a series of patients with acute and subacute recurrent non convulsive behavioral episodes secondary to generalized EEG spike and wave discharges. In some cases the non convulsive seizure episodes seemed to be precipitated by lithium treatment (Ellis and Lee, 1978; Lee, 1985).
12. The behavioral changes in patients with non convulsive status epilepticus include cognitive impairment and a variety of focal neurological deficits including ideational apraxia, bradykinesia, motor perseveration, frontal release reflexes, and positive babinski reflexes. Bizarre affect and behaviors were a prominent feature (six of eleven) of a recently reported series of cases (Lee, 1985). Reports that iv diazepam decreased EEG and behavioral abnormalities in patients with lithium induced encephalopathy is especially suggestive of seizure induced behavioral changes (Weiner et al., 1980; Lee, 1985).
13. Non convulsive status epilepsy may be relevant to understanding excitotoxic features of lithium neurotoxicity because it demonstrates how a subacute nonconvulsive excitotoxic process can produce a wide variety of encephalopathic features. Since lithium neurotoxicity probably reflects a combination of CNS depressant and excitotoxic effects, more work is needed to determine what factors may alter this balance toward more excitotoxic and presumably more serious or irreversible outcomes.
14. While the risk of lithium neurotoxicity is sometimes minimized, a recent review calculated that 10% of the survivors of acute lithium neurotoxicity will suffer permanent neurological sequelae (Sheean, 1991). Clearly, numerous cases of persisting neurological dysfunction following acute episodes of lithium intoxication have been reported (Donaldson and Cunningham, 1983; Schou, 1984; Sheean, 1991).
15. Cerebellar disease may not be prominent during the most acute encephalopathic phase of lithium neurotoxicity (Schou, 1984). However, residual damage from lithium neurotoxicity most often involves cerebellar functions including gait and limb ataxia, nystagmus and dysarthria (Schou, 1984; Sheean, 1991). Evidence of focal cerebellar disease secondary to lithium has been documented with pneumoencephalography (Donaldson and Cunningham, 1983), CT or MRI exams (Sheean, 1991) and autopsy examination (Amdisen et al., 1974). In addition to cerebellar deficits, other neurological dysfunction may persist as well including deficits in pyramidal, extra pyramidal, cognitive and or brain stem systems (Sheean, 1991).
16. Comparison of patients with acute lithium neurotoxicity indicates that risk of developing permanent neurological sequelae is not predicted by most clinical features. Patients with and without sequelae had similar histories of dose and serum level of lithium, duration of lithium treatment, concomitant treatment, age, and psychiatric diagnosis (Donaldson and Cunningham, 1983).
17. Data on the behavioral state of lithium treated patients suggests that lithium neurotoxicity may sometimes be precipitated by psychological stress. West and Meltzer (1979) compared behavioral ratings of patients with acute affective disorders who were receiving lithium treatment on a research ward. They found that peak behavioral ratings for psychosis and anxiety (measured before lithium treatment) were significantly higher in lithium treated patients who developed lithium neurotoxicity during an index admission compared to those who did not.
18. West and Meltzer (1979) hypothesized that those patients experiencing the greatest stress from their acute affective disorder were at greater risk of lithium neurotoxicity. In a similar vein, West (1982) compared the rates of lithium neurotoxicity in treatment studies of acutely ill inpatients receiving lithium for treatment of acute affective disorders versus outpatients receiving lithium treatment for prophylactic purposes. The acutely ill inpatient studies found far higher rates of neurotoxicity (despite a much shorter period of lithium exposure) consistent again with a stress effect on risk of lithium neurotoxicity.
19. Clinical studies of acutely psychotic patients reveal that prolonged, unrelenting states of fear and anxiety can occur in psychotic patients experiencing ego disintegration (Sachar et al., 1970; Carlson and Goodwin, 1973). Severe ego disintegration in psychotic patients is often accompanied by extreme stress induced elevations in corticosteroids (Sachar et al., 1970; Sachar, 1970).
20. The extent of corticosteroid elevations observed in ego disintegrated psychotic patients has not been seen in virtually any other human stress paradigm. For example, stress related corticosteroid responses of parents of children dying of leukemia, soldiers undergoing basic training, helicopter pilots under attack in Viet Nam, and women awaiting surgery for possible breast cancer are all considerably less than seen in the psychotic patients described above (Sachar, 1970).
21. The above behavioral and endocrine data are consistent with the concept that a psychotic induced cognitive disintegration can produce prolonged states of severe stress which would be expected to have potent physiological consequences. Psychological stress in lab animals is known to increase activity of virtually all of the well studied brain neurotransmitter systems including acetylcholine, norepinephrine, dopamine, serotonin, and histamine (Anisman, 1978; Shanks et al., 1991). Thus patients with high levels of psychosis and anxiety may have a unique neurochemical profile that increases their risk of lithium neurotoxicity.
22. A priority for clinical research is to achieve a better psychological and biological understanding of the states of extreme stress which can complicate psychotic illness. For example, ego disintegration has most often been described in first break schizophrenic patients not receiving medication (Sachar et al., 1970). However, ego disintegration clearly also occurs in the extremes of affective illness such as in severely dysphoric phases of mania (Carlson and Goodwin, 1973). Longitudinal behavioral, neuroimaging, and endocrine studies which collect repeated measures and use the patient as his or her own control may assist the study of extreme stress effects in psychotic patients. Such intensive case studies are expected to yield important data for comparison with other clinical research and lab animal data.
23. In humans, persistent neurological dysfunction and focal brain lesions secondary to lithium appear most likely to involve cerebellum (Donaldson and Cunningham, 1983; Schou, 1984; and Sheean, 1991). However, a variety of evidence suggests that lithium related cerebellar disease is different in character than the neurotoxicity produced by lithium and cholinergic agonists.
24. Brain lesions secondary to cholinergic agonists have been specifically reported as not present in cerebellum (Turski et al., 1986). Brain lesions secondary to combined lithium cholinergic agonist treatment (Persinger et al., 1988) have not been described in cerebellum although further focused study is indicated. Cholinergic innervation of cerebellum is less than that of cerebrum and striatum (Hetnarski et al., 1980) and effects of stress on cholinergic activity in cerebellum appear less than observed in cerebrum (Tsarkiris and Kontopoulos, 1993).
25. Organization of arousal processes appears to differ considerably in cerebellum versus cerebrum. Activation of cerebellum appears to heavily depend on an excitatory limb premotor network that includes EAA mediated input from motor cortex and red nucleus to precerebellar nuclei in brain stem (Houk et al., 1993). Multiple recurrent loops connect motor cortex, red nucleus, brain stem amd cerebellum. These loops support burst discharges in excitatory inputs to cerebellum which appear necessary for activation of motor behavior (Tsukahara et al., 1983; Houk et al., 1993).
26. Excitatory input from a pontine nucleus called the inferior olive has been implicated in the generation of tremor in certain animal models of tremor (Longo and Massotti, 1985) as well as in excitotoxic lesions in cerebellum produced by the drugs harmaline and ibogaine (O'Hearn and Molliver, 1993). Electrophysiological studies indicate that harmaline produces excitotoxic lesions in cerebellum by induction of rhythmic bursts of activity in inferior olive neurons which result in sustained, intense activation of cerebellar purkinje cells (O'Hearn and Molliver, 1993). Neurotoxins capable of producing selective excitotoxic lesions of cerebellum are expected to be useful in exploring the potential excitotoxicity of lithium in cerebellum (see below).
27. Understanding of lithium neurotoxicity may be especially aided by a dialogue between basic science and clinical investigators interested in stress effects on brain and behavior. Stress is known to have a direct effect on a variety of neurotransmitters implicated in lithium neurotoxicity (Anisman, 1978; Shanks et al., 1991). For example, the neurotoxic interactions observed between lithium and cholinergic agonists (Persinger et al., 1988) and between lithium and serotonergic agonists (Williams and Jope, 1994) suggest the possibility that stress induced variations in brain cholinergic and serotonergic activity may contribute to the pathophysiology of lithium neurotoxicity. Norepinephrine is another relevant factor. Locus ceruleus lesions have been observed to potentiate the seizures caused by combined lithium cholinergic agonist treatment (Ormandy et al., 1991). The observation that norepinephrine exerts an inhibitory effect on brain stem cholinergic neurons (Williams and Reiner, 1993) suggests the possibility that (e.g., stress induced) depletion of norepinephrine in locus ceruleus could exacerbate lithium cholinergic agonist neurotoxicity by releasing brain stem cholinergic cells from inhibition.
28. Given the effects of stress in potentiating human lithium neurotoxicity (West and Meltzer, 1979; West, 1982), it becomes most important to know more about how stress influences lithium neurotoxicity in experimental animals. The possibility that stress may exacerbate lithium neurotoxicity is eminently testable in experimental animals. Preliminary data indicate that stress can increase lithium pilocarpine toxicity in rats. Using the lithium pilocarpine paradigm, Persinger et al. (1988) preexposed rats to a novel environment (0, 15, 30, 60, or 120 minutes) prior to pilocarpine injection. Results show that exposure to the novel environment prior to pilocarpine injection significantly decreased seizure latency (Persinger et al., 1988).
29. Further formal study of stress effects on lithium neurotoxicity is needed in a variety of standard stress induction paradigms. In particular, it will be important to compare effects of controllable versus uncontrollable stress on seizures resulting from treatment with lithium in combination with cholinergic or serotonergic agonists. The expectation would be that uncontrollable stress would reduce the dosage of cholinergic or serotonergic agonist necessary to induce seizures. Study of interactions between lithium and lower (more physiologic) doses of cholinergic and serotonergic agonists is expected to be especially revealing. Also, the Flinders "hypercholinergic" rat may be useful to test the possibility that stress increases lithium pilocarpine toxicity through a cholinergic mechanism (Overstreet, 1993).
30. Remarkably, the neurotoxicity produced in rats by lithium and cholinergic agonists has not been reported in cerebellum (Persinger et al., 1988; Persinger et al., 1993). Thus, lithium pilocarpine neurotoxicity in rats may not be an appropriate model for the severe cerebellar disease sometimes produced in man by lithium (Donaldson and Cunningham, 1983; Schou, 1984). However, it will be most interesting to test whether lithium exacerbates the neurotoxic effects of certain selective cerebellar excitotoxins (e.g., harmaline, ibogaine). Observations that ibogaine, harmaline and lithium all produce a high frequency resting tremor as well as cerebellar lesions (O'Hearn and Molliver, 1993; Schou, 1984) suggest the possibility that neurotoxicity with these agents may share common pathophysiological mechanisms. A most interesting corollary question is whether lithium induced tremor is associated with increased burst discharges in inferior olive and whether lithium potentiates the inferior olive burst discharge pattern produced by ibogaine or harmaline.
31. Circumstantial evidence also suggests a possible neurotoxic interaction between lithium and serotonergic agonists that may be relevant to lithium induced cerebellar lesions. It has been recently discovered that lithium coadministered with a serotonergic agonist can produce seizure activity (Williams and Jope, 1994). Serotonin is increasingly implicated in cerebellar function. And, serotonergic agonists can produce the same high frequency tremor (Jacobs and Fornal, 1993) that characterizes cerebellar toxins including ibogaine, harmaline and lithium.
32. Clinically, EEG evidence of seizure activity in patients with lithium induced encephalopathy suggest the value of video EEG telemetry (Sachdev, 1990; Meierkord et al., 1991) to further quantify the connection between lithium induced seizure activity and behavioral disturbances. Actual use of more simplified EEG telemetry (minus video component) which uses event recorders to mark behavioral changes and which allows patients to be studied while on psychiatric units (instead of neurology telemetry units) may prove a more practical way to study EEG aspects of lithium neurotoxicity (see Weilburg et al., 1995).
33. Actually, EEG data may prove most valuable clinically for less severe or less acute forms of neurotoxicity since more acute forms of lithium neurotoxicity can often be identified or suspected on clinical grounds alone. For example, Sheean (1991) reports a case of chronic lithium neurotoxicity which persisted for many months before being recognized.
34. Given the advances in automatic data processing of EEG data, it may be time to repeat some of the pharmacoelectroencephalographic analysis of lithium which Itil et al. (1971) pioneered.
35. A large number of preclinical and some clinical studies are ongoing to evaluate neuroprotective effects of pharmacologic agents (Lipton, 1993). The preclinical studies most often evaluate the effectiveness of various agents in reducing hypoxic ischemic brain damage in rats. Of the clinically available drugs, Lipton (1993) argues that memantine (German drug for Parkinson's disease) and nitroglycerin be considered for clinical trials in excitotoxic diseases because of their availability, their well established safety record, and the evidence that they reduce hypoxic ischemic damage in rat studies. Wasterlain et al. (1993) make a similar argument for felbamate which is a newly available anticonvulsant.
36. Preventing excitotoxic effects of acute lithium neurotoxicity may require a pharmacologic agent with the widest possible neuroprotective spectrum. Given the data that 10% of patients with lithium neurotoxicity may develop persistent neurological dysfunction, it seems prudent to consider administration of some sort of neuroprotective agent (e.g., diazepam, felbamate, nitroglycerin) to patients with evidence of severe lithium neurotoxicity (e.g, encephalopathy, seizures and or choreoathetosis). Actually, clinical experience with neuroprotective agents in the areas of stroke, traumatic brain injury and HIV encephalopathy may eventually offer considerable guidance in selecting and dosing neuroprotective agents for patients with lithium neurotoxicity.
37. Other recently considered antidotes for lithium neurotoxicity include administration of phospholipid liposomes (De Maio and Laviani, 1991) and inositol supplementation (Tricklebank et al., 1991). Possible chronic neurotoxic effects of lithium 38. It is known that lithium potentiates excitatory processes in brain (Evans et al., 1990; Dixon et al, 1994; Harvey et al., 1994) and that lithium can potentiate seizures produced by cholinergic (Persinger et al., 1988) and serotonergic (Williams and Jope, 1994) agonists in acute experiments. Bureau and Persinger (1991) raise the question of whether lithium might produce a more subtle insidious form of brain damage when administered chronically (Bureau and Persinger, 1991). Recently, a number of investigators (Dhingra and Rabins, 1991; Altshuler, 1993) have observed that patients with bipolar illness are at increased risk for severe cognitive impairment even when tested in nonacute phases of their affective illnesses. Deficits in brain volume are well known in bipolar patients (Altshuler, 1993). Further study is needed to determine if these deficits in brain volume are specific to medial temporal lobe and whether the deficits are related to duration of illness as some preliminary data suggest (Altshuler, 1993). Clinical research will need to look at the question of whether some form of chronic lithium neurotoxicity could be one of the factors contributing to cognitive and neuroanatomic deficits in bipolar patients.
39. Just as stress has been implicated in potentiating acute neurotoxic effects of lithium (West and Meltzer, 1979; Persinger et al., 1988), we must also consider a possible chronic neurotoxic interaction between lithium and stress. For example, a growing body of animal (Sapolsky, 1990; Wantanabe et al., 1992) and human (Meaney et al., 1993) data indicate that chronic elevations in certain stress hormones (glucocorticoids) can lead to memory impairment. Animal research documents that chronic glucocorticoid exposure (whether induced by stress exposure or drug administration) can produce memory dysfunction, hippocampal dendritic lesions and eventually hippocampal neuronal loss (Sapolsky, 1990; Wantanabe et al., 1992).
40. A research paradigm used to demonstrate glucocorticoid induced hippocampal lesions in rats (Wantanabe et al., 1992) may be useful to study possible chronic excitotoxic effects of lithium or other drugs. For example, if lithium has the potential to contribute to chronic excitotoxic brain injury, then lithium may exacerbate the hippocampal lesions produced by stress or chronic corticosterone treatment. Such research may have special significance for lithium treated patients who develop sustained increases in glucocorticoid hormones as a result of their recurrent affective illness.
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