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RBC ratio and paradoxical lithium neurotoxicity
Prog. Neuro-Psychopharmacol ~ Biol. Psychiat. 1982, Vol, 6. pp. 235-241 Printed in Great Britain. All rights reserved.
LITHIUM AND ELECTROLYTES PLASMA/RBC RATIO AND PARADOXICAL LITHIUM NEUROTOXICITY AVNER ELIZUR, AMIRA YERET, ZVI SEGAL and ERAN GRAFF* Shalvata Mental Health Center, Hod Hasharon, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel *Ichilov Municipal Hospital, Tel Aviv, Israel
(Final form, May 1982)
Abstract Elizur, Avner, Amira Yeret, Zvi Segal and Eran Graff: Lithium and electrolytes plasma/RBC ratio and paradoxical lithium neurotoxicity. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1982, 6 (3): 235-241. i.
2.
3.
4.
Although lithium neurotoxicity and EEG disturbances are known to be associated with toxic plasma lithium levels, it may also be paradoxically manifested when plasma lithium levels are within the therapeutic range. Plasma and RBC lithium and electrolytes levels were measured in 50 patients with affective disorders during the course of lithium therapy. Seventeen of them suffered from lithium neurotoxicity. It is suggested that in the course of lithium treatment, in the manic and depressed phases as well as during prophylaxis, lithium ratio is a better correlate of lithium neurotoxicity than plasma lithium alone, even when the plasma lithium levels are within the therapeutic range. In addition, an increase in the intra-erythrocyte sodium/potassium ratio was observed in toxic patients in comparison to non-toxic patients.
Keywords: paradoxical lithium neurotoxicity; lithium ratio, affective disorder; RBC; (Na/K) ratio.
Introduction Lithium has been widely used for prophylaxis of bipolar affective disorder as well as in acute manic episodes, although less so in acute depression. The therapeutic plasma level is between 0,6 - 1,2 mEq/l. Above this level, and especially above 2,0 - 2,5 mEq/l, severe neurotoxic side effects appear. The most frequent symptoms are tremor, muscle fasciculatiol ataxia, confusion and disorientation, and in the most severe cases, seizures, coma and death. Thus, in the course of lithium therapy, monitoring of serum plasma lithium is routinely carried out. However, severe neurotoxic symptoms and EEG changes have been reported recently in patients whose plasma lithium levels were within the commonly accepted therapeutic range (Zakowska-Dabrowska and Rybakowski, 1973). It was suggested that in such cases lithium ratio is a better correlate of lithium neurotoxicity than plasma lithium (Elizur et al., 1972; Hewick and Murray, 1976; Mendels and Frazer, 1973). It was also suggested that this ratio could be an aid in the differential diagnosis of neurotoxic reactions to a combination of lithium and other drugs (Elizur et al., 1977). The purpose of our present report is to study the relationship between plasma/RBC ratio of lithium and electrolytes and lithium neurotoxicity during the course of lithium treatment in patients with affective disorders.
235
236
A. Elizur et aZ.
Methods Subjects. Fifty patients, hospitalized in the research unit of the Shalvata Mental Health Center, were selected for th~ study. They all met the diagnostic criteria of Feighner et al. (1972) for Primary Bipolar Affective Disorder. They were divided into three clinical group~ Group A: 27 depressed patients; Group B: i0 manic patients, and Group C: 13 bipolar patients in interphase (euthymic). Thlrty-six were female and fourteen male. The ages ranged from 30 to 60, with a mean age of 54 years. Patients with a history of brain trauma, seizure disorder, alcoholism, drug addiction and mental deficiency were excluded. All the patients were in good physical condition and gave their consent to the study. Treatment was started during the acute phase after a drug-free period of one week. Drug treatment. All the patients received 300 mgm lithium carbonate in tablet form. The daily dose ranged between 1200 mgm/day and 1800 mgm/day, depending on individual reaction and plasma levels. The dosage was adjusted to achieve a plasma lithium level of about 1.2 mEq/l. The last dose was administered at 19h., and lithium was the only medication issued regardless of changes in clinical state. Clinical assessments. The diagnosis and clinical evaluations were made by two psychiatrists independently, using the following scales: Personal Data Inventory (PDI); Brief Psychiatric Rating Scale (BPRS); Hamilton Psychiatric Rating Scale (HPRS), and Side Effect Symptom Scale (SESS) with additional symptom scale for lithium toxicity. Laboratory assessments. Plasma and RBC baseline levels of electrolytes were measured after the one week drug-free period. Lithium and electrolytes in plasma and RBC were " measured during the lithium treatment period in the acute phase of the illness, after recovery and during the toxic phase. Blood samples were drawn at 7 h. twice weekly. The levels of lithium were determined by Beckman DB atomic absorption spectrophotometer using the technique describes by Elizur et al. (1972) and Frazer et al. (1972).
Results Lithium neurotoxicity Seventeen of the 50 patients developed various degrees of lithium neurotoxic manifestations during the study period. The degree of lithium neurotoxiclty in the different clinical phases is presented in Table i. Twelve patients became toxic during the acute clinical phase, both manic or depressed, and five during the euthymic period.
Table i The de~ree of lithium neurotoxicity in the different clinical phases
Clinical Phase
Mild
Moderate
Toxicity Severe
Very Severe
Total toxic ~roup
Not present
Depressed
3
4
0
I
8
19
Manic
i
i
i
i
4
6
Euthymic
2
2
I
0
5
8
Total
6
7
2
2
17
33
Paradoxical
lithium neurotoxicity
237
The most striking symptoms were tremor, ataxia, dysarthria, and difficulties in coordination. One patient had carpal and facial myoclonus. In three patients confuslonal states and difficulties in concentration were observed. In the last four patients, the neurotoxicity was so severe that lithium treatment was discontinued. The rest of the patients, with less severe side effects, continued to receive lower lithium doses. The EEGs in 12 of the toxic patients showed bilateral irregular slow waves and irregular diffuse ~ 6 o waves with bltemporal accentuation. The ECGs showed changes in q-T interval as well as flattening of the T waves in all the leads. All other laboratory results were normal. The EEG as well as the ECG returned to normal within 3 to 7 days following the disappearance of the toxic manifestations. Plasma Lithium and Lithium Ratio (LR) Plasma lithium levels and lithium ratio values in the toxic and non-toxlc groups are presented in Table 2. The range of plasma lithium mean levels in the toxic group was 1.16 - 1.45 mEq/l. The range of plasma lithium mean levels in the non-toxic group was .76 - .82 mEq/l. The difference between the two groups was not significant (t = .933).
Table 2 Plasma lithium (mEq/l) and lithium ratio (RBC/plasma lithium x i00) means and s.d. of the means in toxic and non-toxlc patients according to the clinical phase
Non-toxic ~roup Plasma lithium Lithium ratio m s.d. m s.d.
n
Toxic Kroup Plasma lithium m s.d.
19
.82
.18
27.9
2.3
8
1.45
.21
52.7
2.1
Manic
6
.76
.12
24.4
1.4
4
1.16
.25
50.5
3.3
Euthymic
8
.83
.17
27.9
2.4
5
1.18
.07
59.0
0.8
33
.80
.05
27.9
2.1
17
1.27
.13
51.6
2.3
Clinical phase Depressed
Total
n
Lithium ratio m s.d.
In 15 patients, neurotoxic side effects were present even though the plasma lithium levels at that time did not exceed the accepted therapeutic lithium plasma levels. The LR values in the toxic group were between 50.5 - 59.0 percent, whereas the non-toxic values were between 24.4 - 27.9 percent. A significant difference was obtained between the LR values in the toxic and non-toxlc groups (t - 3.74, p E .0001). The LR values of the toxic group were higher than those of the non-toxic group, across all the clinical groups. This difference was significant in the depressed (t = 2.61 p K .01) and euthymic patients (t = 2.71 p ~ .02), but not in the manic patients (t = 1.72 p K .12). Thirteen patients continued to receive lower lithium doses. In this group, the mean plasma lithium level during the toxic phase was m = i.ii mEq/l and s.d. of 0.7 and m = .79 mEq/l and s.d. of 1.7 after recovery. The LR was reduced from 50.9 percent and s.d. of 1.0 during toxicity to 38.2 percent and s.d. of 2.1 after recovery. This change in LR was significant (t = 2.28 p ~ 0.05) whereas the change in plasma lithium was not. There was a tendency for patients with high plasma levels to have high LR values (see Table 3). However, when both toxic and non-toxlc groups were divided according to the plasma lithium levels into three ranges, a significant difference between the LR of the toxic and non-toxic groups was still apparent. Analysis of variance between LR and plasma lithium in the toxic and non-toxic patients was significant according to toxicity (F = 8.7, p ~ .004), but not significant according to plasma lithium levels (F < i). The
A° Elizur et al.
238
interaction was also not significant (F = 1.31, p K .25). The major contribution to the difference in LR between the toxic and non-toxic groups was due to the clinical toxicity factor rather than a simple increase in the plasma lithium.
Table 3 Lithium ratio in toxic and non-toxic patients in difference plasma lithium levels
Plasma lithium
Non-toxic group m s.d.
n
Toxic group m s.d.
n
mEq/1 <0.5
8
27.1
2.0
2
27.4
2.6
0.5-1.5
20
36.5
2.0
13
53.2
2.3
1.5-2.3
5
49.6
0.7
2
59.1
3.1
Plasma and RBC Electrolytes The mean levels of the RBC sodium in the toxic group (m = 24.3 mEq/l, s.d. = 7.9) were higher than the non-toxic values ( m = 21.2 mEq/l, s.d. = 6.8). The mean levels of the RBC potassium in the toxic group (m = 90.2 mEq/l, s.d. = 4.8) were lower than the non-toxic values (m = 93.0 mEq/l, s.d. = 5.2). The differences were not significant. The RBC Na/K ratio values in the toxic and non-toxic groups according to the clinical phase and according to the plasma lithium level are presented in Table 4.
Table 4 RBC sodium/potassium ratio in toxic and non-toxic groups according to the clinical phases and in different plasma lithium levels
Depressed Clinical phase
Plasma lithium mEq/l
Non-toxic group m* s.d. 17 1.3
Toxic Group n m* s.d. 8 27 1.3
t 1.8
~P .08
Manic
6
24
0.6
4
24
1.0
0.03
n.s.
Euthymic
8
14
0.7
5
24
i.i
1.96
.07
< 0.5
8
22
1.0
2
23
i.i
20
18
1.2
13
24
1.0
1.51
.14
5
ii
1.5
2
38
0.5
2.54
.05
18.1
i.i
17
25.2 i.i
2.32
.02
0.5 -1.50 1.51-2.3
Total *in percent
n 19
33
n.s.
The RBC Na/K ratio was significantly higher in the toxic group than in the non-toxic group (t = 2.32, p ~ .02). The differences between the toxic and non-toxic groups were also significant in the depress and euthymic groups, but not in the manic group. When the
Paradoxical
lithium neurotoxicity
239
non-toxic and toxic groups were divided according to three ranges of lithium plasma levels, the RBC Na/K differences between them reached significant levels only in the higher range. The differences between the toxic (t) and non-toxic (nt) groups with regard to plasma magnesium (mt = 2.2mEq/l, s.d. = 0.2; mnt = 2.2mEq/l, s.d. = 0.2) and plasma calcium (m t = 9.9mg%, s.d. = 0.6; mnt = 9.8mg%, s.d. = 0.4) and RBC magnesium (m t = 4.9mEq/l, s.d. = 0.9; mnt = 5.0mEq/l, s.d. = 0.6) were all not significant.
Discussion In 1972, (Elizur et al.) we first reported on a manic patient in whom plasma lithium did not correlate with neurotoxicity, but the lithium ratio did. Since then, several attempts have been made to link neurotoxic side effects to the lithium ratio (Hewick and Murray, 1976; Mendels and Frazer, 1973), especially in those patients where plasma lithium levels were within therapeutic range during the toxic phase. Our present data give further support to the significant association between high LR and neurotoxicity. Their support is twofold: from the longitudinal observation of the toxic group, and from the comparison of the toxic and non-toxic groups. In our sample, 17 patients out of a total of 50 developed clear signs of lithium neurotoxicity. In 13 patients, these side effects disappeared after the reduction of the daily lithium dosage. Longitudinal observations of plasma lithium and LR in this subgroup revealed that the mean LR value was significantly higher during the toxic phase in the same patients, while the increase in the mean plasma lithium level during this period was not. Similar results were found in the comparison of plasma lithium and LR between the toxic and non-toxic groups, i.e., the mean LR was significantly higher in the toxic group than in the non-toxic group, while the difference in the mean plasma lithium values was not. It was documented that there is a positive correlation between the plasma lithium and LR. Our results indicated that the LR values were higher in the toxic group, irrespective the plasma lithium levels.
of
It is suggested that LR can be used as a diagnostic aid in patients with lithium neurotoxicity whose plasma lithium levels are within the therapeutic range (Elizur et al., 1972; Elizur et al., 1977; Hewick and Murray, 1976). Similarly, EEG changes bear a closer relationship to LR than to plasma lithium levels alone (Zakowska-Dabrowska and Rybakowski, 1973). It may also be speculated that altered intra-extra cellular distribution may explain the mechanism involved during lithium neurotoxicity, either by affecting the permeability or the active transport of lithium out of cells (Ehrllch et al., 1978). It has been documented that patients may tolerate lithium without toxicity at one point, and yet experience severe neurotoxic reactions in a different clinical phase, despite the fact that plasma lithium is within or close to, the therapeutic range. A majority of these reports describe neurotoxic reactions in patients during the manic state (Baldessarini and Stevens, 1970; Johnson et al., 1971; Ra, 1975), when lithium therapy is mostly used. There are also some reports of neurotoxic reactions during the depressed state (Ananth and Ruskin, 1974). It is suggested that the difference in LR values might explain the difference in vulnerability to lithium neurotoxicity in the various phases of the affective disorder. In our sample, 12 out of the 17 toxic patients were either manic or depressed when they became toxic. The results indicated that the LR values of the toxic group were higher than in the non-toxic group in all clinical phases. The comparison between the clinical groups revealed that the LR values of the manic and depressed groups during toxicity were higher than the LR values in the euthymic group. Some studies (Almy and Taylor, 1973; Greenspan et al., 1968) indicated that patients may retain more lithium and tolerate higher doses of it without side effects, during the manic phase than when euthymic. However, our data confirms previous reports (West and Metzer 1979) that it is during the acute manic or depressed phase that individuals are more likely
240
A. Elizur et aZ.
to be vulnerable to neurotoxic effects of lithium, and this vulnerability is associated with an increase in the intracellular lithium. Changes in erythrocyte sodium and potassium concentrations have been suggested as being important in the course of lithium therapy (Ehrlich et al., 1978; Mendels and Frazer, 1973; Naylor et al., 1970) and also in determining neurotoxicity (Elizur et al., 1977). In a previous paper (Elizur et al., 1977), we reported an increase in RBC(Na), a decrease in RBC(K) and an increase in RBC Na/K ratio in four patients during lithium toxicity. Our present data give further support to these preliminary findings, that the increase in intra erythrocyte Na/K ratio relate to the incidence of lithium neurotoxic side effect. The RBC Na/K ratio levels in the toxic state were significantly higher than in the non-toxic state in the depressed and euthymic patients, but not in the manic patients. The tendency toward increase in RBC(Na) and decrease in RBC(K), even though not significant, is also evident in the present study. These results, however, should be regarded cautiously. The method used in this study for RBC electrolyte measurements is more valid for lithium and potassium than for sodium, because of the trapped plasma in the packed cells. This explains why our levels of RBC(Na) are higher, relative to what has been published. It seems that further investigations, using different methods for intra cellular sodium and potassium determination, are needed before additional conclusions can be drawn. Birch et al. (1977) found no changes in serum calcium or magnesium in patients treated long-term with lithium. In our study, the comparison between toxic and non-toxic patients with regard to concentration of magnesium and calcium in plasma and erythrocytes, failed to achieve statistical significance.
Conclusions We concluded that in the course of lithium treatment of manic depressive patients, lithium ratio is a better correlate of lithium neurotoxicity than plasma lithium alone. This is especially important when the plasma lithium levels are within the therapeutic range. The changes in lithium ratio were accompanied by an increase in the erythrocyte sodium/potassium ratio.
References ALMY, G.L. and TAYLOR, M.A. (1973). Lithium retention in mania. Arch. Gen. Psych., 29: 232-234. ANANTH, J. and RUSKIN, R. (1974). Unusual reaction to lithium. Can. Med. Assoc. J., iii: 1049-1053. BALDESSARINI, R.J., STEVENS, J.J. (1970). Lithium carbonate for affective disorders. Arch. Gen. Psychiat., 22"72-77. BIRCH, N.J., GREENFIELD, A.A. and HULLIN, R.P. (1977). Lithium therapy and alkaline earth metal metabolism: A biochemical screening study. Psych. Med., 7:613-618. EHRLICH, B.E., DIAMOND, J.M., GOSENFELD, L. and KAUFMAN-DIAMOND,S. (1978). Lithium membranes and manic depressive illness. P sychopharmacol. Bull., 14:21-25. ELIZUR, A., SHOPSIN, B., GERSHON, S. and EHLENBERGER, A. (1972). Intra:extra cellular lithium ratios and clinical course in affective states. Clin. Pharmacol. Ther., 13:947-952. ELIZUR, A., GRAFF, E., STEINER, M. and DAVlDSON, S. (1977). Intra/extra RBC lithium and electrolyte distribution as correlates of neurotoxlc reaction during lithium therapy. In: The Impact of Biology on Modern Psychiatry, E.S. Gershon (ed.), Plenum Press, New York. FRAZER, A., SECUNDA, S.R. and MENDELS, J. (1972). A method for determination of sodium potassium, magnesium and lithium concentration in erythrocytes. Clin. Chem. Acta 36: 499-509. FEIGHNER, J.P., BELINO, E.G., GUZE, S.B., WOODRUFF, Jr., R.B., WINOKUR, G., and MUNOZ, R. (1972). Diagnostic criteria for use in psychiatric research. Arch. Gen. Psychiat. 26__: 57-63.
Paradoxical lithium neurotoxicity
241
GREENSPAN, K., GOODWIN, F.K., BUNNEY, W.E. and DURELL, J. (1968). Lithium ion retention and distribution. Arch. Gen. Psychiat., 19:664-673. HEWICK, D.S. and MURRAY, N. (1976). RBC levels and lithium toxicity. Lancet 471-472. JOHNSON, G., GERSHON, S., BURDOCK, E., FLOYD, A. and HEKIMAN, L. (1971). Comparative effects of lithium and chlorpromazine in the treatment of acute manic states. Br. J. Psychiatry, 119:267-276. MENDELS, J. and FRAZER, A. (1973). Intra-cellular lithium concentration and clinical response toward a membrane theory of depression. Am. J. Psychiat. Res. 10:9-18. NAYLOR, G.J., McNAMEE, H.B. and MOODY, J.P. (1970). Erythrocyte sodium and potassium in depressive illness. J. Psychosomat. Res., 14:173-177. RA, I. (1975). Side effects from lithium. Can. Med. Assoc. J., 112:418. WEST, P. and MELTZER, H.G. (1979). Paradoxical lithium neurotoxicity: A report of five cases and a hypothesis about risk for neurotoxicity. Amer. J. Psychiat., !36:963-966. ZAKOWSKA-DABROWSKA, T. and RYBAKOWSKI, J. (1973). Lithium induced EEG changes: Relation to lithium levels in serum and red blood cells. Acta. Psych. Scand., 49:457-465. Ackn0wled~ement This research was supported by a grant from the Israel Center for Psychobiology. Inquiries and reprint requests should be addressed to: Avner Elizur, M.D. Shalvata Mental Health Center P.O.B. 94 Hod, Hasharon, 45100, Israel
LITHIUM AND ELECTROLYTES PLASMA/RBC RATIO AND PARADOXICAL LITHIUM NEUROTOXICITY AVNER ELIZUR, AMIRA YERET, ZVI SEGAL and ERAN GRAFF* Shalvata Mental Health Center, Hod Hasharon, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel *Ichilov Municipal Hospital, Tel Aviv, Israel
(Final form, May 1982)
Abstract Elizur, Avner, Amira Yeret, Zvi Segal and Eran Graff: Lithium and electrolytes plasma/RBC ratio and paradoxical lithium neurotoxicity. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1982, 6 (3): 235-241. i.
2.
3.
4.
Although lithium neurotoxicity and EEG disturbances are known to be associated with toxic plasma lithium levels, it may also be paradoxically manifested when plasma lithium levels are within the therapeutic range. Plasma and RBC lithium and electrolytes levels were measured in 50 patients with affective disorders during the course of lithium therapy. Seventeen of them suffered from lithium neurotoxicity. It is suggested that in the course of lithium treatment, in the manic and depressed phases as well as during prophylaxis, lithium ratio is a better correlate of lithium neurotoxicity than plasma lithium alone, even when the plasma lithium levels are within the therapeutic range. In addition, an increase in the intra-erythrocyte sodium/potassium ratio was observed in toxic patients in comparison to non-toxic patients.
Keywords: paradoxical lithium neurotoxicity; lithium ratio, affective disorder; RBC; (Na/K) ratio.
Introduction Lithium has been widely used for prophylaxis of bipolar affective disorder as well as in acute manic episodes, although less so in acute depression. The therapeutic plasma level is between 0,6 - 1,2 mEq/l. Above this level, and especially above 2,0 - 2,5 mEq/l, severe neurotoxic side effects appear. The most frequent symptoms are tremor, muscle fasciculatiol ataxia, confusion and disorientation, and in the most severe cases, seizures, coma and death. Thus, in the course of lithium therapy, monitoring of serum plasma lithium is routinely carried out. However, severe neurotoxic symptoms and EEG changes have been reported recently in patients whose plasma lithium levels were within the commonly accepted therapeutic range (Zakowska-Dabrowska and Rybakowski, 1973). It was suggested that in such cases lithium ratio is a better correlate of lithium neurotoxicity than plasma lithium (Elizur et al., 1972; Hewick and Murray, 1976; Mendels and Frazer, 1973). It was also suggested that this ratio could be an aid in the differential diagnosis of neurotoxic reactions to a combination of lithium and other drugs (Elizur et al., 1977). The purpose of our present report is to study the relationship between plasma/RBC ratio of lithium and electrolytes and lithium neurotoxicity during the course of lithium treatment in patients with affective disorders.
235
236
A. Elizur et aZ.
Methods Subjects. Fifty patients, hospitalized in the research unit of the Shalvata Mental Health Center, were selected for th~ study. They all met the diagnostic criteria of Feighner et al. (1972) for Primary Bipolar Affective Disorder. They were divided into three clinical group~ Group A: 27 depressed patients; Group B: i0 manic patients, and Group C: 13 bipolar patients in interphase (euthymic). Thlrty-six were female and fourteen male. The ages ranged from 30 to 60, with a mean age of 54 years. Patients with a history of brain trauma, seizure disorder, alcoholism, drug addiction and mental deficiency were excluded. All the patients were in good physical condition and gave their consent to the study. Treatment was started during the acute phase after a drug-free period of one week. Drug treatment. All the patients received 300 mgm lithium carbonate in tablet form. The daily dose ranged between 1200 mgm/day and 1800 mgm/day, depending on individual reaction and plasma levels. The dosage was adjusted to achieve a plasma lithium level of about 1.2 mEq/l. The last dose was administered at 19h., and lithium was the only medication issued regardless of changes in clinical state. Clinical assessments. The diagnosis and clinical evaluations were made by two psychiatrists independently, using the following scales: Personal Data Inventory (PDI); Brief Psychiatric Rating Scale (BPRS); Hamilton Psychiatric Rating Scale (HPRS), and Side Effect Symptom Scale (SESS) with additional symptom scale for lithium toxicity. Laboratory assessments. Plasma and RBC baseline levels of electrolytes were measured after the one week drug-free period. Lithium and electrolytes in plasma and RBC were " measured during the lithium treatment period in the acute phase of the illness, after recovery and during the toxic phase. Blood samples were drawn at 7 h. twice weekly. The levels of lithium were determined by Beckman DB atomic absorption spectrophotometer using the technique describes by Elizur et al. (1972) and Frazer et al. (1972).
Results Lithium neurotoxicity Seventeen of the 50 patients developed various degrees of lithium neurotoxic manifestations during the study period. The degree of lithium neurotoxiclty in the different clinical phases is presented in Table i. Twelve patients became toxic during the acute clinical phase, both manic or depressed, and five during the euthymic period.
Table i The de~ree of lithium neurotoxicity in the different clinical phases
Clinical Phase
Mild
Moderate
Toxicity Severe
Very Severe
Total toxic ~roup
Not present
Depressed
3
4
0
I
8
19
Manic
i
i
i
i
4
6
Euthymic
2
2
I
0
5
8
Total
6
7
2
2
17
33
Paradoxical
lithium neurotoxicity
237
The most striking symptoms were tremor, ataxia, dysarthria, and difficulties in coordination. One patient had carpal and facial myoclonus. In three patients confuslonal states and difficulties in concentration were observed. In the last four patients, the neurotoxicity was so severe that lithium treatment was discontinued. The rest of the patients, with less severe side effects, continued to receive lower lithium doses. The EEGs in 12 of the toxic patients showed bilateral irregular slow waves and irregular diffuse ~ 6 o waves with bltemporal accentuation. The ECGs showed changes in q-T interval as well as flattening of the T waves in all the leads. All other laboratory results were normal. The EEG as well as the ECG returned to normal within 3 to 7 days following the disappearance of the toxic manifestations. Plasma Lithium and Lithium Ratio (LR) Plasma lithium levels and lithium ratio values in the toxic and non-toxlc groups are presented in Table 2. The range of plasma lithium mean levels in the toxic group was 1.16 - 1.45 mEq/l. The range of plasma lithium mean levels in the non-toxic group was .76 - .82 mEq/l. The difference between the two groups was not significant (t = .933).
Table 2 Plasma lithium (mEq/l) and lithium ratio (RBC/plasma lithium x i00) means and s.d. of the means in toxic and non-toxlc patients according to the clinical phase
Non-toxic ~roup Plasma lithium Lithium ratio m s.d. m s.d.
n
Toxic Kroup Plasma lithium m s.d.
19
.82
.18
27.9
2.3
8
1.45
.21
52.7
2.1
Manic
6
.76
.12
24.4
1.4
4
1.16
.25
50.5
3.3
Euthymic
8
.83
.17
27.9
2.4
5
1.18
.07
59.0
0.8
33
.80
.05
27.9
2.1
17
1.27
.13
51.6
2.3
Clinical phase Depressed
Total
n
Lithium ratio m s.d.
In 15 patients, neurotoxic side effects were present even though the plasma lithium levels at that time did not exceed the accepted therapeutic lithium plasma levels. The LR values in the toxic group were between 50.5 - 59.0 percent, whereas the non-toxic values were between 24.4 - 27.9 percent. A significant difference was obtained between the LR values in the toxic and non-toxlc groups (t - 3.74, p E .0001). The LR values of the toxic group were higher than those of the non-toxic group, across all the clinical groups. This difference was significant in the depressed (t = 2.61 p K .01) and euthymic patients (t = 2.71 p ~ .02), but not in the manic patients (t = 1.72 p K .12). Thirteen patients continued to receive lower lithium doses. In this group, the mean plasma lithium level during the toxic phase was m = i.ii mEq/l and s.d. of 0.7 and m = .79 mEq/l and s.d. of 1.7 after recovery. The LR was reduced from 50.9 percent and s.d. of 1.0 during toxicity to 38.2 percent and s.d. of 2.1 after recovery. This change in LR was significant (t = 2.28 p ~ 0.05) whereas the change in plasma lithium was not. There was a tendency for patients with high plasma levels to have high LR values (see Table 3). However, when both toxic and non-toxlc groups were divided according to the plasma lithium levels into three ranges, a significant difference between the LR of the toxic and non-toxic groups was still apparent. Analysis of variance between LR and plasma lithium in the toxic and non-toxic patients was significant according to toxicity (F = 8.7, p ~ .004), but not significant according to plasma lithium levels (F < i). The
A° Elizur et al.
238
interaction was also not significant (F = 1.31, p K .25). The major contribution to the difference in LR between the toxic and non-toxic groups was due to the clinical toxicity factor rather than a simple increase in the plasma lithium.
Table 3 Lithium ratio in toxic and non-toxic patients in difference plasma lithium levels
Plasma lithium
Non-toxic group m s.d.
n
Toxic group m s.d.
n
mEq/1 <0.5
8
27.1
2.0
2
27.4
2.6
0.5-1.5
20
36.5
2.0
13
53.2
2.3
1.5-2.3
5
49.6
0.7
2
59.1
3.1
Plasma and RBC Electrolytes The mean levels of the RBC sodium in the toxic group (m = 24.3 mEq/l, s.d. = 7.9) were higher than the non-toxic values ( m = 21.2 mEq/l, s.d. = 6.8). The mean levels of the RBC potassium in the toxic group (m = 90.2 mEq/l, s.d. = 4.8) were lower than the non-toxic values (m = 93.0 mEq/l, s.d. = 5.2). The differences were not significant. The RBC Na/K ratio values in the toxic and non-toxic groups according to the clinical phase and according to the plasma lithium level are presented in Table 4.
Table 4 RBC sodium/potassium ratio in toxic and non-toxic groups according to the clinical phases and in different plasma lithium levels
Depressed Clinical phase
Plasma lithium mEq/l
Non-toxic group m* s.d. 17 1.3
Toxic Group n m* s.d. 8 27 1.3
t 1.8
~P .08
Manic
6
24
0.6
4
24
1.0
0.03
n.s.
Euthymic
8
14
0.7
5
24
i.i
1.96
.07
< 0.5
8
22
1.0
2
23
i.i
20
18
1.2
13
24
1.0
1.51
.14
5
ii
1.5
2
38
0.5
2.54
.05
18.1
i.i
17
25.2 i.i
2.32
.02
0.5 -1.50 1.51-2.3
Total *in percent
n 19
33
n.s.
The RBC Na/K ratio was significantly higher in the toxic group than in the non-toxic group (t = 2.32, p ~ .02). The differences between the toxic and non-toxic groups were also significant in the depress and euthymic groups, but not in the manic group. When the
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lithium neurotoxicity
239
non-toxic and toxic groups were divided according to three ranges of lithium plasma levels, the RBC Na/K differences between them reached significant levels only in the higher range. The differences between the toxic (t) and non-toxic (nt) groups with regard to plasma magnesium (mt = 2.2mEq/l, s.d. = 0.2; mnt = 2.2mEq/l, s.d. = 0.2) and plasma calcium (m t = 9.9mg%, s.d. = 0.6; mnt = 9.8mg%, s.d. = 0.4) and RBC magnesium (m t = 4.9mEq/l, s.d. = 0.9; mnt = 5.0mEq/l, s.d. = 0.6) were all not significant.
Discussion In 1972, (Elizur et al.) we first reported on a manic patient in whom plasma lithium did not correlate with neurotoxicity, but the lithium ratio did. Since then, several attempts have been made to link neurotoxic side effects to the lithium ratio (Hewick and Murray, 1976; Mendels and Frazer, 1973), especially in those patients where plasma lithium levels were within therapeutic range during the toxic phase. Our present data give further support to the significant association between high LR and neurotoxicity. Their support is twofold: from the longitudinal observation of the toxic group, and from the comparison of the toxic and non-toxic groups. In our sample, 17 patients out of a total of 50 developed clear signs of lithium neurotoxicity. In 13 patients, these side effects disappeared after the reduction of the daily lithium dosage. Longitudinal observations of plasma lithium and LR in this subgroup revealed that the mean LR value was significantly higher during the toxic phase in the same patients, while the increase in the mean plasma lithium level during this period was not. Similar results were found in the comparison of plasma lithium and LR between the toxic and non-toxic groups, i.e., the mean LR was significantly higher in the toxic group than in the non-toxic group, while the difference in the mean plasma lithium values was not. It was documented that there is a positive correlation between the plasma lithium and LR. Our results indicated that the LR values were higher in the toxic group, irrespective the plasma lithium levels.
of
It is suggested that LR can be used as a diagnostic aid in patients with lithium neurotoxicity whose plasma lithium levels are within the therapeutic range (Elizur et al., 1972; Elizur et al., 1977; Hewick and Murray, 1976). Similarly, EEG changes bear a closer relationship to LR than to plasma lithium levels alone (Zakowska-Dabrowska and Rybakowski, 1973). It may also be speculated that altered intra-extra cellular distribution may explain the mechanism involved during lithium neurotoxicity, either by affecting the permeability or the active transport of lithium out of cells (Ehrllch et al., 1978). It has been documented that patients may tolerate lithium without toxicity at one point, and yet experience severe neurotoxic reactions in a different clinical phase, despite the fact that plasma lithium is within or close to, the therapeutic range. A majority of these reports describe neurotoxic reactions in patients during the manic state (Baldessarini and Stevens, 1970; Johnson et al., 1971; Ra, 1975), when lithium therapy is mostly used. There are also some reports of neurotoxic reactions during the depressed state (Ananth and Ruskin, 1974). It is suggested that the difference in LR values might explain the difference in vulnerability to lithium neurotoxicity in the various phases of the affective disorder. In our sample, 12 out of the 17 toxic patients were either manic or depressed when they became toxic. The results indicated that the LR values of the toxic group were higher than in the non-toxic group in all clinical phases. The comparison between the clinical groups revealed that the LR values of the manic and depressed groups during toxicity were higher than the LR values in the euthymic group. Some studies (Almy and Taylor, 1973; Greenspan et al., 1968) indicated that patients may retain more lithium and tolerate higher doses of it without side effects, during the manic phase than when euthymic. However, our data confirms previous reports (West and Metzer 1979) that it is during the acute manic or depressed phase that individuals are more likely
240
A. Elizur et aZ.
to be vulnerable to neurotoxic effects of lithium, and this vulnerability is associated with an increase in the intracellular lithium. Changes in erythrocyte sodium and potassium concentrations have been suggested as being important in the course of lithium therapy (Ehrlich et al., 1978; Mendels and Frazer, 1973; Naylor et al., 1970) and also in determining neurotoxicity (Elizur et al., 1977). In a previous paper (Elizur et al., 1977), we reported an increase in RBC(Na), a decrease in RBC(K) and an increase in RBC Na/K ratio in four patients during lithium toxicity. Our present data give further support to these preliminary findings, that the increase in intra erythrocyte Na/K ratio relate to the incidence of lithium neurotoxic side effect. The RBC Na/K ratio levels in the toxic state were significantly higher than in the non-toxic state in the depressed and euthymic patients, but not in the manic patients. The tendency toward increase in RBC(Na) and decrease in RBC(K), even though not significant, is also evident in the present study. These results, however, should be regarded cautiously. The method used in this study for RBC electrolyte measurements is more valid for lithium and potassium than for sodium, because of the trapped plasma in the packed cells. This explains why our levels of RBC(Na) are higher, relative to what has been published. It seems that further investigations, using different methods for intra cellular sodium and potassium determination, are needed before additional conclusions can be drawn. Birch et al. (1977) found no changes in serum calcium or magnesium in patients treated long-term with lithium. In our study, the comparison between toxic and non-toxic patients with regard to concentration of magnesium and calcium in plasma and erythrocytes, failed to achieve statistical significance.
Conclusions We concluded that in the course of lithium treatment of manic depressive patients, lithium ratio is a better correlate of lithium neurotoxicity than plasma lithium alone. This is especially important when the plasma lithium levels are within the therapeutic range. The changes in lithium ratio were accompanied by an increase in the erythrocyte sodium/potassium ratio.
References ALMY, G.L. and TAYLOR, M.A. (1973). Lithium retention in mania. Arch. Gen. Psych., 29: 232-234. ANANTH, J. and RUSKIN, R. (1974). Unusual reaction to lithium. Can. Med. Assoc. J., iii: 1049-1053. BALDESSARINI, R.J., STEVENS, J.J. (1970). Lithium carbonate for affective disorders. Arch. Gen. Psychiat., 22"72-77. BIRCH, N.J., GREENFIELD, A.A. and HULLIN, R.P. (1977). Lithium therapy and alkaline earth metal metabolism: A biochemical screening study. Psych. Med., 7:613-618. EHRLICH, B.E., DIAMOND, J.M., GOSENFELD, L. and KAUFMAN-DIAMOND,S. (1978). Lithium membranes and manic depressive illness. P sychopharmacol. Bull., 14:21-25. ELIZUR, A., SHOPSIN, B., GERSHON, S. and EHLENBERGER, A. (1972). Intra:extra cellular lithium ratios and clinical course in affective states. Clin. Pharmacol. Ther., 13:947-952. ELIZUR, A., GRAFF, E., STEINER, M. and DAVlDSON, S. (1977). Intra/extra RBC lithium and electrolyte distribution as correlates of neurotoxlc reaction during lithium therapy. In: The Impact of Biology on Modern Psychiatry, E.S. Gershon (ed.), Plenum Press, New York. FRAZER, A., SECUNDA, S.R. and MENDELS, J. (1972). A method for determination of sodium potassium, magnesium and lithium concentration in erythrocytes. Clin. Chem. Acta 36: 499-509. FEIGHNER, J.P., BELINO, E.G., GUZE, S.B., WOODRUFF, Jr., R.B., WINOKUR, G., and MUNOZ, R. (1972). Diagnostic criteria for use in psychiatric research. Arch. Gen. Psychiat. 26__: 57-63.
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GREENSPAN, K., GOODWIN, F.K., BUNNEY, W.E. and DURELL, J. (1968). Lithium ion retention and distribution. Arch. Gen. Psychiat., 19:664-673. HEWICK, D.S. and MURRAY, N. (1976). RBC levels and lithium toxicity. Lancet 471-472. JOHNSON, G., GERSHON, S., BURDOCK, E., FLOYD, A. and HEKIMAN, L. (1971). Comparative effects of lithium and chlorpromazine in the treatment of acute manic states. Br. J. Psychiatry, 119:267-276. MENDELS, J. and FRAZER, A. (1973). Intra-cellular lithium concentration and clinical response toward a membrane theory of depression. Am. J. Psychiat. Res. 10:9-18. NAYLOR, G.J., McNAMEE, H.B. and MOODY, J.P. (1970). Erythrocyte sodium and potassium in depressive illness. J. Psychosomat. Res., 14:173-177. RA, I. (1975). Side effects from lithium. Can. Med. Assoc. J., 112:418. WEST, P. and MELTZER, H.G. (1979). Paradoxical lithium neurotoxicity: A report of five cases and a hypothesis about risk for neurotoxicity. Amer. J. Psychiat., !36:963-966. ZAKOWSKA-DABROWSKA, T. and RYBAKOWSKI, J. (1973). Lithium induced EEG changes: Relation to lithium levels in serum and red blood cells. Acta. Psych. Scand., 49:457-465. Ackn0wled~ement This research was supported by a grant from the Israel Center for Psychobiology. Inquiries and reprint requests should be addressed to: Avner Elizur, M.D. Shalvata Mental Health Center P.O.B. 94 Hod, Hasharon, 45100, Israel