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Carbamazepine and PIP-syndrome in temporal lobe epilepsy
EPILEPSY RESEARCH ELSEVIER
Epilepsy Research 22 (1995) 215-220
Carbamazepine and PIP-syndrome in temporal lobe epilepsy Bettina Schrnitz a,* Michael R. Trirnble b a Psychiatrische Klinik und Poliklinik, Klinikum Benjamin Franklin, Eschenallee 3, 14050 Berlin, Germany b Department of Neurology, Institute of Neurology, Queen Square, London WC1N 3BG, UK Received 20 December 1994; revised 16 June 1995; accepted 18 June 1995
Abstract
We describe four patients with left temporal lobe epilepsy who developed psychosis, intermittent polydipsia and hyponatremia (PIP-syndrome) while being treated with carbamazepine. These cases illustrate the close links between dysfunction of the limbic system causing epileptic seizures and psychosis on the one hand and dysregulation in hypothalamic centers manifestating in polydipsia and osmodysregulation on the other. Keywords: Psychosis; Hyponatremia; Polydipsia; Carbamazepine
1. Introduction
1.1. The PIP-syndrome Symptoms of osmodysregulation are very common in psychiatric patients. The first description was in the 1930s [1,2]. Polydipsia has been reported in 6 to 17% [3], polyuria in 36 to 45% [4] and disturbed water homeostasis as measured by abnormal diurnal weight gain in 70% [5] of chronic psychiatric patients. The triad of psychosis, intermittent hyponatremia and polydipsia is called PIP-syndrome [6]. Closely related syndromes and synonyms are 'compulsive water drinking', 'self-induced water-intoxication with psychosis' and 'psychogenic polydipsia'. Frequently, symptoms remain subclinical but fatalities occur. In schizophrenic patients under 53 years, 18% of deaths are related to water intoxication [7].
* Corresponding author.
Diagnosis can be difficult because patients may make an effort to hide the excessive drinking. The psychiatric diagnosis in 87% of cases of polydipsia with water intoxication is schizophrenia [8]. There are data suggesting that patients with PIPsyndrome have more evidence for diffuse brain damage when compared with other psychotic patients. They have greater impairment in cognitive functioning [9] and larger ventricles and smaller brain size as detected by CT and MRI [10]. When comparing twelve schizophrenic patients who had histories of polydipsia and hyponatremia with twelve schizophrenics without such histories, Suddath et al. [11] noted decreased temporal grey, and smaller hippocampi and amygdalae in the former group. A history of epilepsy is not a recognized risk factor for the development of the PIP-syndrome [12]. However, epilepsy and drinking behaviour are related. Lennox and Cobb [13] in a review of the auras of 750 patients described 'asking for water' ictally in three cases. Remillard et al. [14], summarizing their expe-
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rience of 20 years, described twenty patients with periictal water-drinking, which sometimes was the only clinical manifestation associated with electrographic seizure discharges. Some patients were investigated with depth electrodes. All ictal recordings of drinking behaviour showed discharges of one temporal lobe, especially the hippocampus, the amygdala and the parahippocampal gyrus. The involvement of temporal lobe discharges in ictal drinking was supported by a case report by Cascino and Sutula [15] who described a patient with pathologically confirmed right hippocampal sclerosis and ictal compulsive water-drinking. Hyponatremia in patients with epilepsy has been described as a complication of treatment with carbamazepine or oxcarbazepine especially with higher doses [16,17]. The biochemical changes in these patients are consistent with an inappropriate antidiuretic state which is either due to SIAl)H, an agonistic ADH-like effect of carbamazepine or an increased renal ADH sensitivity. Serum ADH measurements have not been consistent, and the exact mechanism of hyponatremia is therefore still unsolved. Polydipsia with carbamazepine treatment has not been described. We describe four patients with long-standing, severe focal epilepsies who developed a PIP-syndrome on treatment with carbamazepine. We will discuss the links between temporal lobe epilepsy (TLE), PIP-syndrome and carbamazepine treatment with respect to anatomical and functional interactions.
2. Case reports 2.1. Case I
Mr. A is a 53 year old man with epilepsy since the age of 21. This started some months after a head injury. He has simple and complex focal seizures and secondarily generalized tonic-clonic seizures. Simple seizure symptoms are an epigastric rising sensation, a feeling of derealisation, speech arrest and a tonic head movement to the right. Oral automatisms are seen during complex focal seizures. Neurological examination is normal. Interictal EEGs show irregularities and isolated spikes over the left temporal
lobe; the CT and MRI scans are normal. The epilepsy is pharmacoresistant. The patient has always been strongly interested in religion and is an active member of Jehovah's witnesses. He was admitted to a psychiatric ward at the age of 30 with a diagnosis of 'neurosis with depressive, hysteric and obsessive elements'. Since the age of 35 he has had recurrent depressive episodes which are characterized by sleeplessness, agitation, brooding over religious questions, hypochondriacal complaints and pseudoseizures. At the age of 40 he had a second psychiatric admission. This time the diagnosis was 'paranoid-hallucinatory psychosis' and 'borderline-syndrome'. Since then, psychotic episodes have recurred about once a year. These psychoses are accompanied by an increase in seizure frequency and involve religious or grandiose delusions and auditory and visual hallucinations. Since the age of 39 the patient has been taking carbamazepine with a maximum dose of 1,500 mg daily (maximum serum concentration 57 /xmol/1). With this treatment his serum sodium levels were subnormal averaging 130 mmol/l. At 49, Mr A. was admitted with ankle edema, drinking at least six litres of water daily due to increased thirst. Serum sodium was 125 mmol/1. He was agitated and sleepless. He had a series of seizures, most of them being non-epileptic as confirmed by EEG. Subsequently he developed delusions. He thought he was King Solomon. He was treated with water restriction and haloperidol. Urine volume decreased from 6,500 ml to 1,250 ml daily within three days. Serum osmolality was 270 mosm/1 and urine osmolality 365 m o s m / l after two days of water restriction. On the basis of the low blood and relatively low urine osmolality, undetectable serum ADH and polyuria, a diagnosis of psychogenic polydipsia was made. With treatment, serum sodium levels normalized and the psychosis resolved. Another prolonged episode with depressive psychosis, increase in seizure frequency, polydipsia and hyponatremia (122 mmol/1) occurred three years later. 2.2. Case 2
Mrs B. is a 48 year old woman who had complicated febrile seizures during a cholera infection at
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217
the age of five. Since the age of eight she has suffered from epilepsy. She has simple focal seizures consisting in a rising epigastric sensation, complex focal seizures with initial tonic flexion of both arms and subsequently vocal and gestural automatisms and secondarily generalized tonic-clonic seizures. At the age of 45 she had a depressed occipital skull fracture caused by a fall in an epileptic seizure. The epilepsy is pharmacoresistant. The interictal EEG shows a left temporo-basal spike focus; CT scan and neurological examination are normal. Since the age of 43 she has been treated with carbamazepine in monotherapy in a maximum dose of 1,050 mg daily (maximum serum concentration 68 ~mol/1). In the same year she experienced a first postictal psychotic episode leading to admission to a psychiatric hospital. One year later, again following a tonic-clonic seizure, she became progressively dysphoric. Three days postictally she tried to kill herself by repeatedly electrifying herself with a lamp. When brought to hospital she described various physical complaints, especially pains in her neck and stomach. She repeatedly touched her neck and swallowed constantly. She said that she was very thirsty and that she had a dry mouth. Her desire for water was frenzied and demanded physical restraint. She appeared drowsy, confused and her speech was dysarthric. She had a mild tremor and some psychomotor retardation. Her serum sodium was 111 mmol/l, serum potassium 2.9 mmol/l, and the haematocrit 34%. The sodium level normalized within twenty-four hours with water restriction and hyperosmolar infusions. Her urine volume during this period was 5,600 ml with a concentration of sodium of 30 mmol/l, of potassium of 7 m m o l / l and urine osmolality of 99 mosm/1. Under neuroleptic treatment and continued water restriction her psychiatric state improved within a few days. Two years later she developed a similar brief postictal paranoid-hypochondriac psychosis with polydipsia and mild hyponatremia.
plex focal seizures with oral automatisms and secondarily generalized tonic-clonic seizures. The epilepsy is pharmacoresistant. Interictal EEGs show a left anterior temporal spike focus; CT scan and neurological examination are normal. At the age of fourteen he believed he was being spied upon by the BBC. Since then he has developed a chronic schizophrenic illness. The psychotic symptoms appear to be more florid with increased seizure frequency. At age 45 he was on combined medication and it was decided to put him on carbamazepine monotherapy. After 11 days at 1,000 mg he became drowsy and confused. He developed muscular twitching and tonic-clonic seizures. Carbamazepine was increased up to 1,800 mg daily. The patient complained of being thirsty but did not admit to drinking excessively. He was observed to drink large amounts of water at night. He also developed polyuria and his serum sodium was found to be 114 mmol/1 while his plasma osmolality was only 242 mosm. Urine osmolality was not decreased. A carbamazepine-induced SIADH syndrome was suspected (carbamazepine serum concentration at this stage was 47 /xmol/1). Carbamazepine was subsequently discontinued and the patient was put on phenytoin monotherapy. Four years later, Mr C. was seizure free for some months on 600 mg phenytoin daily. When seizures recurred he was admitted to hospital and his chronic psychotic state appeared worsened. His phenytoin level was lower than before (51 /~mol/1 versus 79 /xmol/l) and his serum sodium level was 123 mmol/l. He had polydipsia with a daily fluid intake of at least six litres. He stated that he drank under the influence of electrical frequencies. With fluid restriction his serum sodium normalized and his urine was normally concentrated. His medication was therefore not altered. Both seizure frequency and his psychotic symptoms improved with maintained water restriction.
2.3. Case 3
2.4. Case 4
Mr C. is a 49 year old man who had febrile seizures in his second year of life due to malaria. Since the age of five he has had simple focal seizures with an alternating sensation of heat and cold, com-
Mr D. is a 52 year old man who has suffered from epilepsy since the age of 30. He has simple focal seizures with a d6j~t vu sensation, complex focal seizures consisting in an arrest reaction and secon-
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darily generalized tonic-clonic seizures. Neurological examination is normal. His EEG shows a left anterior temporal spike focus in the interictal state and bilateral temporal discharges ictally. Mild internal and external atrophy was seen on the CT scan. The epilepsy has been pharmacoresistant. The patient has always been strongly religious and is an active member of Jehovah's witnesses. He has had postictal automatisms which became more severe and prolonged with increasing duration of epilepsy. The postictal behaviour includes compulsive eating, urinating and defecating, profuse sweating, verbal and physical aggression, offensive sexual behaviour including undressing and public masturbation. Since about 40 the patient also has had postictal hallucinations, and sexual, religious and grandiose delusions. The patient was enuretic until age 18. Enuresis reoccurred two or three years after onset of epilepsy together with polyuria. Mild hyponatremia around 128-130 mmol/l together with serum hypoosmolality (242-266 mosm/1) had been observed since onset of treatment with carbamazepine at the age of 37, initially given together with phenytoin. When admitted at 46 for further investigation of enuresis he had nocturnal polydipsia (which he had denied before). He was by then on 1,200 mg carbamazepine (serum concentration 30 /xmol/l) and 750
mg primidone (serum concentration 46 /zmol/l daily). He admitted to drinking about six litres of water daily because of increased thirst. Maximal polyuria however was 9.2 1 in 24 hours during admission and might have been even higher outside hospital since serum sodium levels normalized during admission. On several occasions urine osmolality was inappropriately high compared to serum osmolality (e.g. 454 mosm/1 versus 266 mosm/1). Water restriction tests were performed twice (age 46 and 47). Serum sodium level normalized and urine osmolality increased (669 mosm/1) at least temporarily.
3. Discussion
The reported case histories are characterized by epilepsy, psychosis, polydipsia and hyponatremia with carbamazepine treatment. The four cases, although not entirely homogenous, reflect the links between seizure activity and disorders of limbic-hypothalamic systems, behavioural changes and endocrine dysfunction. The epileptic syndrome of the four patients is remarkably uniform (Table 1). All patients suffer from pharmacoresistant left temporal lobe epilepsy with different seizure classes and high seizure frequency. Seizure symptoms are compatible with an
Table 1 Clinical data of patients
Sex Age at onset of epilepsy Age at onset of psychosis Onset of treatment with Carbamazepine First recognized polydipsia Etiology of epilepsy Type of epilepsy Seizure frequency (cfs a) EEG CT Type of psychosis Medication at first polydipsia Lowest serum sodium a cfs = complex focal seizures.
Mr A.
Mrs B.
Mr C.
Mr D.
Male 21 years 40 years 39 years
Female 8 years 43 years 43 years
Male 5 years 14 years 37 years
Male 30 years 40 years 45 years
49 years Traumatic Temporal 16/month Left temporal Normal Parictal Carbamazepine, melperon 122 mmol/1
44 years Febrile seizures Temporal 8/month Left temporal Normal Postictal Carbamazepine
45 years Febrile seizures Temporal 12/month Left temporal Normal Chronic Carbamazepine, chlorpromazine 114 mmol/l
46 years Unknown Temporal 10/month Left fronto-temporal Atrophy Postictal Carbamazepine, primidone 128 mmol/1
111 mmol/l
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amygdala-hippocampal focus in all cases [18]. It would have been desirable to have ictal video-telemetry in all cases. But this was not available in three patients. The psychotic syndromes are less uniform being recurrent periictally driven psychotic episodes with affective symptoms (Mr A.), three brief postictal hypochondriacal-paranoid psychotic episodes (Mrs B.), a chronic schizophrenic illness with Schneiderian first rank symptoms (Mr C.) and brief recurrent postictal automatisms with paranoid-hallucinatory symptoms (Mr D.). Although only one patient was chronically psychotic and the interictal psychiatric state in the three others was not normal with various traits such as hyposexuality, religiosity and suspiciousness suggesting the type of personality disorder which has been described in the context of temporal lobe epilepsy [19], it is important to note that the psychoses of these patients differ from the typical schizophrenia associated with PIP-syndrome in the literature [12]. Combining epileptological, psychiatric and social data, all patients had a chronic-progressive course with intractable seizures, social isolation, professional failure, and personality deterioration. All polydipsic episodes manifested initially with carbamazepine treatment in doses between 1,000 and 1,500 mg daily and maximum serum levels ranging between 30 and 68 /zmol/1. Patients had been taking carbamazepine for at least six months before manifestation of the PIP-syndrome, but three patients had been subclinically hyponatremic before. Mr C. had a second less severe polydipsic and hyponatremic episode while on phenytoin after discontinuation of carbamazepine suggesting that treatment with carbamazepine is not the crucial etiological factor in all episodes of this case. Maximal hyponatremia varied between 111 and 128 mmol/1. The pathogenesis of the hyponatremia is unclear although a combination of polydipsia and renal sodium loss is likely to be relevant in all cases. The limbic system has extensive functional links with the hypothalamus, and one explanation for the excessive drinking, ictally or postictally, could be by spread of seizure activity within limbic-hypothalamic circuits. Alternatively it could be viewed as a postictal disinhibition. Treatment with carbamazepine is likely to be an
Epileptic seizures Psychosis
/--..
T
Hyponatremia
,, Polydipsia
J ""
Carbamazepine Fig. 1. Linksbetweenepilepsy,psychosisand osmoticdysregulation suggestedby case studies.
etiological cofactor for the clinical manifestation of PIP-syndrome in our cases. The SIADH-like state with carbamazepine treatment may lower the threshold for developing hyponatremia with water loading in the setting of psychosis. Carbamazepine is certainly not obligatory for the development of a PIPsyndrome in epilepsy since one of our patients had a second episode with phenytoin.
4. Conclusion We describe four patients with left temporal lobe epilepsy who developed a PIP-syndrome on treatment with carbamazepine. The patients histories are not homogenous and pathophysiological mechanisms are likely to be complex. Nevertheless these patients suggest links between epilepsy, psychosis and osmotic dysregulation (Fig. 1). Chronic severe epilepsy with involvement of the limbic system may cause transient or persistent changes in neuromodulators and neurohormones in limbic-hypothalamic pathways which underlie psychosis, polydipsia and osmodysregulation. Carbamazepine and perhaps some other anticonvulsants may act as a trigger or a modifier. The PIP-syndrome is potentially fatal, the polydipsia often covert. We report these cases so that clinicians can be more aware of the problem which may exacerbate both epilepsy and psychosis and may arise when carbamazepine is given to elderly epilepsy patients with a history of psychosis.
Acknowledgements The first author was supported by a grant of the Deutsche Forschungsgemeinschaft (Grant 864/1-2). The work was also supported by the Raymond Way
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Foundation. The authors are grateful to John Duncan and Dieter Schmidt for critical comments.
References [1] Hoskins, R.G., Schizophrenia from the physiological point of view, Ann. lnt. Med., 30 (1933) 123-140. [2] Sleeper, F.H., Investigation of polyuria in schizophrenia, Am. J. Psychiatry, 91 (1935) 1019-1031. [3] Illowsky, B.P. and Kirch, D.G., Polydipsia and hponatremia in psychiatric patients, Am. J. Psychiatry, 145 (1988) 675682. [4] Vieweg, W.V.R., David, J.J., Rowe, W.T., Yank, G.R. and Spradlin, W.W., Diurnal variation of urinary excretion for patients with psychosis, intermittent hyponatremia, and polydipsia (PIP syndrome), Biol. Psychiatry, 21 (1986) 10311042. [5] Vieweg, W.V.R., David, J.J., Rowe, W.T., Peach, M.J., Vendhuis, J.D., Kaiser, D.L. and Spradlin, W.W., Diurnal weight gain as a predictor of serum concentration in patients with psychosis, intermittent hyponatremia, and polydipsia (PIP syndrome), Psychiatry Res., 6 (1988) 81-97. [6] Vieweg, W.V.R., David, J.J., Rowe, W.T., Peach, M.J., Vendhuis, J.D., Kaiser, D.L. and Spradlin, W.W., Psychogenic polydipsia and waterintoxication--Concepts that have failed, BioL Psychiatry, 20 (1985) 1308-1320. [7] Vieweg, W.V.R., David, J.J., Rowe, W.T., Wampner, G.I., Burns, W.I. and Spradlin, W,W., Death from self-induced water intoxication among patients with schizophrenic disorders, J. Nerv. Ment. Dis., 173 (1985) 161-165. [8] Gebel, F., Meng, H., Michot, F. and Truninger, B., Psy-
chogenic water intoxication, Schweiz. Med. Wochenschr., 119 (1992) 169-177. [9] Schnur, D.B., Wirkowski, E., Mukharjee, S., Reddy, R. and Decina, P., Cognition, water balance and schizophrenia. In: APA 1992; 145th Annual Meeting, 1992, p. 193 (Abstract). [10] Kirch, D.G., Elkashef, A., Suddath, R.L., Foote, M., Vieweg, W.V.R. and Wyatt, R.J., The neuroanatomy of polydipsiahyponatremia. In: APA 1992; 145th Annual Meeting, 1992, p. 193 (Abstract). [11] Suddath, R.L., Foote, M., Godelski, L., Vieweg, W.V.R., Weinberger, D.R. and Kirch, D.G., MRI of polydipsia-hyponatremia. Presented at 14th Annual Meeting of American Psychiatric Association, San Francisco, 1989. [12] De Leon, J., Verghese, C., Tracy, J.I., Josiassen, R.C. and Simpson, G.M., Biol. Psychiatry, 35 (1994) 408-419. [13] Lennox, W.G. and Cobb, S., Aura in epilepsy; a statistical review of 1,359 cases, Arch. Neurol. Psychiatry, 30 (1933) 374-387. [14] Remillard, G.M., Andermann, F., Gloor, P., Olivier, A. and Martin, J.B., Water-drinking as ictal behavior in complex partial seizures, Neurology, 31 (1992) 117-124. [15] Cascino, G.D. and Sutula, T.P., Thirst and compulsive water drinking in medial basal limbic epilepsy: An electroclinical and neuropathological correlation, J. Neurol. Neurosurg. Psychiatry, 51 (1989) 680-681. [16] Ashton, M.G., Ball, S.G., Thomas, S.G. and Lee, M.R., Water intoxication with carbamazepine treatment, Br. Med. 3"., 1 (1977) 1134-1135. [17] Johannessen, A.C. and Nielsen, O.A., Hyponatremia induced by oxcarbazepine, Epilepsy Res., 1 (1987) 155-156. [18] Commission on Classification and Terminology of the ILAE, Proposal for revised classification of epilepsies and epileptic syndromes, Epilepsia, 30 (1989) 389-399. [19] Geschwind, N., Behavioural changes in temporal lobe epilepsy, PsychoL Med., 9 (1978) 217-219.
Epilepsy Research 22 (1995) 215-220
Carbamazepine and PIP-syndrome in temporal lobe epilepsy Bettina Schrnitz a,* Michael R. Trirnble b a Psychiatrische Klinik und Poliklinik, Klinikum Benjamin Franklin, Eschenallee 3, 14050 Berlin, Germany b Department of Neurology, Institute of Neurology, Queen Square, London WC1N 3BG, UK Received 20 December 1994; revised 16 June 1995; accepted 18 June 1995
Abstract
We describe four patients with left temporal lobe epilepsy who developed psychosis, intermittent polydipsia and hyponatremia (PIP-syndrome) while being treated with carbamazepine. These cases illustrate the close links between dysfunction of the limbic system causing epileptic seizures and psychosis on the one hand and dysregulation in hypothalamic centers manifestating in polydipsia and osmodysregulation on the other. Keywords: Psychosis; Hyponatremia; Polydipsia; Carbamazepine
1. Introduction
1.1. The PIP-syndrome Symptoms of osmodysregulation are very common in psychiatric patients. The first description was in the 1930s [1,2]. Polydipsia has been reported in 6 to 17% [3], polyuria in 36 to 45% [4] and disturbed water homeostasis as measured by abnormal diurnal weight gain in 70% [5] of chronic psychiatric patients. The triad of psychosis, intermittent hyponatremia and polydipsia is called PIP-syndrome [6]. Closely related syndromes and synonyms are 'compulsive water drinking', 'self-induced water-intoxication with psychosis' and 'psychogenic polydipsia'. Frequently, symptoms remain subclinical but fatalities occur. In schizophrenic patients under 53 years, 18% of deaths are related to water intoxication [7].
* Corresponding author.
Diagnosis can be difficult because patients may make an effort to hide the excessive drinking. The psychiatric diagnosis in 87% of cases of polydipsia with water intoxication is schizophrenia [8]. There are data suggesting that patients with PIPsyndrome have more evidence for diffuse brain damage when compared with other psychotic patients. They have greater impairment in cognitive functioning [9] and larger ventricles and smaller brain size as detected by CT and MRI [10]. When comparing twelve schizophrenic patients who had histories of polydipsia and hyponatremia with twelve schizophrenics without such histories, Suddath et al. [11] noted decreased temporal grey, and smaller hippocampi and amygdalae in the former group. A history of epilepsy is not a recognized risk factor for the development of the PIP-syndrome [12]. However, epilepsy and drinking behaviour are related. Lennox and Cobb [13] in a review of the auras of 750 patients described 'asking for water' ictally in three cases. Remillard et al. [14], summarizing their expe-
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rience of 20 years, described twenty patients with periictal water-drinking, which sometimes was the only clinical manifestation associated with electrographic seizure discharges. Some patients were investigated with depth electrodes. All ictal recordings of drinking behaviour showed discharges of one temporal lobe, especially the hippocampus, the amygdala and the parahippocampal gyrus. The involvement of temporal lobe discharges in ictal drinking was supported by a case report by Cascino and Sutula [15] who described a patient with pathologically confirmed right hippocampal sclerosis and ictal compulsive water-drinking. Hyponatremia in patients with epilepsy has been described as a complication of treatment with carbamazepine or oxcarbazepine especially with higher doses [16,17]. The biochemical changes in these patients are consistent with an inappropriate antidiuretic state which is either due to SIAl)H, an agonistic ADH-like effect of carbamazepine or an increased renal ADH sensitivity. Serum ADH measurements have not been consistent, and the exact mechanism of hyponatremia is therefore still unsolved. Polydipsia with carbamazepine treatment has not been described. We describe four patients with long-standing, severe focal epilepsies who developed a PIP-syndrome on treatment with carbamazepine. We will discuss the links between temporal lobe epilepsy (TLE), PIP-syndrome and carbamazepine treatment with respect to anatomical and functional interactions.
2. Case reports 2.1. Case I
Mr. A is a 53 year old man with epilepsy since the age of 21. This started some months after a head injury. He has simple and complex focal seizures and secondarily generalized tonic-clonic seizures. Simple seizure symptoms are an epigastric rising sensation, a feeling of derealisation, speech arrest and a tonic head movement to the right. Oral automatisms are seen during complex focal seizures. Neurological examination is normal. Interictal EEGs show irregularities and isolated spikes over the left temporal
lobe; the CT and MRI scans are normal. The epilepsy is pharmacoresistant. The patient has always been strongly interested in religion and is an active member of Jehovah's witnesses. He was admitted to a psychiatric ward at the age of 30 with a diagnosis of 'neurosis with depressive, hysteric and obsessive elements'. Since the age of 35 he has had recurrent depressive episodes which are characterized by sleeplessness, agitation, brooding over religious questions, hypochondriacal complaints and pseudoseizures. At the age of 40 he had a second psychiatric admission. This time the diagnosis was 'paranoid-hallucinatory psychosis' and 'borderline-syndrome'. Since then, psychotic episodes have recurred about once a year. These psychoses are accompanied by an increase in seizure frequency and involve religious or grandiose delusions and auditory and visual hallucinations. Since the age of 39 the patient has been taking carbamazepine with a maximum dose of 1,500 mg daily (maximum serum concentration 57 /xmol/1). With this treatment his serum sodium levels were subnormal averaging 130 mmol/l. At 49, Mr A. was admitted with ankle edema, drinking at least six litres of water daily due to increased thirst. Serum sodium was 125 mmol/1. He was agitated and sleepless. He had a series of seizures, most of them being non-epileptic as confirmed by EEG. Subsequently he developed delusions. He thought he was King Solomon. He was treated with water restriction and haloperidol. Urine volume decreased from 6,500 ml to 1,250 ml daily within three days. Serum osmolality was 270 mosm/1 and urine osmolality 365 m o s m / l after two days of water restriction. On the basis of the low blood and relatively low urine osmolality, undetectable serum ADH and polyuria, a diagnosis of psychogenic polydipsia was made. With treatment, serum sodium levels normalized and the psychosis resolved. Another prolonged episode with depressive psychosis, increase in seizure frequency, polydipsia and hyponatremia (122 mmol/1) occurred three years later. 2.2. Case 2
Mrs B. is a 48 year old woman who had complicated febrile seizures during a cholera infection at
B. Schmitz, M.R. Trimble/ Epilepsy Research 22 (1995) 215-220
217
the age of five. Since the age of eight she has suffered from epilepsy. She has simple focal seizures consisting in a rising epigastric sensation, complex focal seizures with initial tonic flexion of both arms and subsequently vocal and gestural automatisms and secondarily generalized tonic-clonic seizures. At the age of 45 she had a depressed occipital skull fracture caused by a fall in an epileptic seizure. The epilepsy is pharmacoresistant. The interictal EEG shows a left temporo-basal spike focus; CT scan and neurological examination are normal. Since the age of 43 she has been treated with carbamazepine in monotherapy in a maximum dose of 1,050 mg daily (maximum serum concentration 68 ~mol/1). In the same year she experienced a first postictal psychotic episode leading to admission to a psychiatric hospital. One year later, again following a tonic-clonic seizure, she became progressively dysphoric. Three days postictally she tried to kill herself by repeatedly electrifying herself with a lamp. When brought to hospital she described various physical complaints, especially pains in her neck and stomach. She repeatedly touched her neck and swallowed constantly. She said that she was very thirsty and that she had a dry mouth. Her desire for water was frenzied and demanded physical restraint. She appeared drowsy, confused and her speech was dysarthric. She had a mild tremor and some psychomotor retardation. Her serum sodium was 111 mmol/l, serum potassium 2.9 mmol/l, and the haematocrit 34%. The sodium level normalized within twenty-four hours with water restriction and hyperosmolar infusions. Her urine volume during this period was 5,600 ml with a concentration of sodium of 30 mmol/l, of potassium of 7 m m o l / l and urine osmolality of 99 mosm/1. Under neuroleptic treatment and continued water restriction her psychiatric state improved within a few days. Two years later she developed a similar brief postictal paranoid-hypochondriac psychosis with polydipsia and mild hyponatremia.
plex focal seizures with oral automatisms and secondarily generalized tonic-clonic seizures. The epilepsy is pharmacoresistant. Interictal EEGs show a left anterior temporal spike focus; CT scan and neurological examination are normal. At the age of fourteen he believed he was being spied upon by the BBC. Since then he has developed a chronic schizophrenic illness. The psychotic symptoms appear to be more florid with increased seizure frequency. At age 45 he was on combined medication and it was decided to put him on carbamazepine monotherapy. After 11 days at 1,000 mg he became drowsy and confused. He developed muscular twitching and tonic-clonic seizures. Carbamazepine was increased up to 1,800 mg daily. The patient complained of being thirsty but did not admit to drinking excessively. He was observed to drink large amounts of water at night. He also developed polyuria and his serum sodium was found to be 114 mmol/1 while his plasma osmolality was only 242 mosm. Urine osmolality was not decreased. A carbamazepine-induced SIADH syndrome was suspected (carbamazepine serum concentration at this stage was 47 /xmol/1). Carbamazepine was subsequently discontinued and the patient was put on phenytoin monotherapy. Four years later, Mr C. was seizure free for some months on 600 mg phenytoin daily. When seizures recurred he was admitted to hospital and his chronic psychotic state appeared worsened. His phenytoin level was lower than before (51 /~mol/1 versus 79 /xmol/l) and his serum sodium level was 123 mmol/l. He had polydipsia with a daily fluid intake of at least six litres. He stated that he drank under the influence of electrical frequencies. With fluid restriction his serum sodium normalized and his urine was normally concentrated. His medication was therefore not altered. Both seizure frequency and his psychotic symptoms improved with maintained water restriction.
2.3. Case 3
2.4. Case 4
Mr C. is a 49 year old man who had febrile seizures in his second year of life due to malaria. Since the age of five he has had simple focal seizures with an alternating sensation of heat and cold, com-
Mr D. is a 52 year old man who has suffered from epilepsy since the age of 30. He has simple focal seizures with a d6j~t vu sensation, complex focal seizures consisting in an arrest reaction and secon-
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darily generalized tonic-clonic seizures. Neurological examination is normal. His EEG shows a left anterior temporal spike focus in the interictal state and bilateral temporal discharges ictally. Mild internal and external atrophy was seen on the CT scan. The epilepsy has been pharmacoresistant. The patient has always been strongly religious and is an active member of Jehovah's witnesses. He has had postictal automatisms which became more severe and prolonged with increasing duration of epilepsy. The postictal behaviour includes compulsive eating, urinating and defecating, profuse sweating, verbal and physical aggression, offensive sexual behaviour including undressing and public masturbation. Since about 40 the patient also has had postictal hallucinations, and sexual, religious and grandiose delusions. The patient was enuretic until age 18. Enuresis reoccurred two or three years after onset of epilepsy together with polyuria. Mild hyponatremia around 128-130 mmol/l together with serum hypoosmolality (242-266 mosm/1) had been observed since onset of treatment with carbamazepine at the age of 37, initially given together with phenytoin. When admitted at 46 for further investigation of enuresis he had nocturnal polydipsia (which he had denied before). He was by then on 1,200 mg carbamazepine (serum concentration 30 /xmol/l) and 750
mg primidone (serum concentration 46 /zmol/l daily). He admitted to drinking about six litres of water daily because of increased thirst. Maximal polyuria however was 9.2 1 in 24 hours during admission and might have been even higher outside hospital since serum sodium levels normalized during admission. On several occasions urine osmolality was inappropriately high compared to serum osmolality (e.g. 454 mosm/1 versus 266 mosm/1). Water restriction tests were performed twice (age 46 and 47). Serum sodium level normalized and urine osmolality increased (669 mosm/1) at least temporarily.
3. Discussion
The reported case histories are characterized by epilepsy, psychosis, polydipsia and hyponatremia with carbamazepine treatment. The four cases, although not entirely homogenous, reflect the links between seizure activity and disorders of limbic-hypothalamic systems, behavioural changes and endocrine dysfunction. The epileptic syndrome of the four patients is remarkably uniform (Table 1). All patients suffer from pharmacoresistant left temporal lobe epilepsy with different seizure classes and high seizure frequency. Seizure symptoms are compatible with an
Table 1 Clinical data of patients
Sex Age at onset of epilepsy Age at onset of psychosis Onset of treatment with Carbamazepine First recognized polydipsia Etiology of epilepsy Type of epilepsy Seizure frequency (cfs a) EEG CT Type of psychosis Medication at first polydipsia Lowest serum sodium a cfs = complex focal seizures.
Mr A.
Mrs B.
Mr C.
Mr D.
Male 21 years 40 years 39 years
Female 8 years 43 years 43 years
Male 5 years 14 years 37 years
Male 30 years 40 years 45 years
49 years Traumatic Temporal 16/month Left temporal Normal Parictal Carbamazepine, melperon 122 mmol/1
44 years Febrile seizures Temporal 8/month Left temporal Normal Postictal Carbamazepine
45 years Febrile seizures Temporal 12/month Left temporal Normal Chronic Carbamazepine, chlorpromazine 114 mmol/l
46 years Unknown Temporal 10/month Left fronto-temporal Atrophy Postictal Carbamazepine, primidone 128 mmol/1
111 mmol/l
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amygdala-hippocampal focus in all cases [18]. It would have been desirable to have ictal video-telemetry in all cases. But this was not available in three patients. The psychotic syndromes are less uniform being recurrent periictally driven psychotic episodes with affective symptoms (Mr A.), three brief postictal hypochondriacal-paranoid psychotic episodes (Mrs B.), a chronic schizophrenic illness with Schneiderian first rank symptoms (Mr C.) and brief recurrent postictal automatisms with paranoid-hallucinatory symptoms (Mr D.). Although only one patient was chronically psychotic and the interictal psychiatric state in the three others was not normal with various traits such as hyposexuality, religiosity and suspiciousness suggesting the type of personality disorder which has been described in the context of temporal lobe epilepsy [19], it is important to note that the psychoses of these patients differ from the typical schizophrenia associated with PIP-syndrome in the literature [12]. Combining epileptological, psychiatric and social data, all patients had a chronic-progressive course with intractable seizures, social isolation, professional failure, and personality deterioration. All polydipsic episodes manifested initially with carbamazepine treatment in doses between 1,000 and 1,500 mg daily and maximum serum levels ranging between 30 and 68 /zmol/1. Patients had been taking carbamazepine for at least six months before manifestation of the PIP-syndrome, but three patients had been subclinically hyponatremic before. Mr C. had a second less severe polydipsic and hyponatremic episode while on phenytoin after discontinuation of carbamazepine suggesting that treatment with carbamazepine is not the crucial etiological factor in all episodes of this case. Maximal hyponatremia varied between 111 and 128 mmol/1. The pathogenesis of the hyponatremia is unclear although a combination of polydipsia and renal sodium loss is likely to be relevant in all cases. The limbic system has extensive functional links with the hypothalamus, and one explanation for the excessive drinking, ictally or postictally, could be by spread of seizure activity within limbic-hypothalamic circuits. Alternatively it could be viewed as a postictal disinhibition. Treatment with carbamazepine is likely to be an
Epileptic seizures Psychosis
/--..
T
Hyponatremia
,, Polydipsia
J ""
Carbamazepine Fig. 1. Linksbetweenepilepsy,psychosisand osmoticdysregulation suggestedby case studies.
etiological cofactor for the clinical manifestation of PIP-syndrome in our cases. The SIADH-like state with carbamazepine treatment may lower the threshold for developing hyponatremia with water loading in the setting of psychosis. Carbamazepine is certainly not obligatory for the development of a PIPsyndrome in epilepsy since one of our patients had a second episode with phenytoin.
4. Conclusion We describe four patients with left temporal lobe epilepsy who developed a PIP-syndrome on treatment with carbamazepine. The patients histories are not homogenous and pathophysiological mechanisms are likely to be complex. Nevertheless these patients suggest links between epilepsy, psychosis and osmotic dysregulation (Fig. 1). Chronic severe epilepsy with involvement of the limbic system may cause transient or persistent changes in neuromodulators and neurohormones in limbic-hypothalamic pathways which underlie psychosis, polydipsia and osmodysregulation. Carbamazepine and perhaps some other anticonvulsants may act as a trigger or a modifier. The PIP-syndrome is potentially fatal, the polydipsia often covert. We report these cases so that clinicians can be more aware of the problem which may exacerbate both epilepsy and psychosis and may arise when carbamazepine is given to elderly epilepsy patients with a history of psychosis.
Acknowledgements The first author was supported by a grant of the Deutsche Forschungsgemeinschaft (Grant 864/1-2). The work was also supported by the Raymond Way
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Foundation. The authors are grateful to John Duncan and Dieter Schmidt for critical comments.
References [1] Hoskins, R.G., Schizophrenia from the physiological point of view, Ann. lnt. Med., 30 (1933) 123-140. [2] Sleeper, F.H., Investigation of polyuria in schizophrenia, Am. J. Psychiatry, 91 (1935) 1019-1031. [3] Illowsky, B.P. and Kirch, D.G., Polydipsia and hponatremia in psychiatric patients, Am. J. Psychiatry, 145 (1988) 675682. [4] Vieweg, W.V.R., David, J.J., Rowe, W.T., Yank, G.R. and Spradlin, W.W., Diurnal variation of urinary excretion for patients with psychosis, intermittent hyponatremia, and polydipsia (PIP syndrome), Biol. Psychiatry, 21 (1986) 10311042. [5] Vieweg, W.V.R., David, J.J., Rowe, W.T., Peach, M.J., Vendhuis, J.D., Kaiser, D.L. and Spradlin, W.W., Diurnal weight gain as a predictor of serum concentration in patients with psychosis, intermittent hyponatremia, and polydipsia (PIP syndrome), Psychiatry Res., 6 (1988) 81-97. [6] Vieweg, W.V.R., David, J.J., Rowe, W.T., Peach, M.J., Vendhuis, J.D., Kaiser, D.L. and Spradlin, W.W., Psychogenic polydipsia and waterintoxication--Concepts that have failed, BioL Psychiatry, 20 (1985) 1308-1320. [7] Vieweg, W.V.R., David, J.J., Rowe, W.T., Wampner, G.I., Burns, W.I. and Spradlin, W,W., Death from self-induced water intoxication among patients with schizophrenic disorders, J. Nerv. Ment. Dis., 173 (1985) 161-165. [8] Gebel, F., Meng, H., Michot, F. and Truninger, B., Psy-
chogenic water intoxication, Schweiz. Med. Wochenschr., 119 (1992) 169-177. [9] Schnur, D.B., Wirkowski, E., Mukharjee, S., Reddy, R. and Decina, P., Cognition, water balance and schizophrenia. In: APA 1992; 145th Annual Meeting, 1992, p. 193 (Abstract). [10] Kirch, D.G., Elkashef, A., Suddath, R.L., Foote, M., Vieweg, W.V.R. and Wyatt, R.J., The neuroanatomy of polydipsiahyponatremia. In: APA 1992; 145th Annual Meeting, 1992, p. 193 (Abstract). [11] Suddath, R.L., Foote, M., Godelski, L., Vieweg, W.V.R., Weinberger, D.R. and Kirch, D.G., MRI of polydipsia-hyponatremia. Presented at 14th Annual Meeting of American Psychiatric Association, San Francisco, 1989. [12] De Leon, J., Verghese, C., Tracy, J.I., Josiassen, R.C. and Simpson, G.M., Biol. Psychiatry, 35 (1994) 408-419. [13] Lennox, W.G. and Cobb, S., Aura in epilepsy; a statistical review of 1,359 cases, Arch. Neurol. Psychiatry, 30 (1933) 374-387. [14] Remillard, G.M., Andermann, F., Gloor, P., Olivier, A. and Martin, J.B., Water-drinking as ictal behavior in complex partial seizures, Neurology, 31 (1992) 117-124. [15] Cascino, G.D. and Sutula, T.P., Thirst and compulsive water drinking in medial basal limbic epilepsy: An electroclinical and neuropathological correlation, J. Neurol. Neurosurg. Psychiatry, 51 (1989) 680-681. [16] Ashton, M.G., Ball, S.G., Thomas, S.G. and Lee, M.R., Water intoxication with carbamazepine treatment, Br. Med. 3"., 1 (1977) 1134-1135. [17] Johannessen, A.C. and Nielsen, O.A., Hyponatremia induced by oxcarbazepine, Epilepsy Res., 1 (1987) 155-156. [18] Commission on Classification and Terminology of the ILAE, Proposal for revised classification of epilepsies and epileptic syndromes, Epilepsia, 30 (1989) 389-399. [19] Geschwind, N., Behavioural changes in temporal lobe epilepsy, PsychoL Med., 9 (1978) 217-219.