.:: Show Full Text Page ::.

July2004 Vol.41 Issue: 2

Table of Contents
Full Text
PDF

Effects of antiepileptics therapy on sleep pattern of non-epileptic patients

M. O. Abdulghani, T. K. Alloush, T. Asaad, M. Hemeda, N. Salah, L. Elsayed

Department of Neurology, Ain Shams University

ABSTRACT

Background: Many drugs with central nervous system effects can alter patterns of sleep and wakefulness. Most antiepileptics (AEDs) give rise to consolidation of sleep in epileptic patients. Because most of the major AEDs are used for bipolar affective disorders and neuropathic pain, there are emerging opportunities to study these drugs in a variety of populations in which the effects of epilepsy on sleep are absent. Aim of the work: To assess whether antiepileptic drugs exampliefied by (carbamazepine and valproate) have a direct independent role on sleep parameters in non-epileptic patients, or its effect is only secondary to control of epilepsy as previously described in epileptic patients. Subjects and Methods: We studied 60 patients. They were divided equally into two groups; group (1): diabetic neuropathy, and group (2): patients with bipolar affective disorders, without psychosis. Each group was subdivided into two subgroups for therapeutic purpose. Twenty healthy subjects were selected as a control group. All patients were subjected to an overnight polysomnographic study (PSG). The PSG assessment was repeated for all patients after one month from the treatment. Results: Carbamazepine or valproate monotherapy for one month was found to improve sleep continuity and increase the depth of sleep in both groups. Valproate monotherapy increase the REM latency in both groups. Therapy with either drug for one month was found to decrease periodic limb movement (PLM) index. Conclusion: Our study supports the assertion that antiepileptic drugs exampliefied by (carbamazepine and valproate) have a role in sleep normalization in non-epileptic, and can be used independently to improve sleep quality and quantity in other neuropsychiatric disorders such as pain, depression, and PLM.

(Egypt J. Neurol. Psychiat. Neurosurg., 2004, 41(2): 433-442).

INTRODUCTION

Sleep disorders, both insomnia and hypersomnia, are commonly associated with various co-morbid conditions, including general medical and neuropsychiatric disorders. Neurologic illnesses e.g. diabetic neuropathy may cause a variety of sleep disturbances, and sleep disorders may have a profound deleterious effects on the natural course of the neurologic illness¹.

Nearly almost all psychiatric illnesses can cause sleep disturbances e.g. in bipolar affective disorders, insomnia is noted more frequently than hypersomnia. Sleep continuity is also affected².

Because most of the major antiepileptics are used for bipolar disorder and neuropathic pain, there are emerging opportunities to study these drugs in a

variety of populations in which the effects of epilepsy on sleep are absent.

SUBJECTS AND METHODS

Subjects:

The patients were recruited from the outpatient clinics of neurology, psychiatry, and endocrinology departments, Ain Shams University Hospital.

This study included the following:

A) Patients group: was divided into:

Group I (GI): included 30 patients with diabetic neuropathy diagnosed clinically and/or neurophysiologically by nerve conduction study with age range from 20-50 years. Diabetic patients with CNS insult or other medical diseases were excluded from the study.

Group II (GII): included 30 patients fulfilling the ICD-10 criteria of bipolar affective disorders (BAD), without psychosis in remission state with an age range from 20-50 years. Patients never received valproate (VPA) or carbamazepine (CBZ) or they were off of these drugs for at least two weeks. Patients with other axis-1 disorders or on antipsychotic medications were excluded.

B) Control Group:

Included 20 healthy individuals from the information bank of the sleep laboratory who match patient groups for age and sex.

Methodology:

Phase I Assessments:

Group I:

All diabetic patients were subjected to:

1. Thorough clinical and neurological assessment especially evaluation for the neuropathy.

2. Sleep history: All participants underwent a standardized sleep questionnaire³.

2. Laboratory investigations: which included fasting and postprandial blood glucose levels, liver and kidney function tests.

3. Neurophysiological assessment included:

a. Nerve conduction study: median nerve and the common peroneal nerve were studied bilaterally for motor and sensory conductivity.

b. Polysomnographic (PSG) overnight study: with Four Electroencephalogram (EEG) channel, (C4-O1, C3-O2, A1-C3, and A1-C4), was applied according to the international 10-20 systems of electrode placement, Electro- oculogram (EOG), chin and leg Electromyogram (EMG), nasal airflow, respiratory effort (using intercostal EMG), electrocardiogram, oxygen saturation (through pulse oximetry [Nellcor 2000]), body position and snoring assessment. The polygraph machine used was a telefactor polygraph, and the software was semi-automated sleep scoring system (SASSSY, Version 4.X, Telefactor Corporation., West Conshohocken, PA)

4. Half of the diabetic patients (GIA) received CBZ at the dose of 600-1000 mg/ day for one month, the other half (GI B) patients were given VPA at the dose of 600-1000mg / day for one month.

Group II:

All patients with BAD were subjected to:

1. Thorough clinical and psychiatric examination.

2. Sleep history: as in group I.

2. Polysomnographic overnight study as in group I.

3. Half of patients (GII A) received CBZ at the dose of 600-1000 mg/day for one month, and the other half (GII B) patients received VPA at the dose of 600-1000 mg / day for one month.

Phase II Assessments:

The PSG assessment was repeated for the two groups after one month from the treatment.

RESULTS

Polysomnographic assessment

Sleep measures were sub-divided into three categories; (a) sleep latency and continuity measures (number of awakening, sleep efficiency, and arousal index), (b) sleep architectures including Non-rapid eye movement (NREM) sleep staging, breathing events [respiratory disturbance index (RDI)] and movement analysis, (c) rapid eye movement (REM ) sleep analysis including REM%, REM latency, duration of the first REM period.

In diabetic neuropathy subgroup A (before and after CBZ therapy), it was found that (Table 1):

(a) There is significant shorter sleep onset, decrease in a number of awakening and arousal index (P<0.05), and increase sleep efficiency (P<0.01).

(b) There is significant improvement in the depth of sleep [decrease in the percentage of stages 1&2 NREM sleep (P<0.01, P<0.05 respectively), and increase in the percentage of slow wave sleep (SWS) (P<0.01)]. There is

significant shorter latency to SWS (P<0.05), and there is significant decrease in PLM index (P<0.05) in patients after therapy.

(c) There is significant increase in the duration of the first REM period (P<0.05). There is no significant changes in the REM% and REM latency in patients after therapy.

These findings reveal better sleep quantity (indicated by increased sleep efficiency) and the quality (indicated by shorter sleep latency, decreased in number of awakenings after sleep onset, increased deep sleep, shorter latency to deep sleep, and decreased in PLM index) after CBZ monotherapy for one month.

In diabetic neuropathy subgroup B (before and after VPA therapy), it was found that (Table 2):

(a) There is significant shorter sleep onset, decrease in arousal index (P<0.05), and highly significant increase in sleep efficiency (P=0.000) in patients after therapy.

(b) There is significant decrease in the percentage of stages 1&2 NREM sleep (P<0.05), and increase in the percentage of SWS (P=0.000). There is significant shorter latency to SWS (P<0.05), and there is significant decrease in RDI, PLM index (P<0.05) in patients after therapy.

(c) There is significant increase in REM latency and increase in the duration of the first REM period (P<0.01) in patients after therapy

These findings reveal better sleep quantity (indicated by increased sleep efficiency) and the quality (indicated by shorter sleep latency, decreased in arousal index, increased deep sleep, shorter latency to deep sleep , and decreased in PLM index) after VPA monotherapy for one month.

In patients with BAD subgroup A (before and after CBZ), it was found that (Table 3):

(a) There is significant improvement in sleep latency and continuity measures [shorter sleep onset and decrease in a number of awakening (P<0.05) , highly significant increase in sleep

efficiency and arousal index (P=0.000) ]in patients after therapy.

(b) There is significant improvement in the depth of sleep [decrease in the percentage of stage 2 NREM sleep (P<0.01), and increase in the percentage of SWS (P<0.01)]. There is significant shorter latency to SWS (P<0.05).

(c) There is significant increase in REM latency (P<0.01) in patients after therapy. There is no significant changes in other REM parameters.

These findings reveal better sleep quantity (indicated by increased sleep efficiency) and the quality (indicated by shorter sleep latency, decreased in number of awakenings after sleep onset, decreased arousal index, increased deep sleep, and shorter latency to deep sleep after CBZ monotherapy for one month.

In patients with BAD subgroup B (before and after VPA therapy), it was found that (Table 4):

(a) There is highly significant shorter onset to sleep (P=0.000), significant increase in sleep efficiency (P<0.01), and decrease in number of awakening (P<0.01) and arousal index (P<0.05) in patients after therapy.

(b) There is significant decrease in stage 2 NREM sleep % (P<0.01), increase SWS% (P<0.05). There is statistically significant shorter onset to SWS (P<0.05) in patients after therapy.

(c ) There is significant increased in REM sleep latency (P<0.05) in patients after therapy.

These findings reveal better sleep quantity (indicated by increased sleep efficiency) and the quality (indicated by shorter sleep latency, decreased in number of awakenings after sleep onset, decreased arousal index, increased deep sleep, and shorter latency to deep sleep after VPA monotherapy for one month.

Comparing the effect of CBZ monotherapy on both groups revealed improvement in sleep continuity, increase in the depth of sleep, unchanged REM latency and percentage of REM sleep. Meaning that carbamazepine improved both sleep quantity and quality (Table 5).

Comparing the effect of VPA monotherapy on both groups revealed shorter sleep latency, increased sleep efficiency, increase the depth of sleep,

increased REM latency. Meaning that valproate improved both sleep quantity and quality (Table 6).

Table 1. Comparison of sleep parameters among G1 A before and after carbamazepine therapy.

P- value	After therapy Mean±SD	Before therapy Mean±SD	Sleep parameters
<0.05	9.53±2.47	11.40±2.44	Number of awakening
<0.05	12.83±6.04	21.87±15.61	Sleep latency
<0.01	89.55±3.08	78.49±13.85	Sleep efficiency
<0.05	5.32±4.13	11.67±10.70	Arousal index
<0.01	2.92±1.08	7.11±7.08	Stage 1%
<0.05	44.59±11.45	51.03±12.41	Stage 2%
<0.01	34.55±8.27	24.85±12.13	SWS %
<0.05	24.2±18.73	38.33±24.96	SWS latency
NS	0.38±1.44	0.41±1.44	RDI
<0.05	4.45±8.47	7.33±10.39	PLM index
NS	17.98±6.09	17.10±5.92	REM %
NS	83.0±25.32	77.30±25.11	REM latency
<0.05	15.53±6.45	11.60±5.96	Duration of1^stREM period

SWS: slow wave sleep. RDI: respiratory disturbance index. PLM: periodic limb movement.

REM: rapid eye movement. NS :non-significant

Table 2. Comparison of sleep parameters among G1B before and after valproate therapy.

P- value	After therapy Mean±SD	Before therapy Mean±SD	Sleep parameters
NS	10.27±2.31	10.87±2.13	Number of awakening
<0.05	22.20±12.68	38.17±27.02	Sleep latency
= 0.000	83.37±5.54	73.13±10.40	sleep efficiency
<0.05	5.16±3.70	10.58±9.16	Arousal index
<0.05	3.99±1.89	5.66±4.18	Stage 1%
<0.05	48.30±6.97	54.16±7.03	Stage 2%
= 0.000	27.89±4.31	20.82±6.3	SWS %
<0.05	45.00±20.27	57.40±29.78	SWS latency
<0.05	0.41±0.79	0.70±0.81	RDI
<0.05	2.99±5.16	6.07±9.17	PLM index
NS	19.85±5.64	19.35±7.75	REM %
<0.05	95.57±21.21	83.80±24.48	REM latency
<0.01	17.87±5.15	12.73±7.52	Duration of 1^st REM period

SWS: slow wave sleep. RDI: respiratory disturbance index. PLM: periodic limb movement.

REM: rapid eye movement. NS :non-significant

P- value

After therapy

Mean±SD

Before therapy

Mean±SD

Sleep parameter

<0.01

7.67±2.26

10.20±2.01

Number of awakening

=0.000

19.97±8.03

42.9±21.48

Sleep latency

<0.01

84.73±5.48

71.68±13.58

sleep efficiency

<0.05

3.02±2.02

6.01±3.57

Arousal index

NS

5.57±3.94

4.45±2.35

Stage 1%

<0.01

64.11±5.77

56.5±7.49

Stage 2%

<0.05

30.02±5.41

22.71±7.56

SWS %

<0.05

45.80±18.79

62.13±30.12

SWS latency

NS

0.00±0.00

0.00±0.00

RDI

NS

0.00±0.00

0.00±0.00

PLM index

NS

17.61±3.80

15.21±4.94

REM %

<0.05

91.53±22.97

78.47±18.11

REM latency

NS

16.27±7.22

13.60±6.62

Duration of1^stREM period

SWS: slow wave sleep. RDI: respiratory disturbance index. PLM: periodic limb movement.

REM: rapid eye movement. NS :non-significant

Table 5. Comparison of sleep parameters among G1A and G2A after CBZ therapy

G2A

P. value After therapy

G1A

P. value after therapy

Sleep parameters

<0.01

<0.05

Number o f awakening

<0.01

<0.05

Sleep latency

= 0.000

<0.01

sleep efficiency

=0.000

<0.05

Arousal index

NS

<0.01

Stage 1%

<0.01

<0.05

Stage 2%

<0.01

<0.01

SWS %

<0.05

<0.05

SWS latency

NS

NS

RDI

NS

<0.05

PLM index

NS

NS

REM %

<0.01

NS

REM latency

NS

<0.05

Duration of 1^st REM period

SWS: slow wave sleep. RDI: respiratory disturbance index. PLM: periodic limb movement.

REM: rapid eye movement. NS :non-significant

Table 6. Comparison of sleep parameters among G1B and G2B after VPA therapy

G2B P. value After therapy	G1B P. value after therapy	Sleep parameter
<0.01	NS	Number of awakening
= 0.000	<0.05	Sleep latency
<0.01	= 0.000	sleep efficiency
<0.05	<0.05	Arousal index
NS	<0.05	Stage 1%
<0.01	<0.05	Stage 2%
<0.05	= 0.000	SWS %
<0.05	<0.05	SWS latency
NS	<0.05	RDI
NS	<0.05	PLM index
NS	NS	REM %
<0.05	<0.05	REM latency
NS	<0.01	Duration of 1^st REM period

SWS: slow wave sleep. RDI: respiratory disturbance index. PLM: periodic limb movement.

REM: rapid eye movement. NS :non-significant

DISCUSSION

Many drugs with central nervous system CNS effects can alter patterns of sleep and wakefulness. Several sleep disorders are caused by dependence on psychoactive drugs. In addition, some medications can exacerbate primary sleep disorders, thereby affecting sleep indirectly. On the other hand, most AEDs give rise to normalization and stabilization of sleep⁴.

As detailed in the literature generally, the effects of AEDs on sleep architecture comes primarily from studies of patients with epilepsy. The sleep disturbance in epileptic patients is believed to be related to the nocturnal occurrence of generalized tonic-clonic seizures or repetitive partial seizures, the severity of seizure disorder, and the influence of AEDs⁵.

Previous studies have shown that, the majority of AEDs may either delay REM sleep onset or suppress REM sleep percentages, even though many AEDs differentially affect seizure types⁶. With this in mind, it appears that the AEDs can affect sleep and seizures either

simultaneously or independently. Because most of the major AEDs are used for BAD and neuropathic pain, there are emerging opportunities to study these drugs in a variety of populations in which the effects of epilepsy on sleep are absent.

The present study is aimed at assessing whether antiepileptic drugs exampliefied by (carbamazepine and valproate) have a direct independent role on sleep parameters in non-epileptic patients, or its effect is only secondary to control of epilepsy previously described in epileptic patients.

The study of the effect of CBZ in diabetic neuropathy subgroup A (Table 1) revealed significant improvements in sleep efficiency and continuity measures. These findings are in agreement with previous study⁷ which reported better sleep

quantity (indicated by sleep efficiency) and the quality (indicated by sleep latency and number of awakenings after sleep onset) after CBZ monotherapy for six months in 18 patients with generalized tonic-clonic epilepsy.

This study revealed that this group of patients (diabetic neuropathy subgroup A) slept deeper than before therapy. Similar findings had been shown by other researchers who reported increased SWS in 12 normal subjects, treated with CBZ⁸

There is significant shorter latency to SWS. This effect is logic because of reduction of stages 1 & 2 NREM sleep after CBZ therapy. Also there is significant reduction in PLM index in patients after therapy. This is consistent with other studies that have shown the efficacy of CBZ on restless legs syndrome⁹.

The duration of the first REM period is significantly increased in patients after CBZ therapy. No significant changes in the REM% and REM latency. This effect are consistent with previous studies¹⁰.

The study of the effect of VPA in diabetic neuropathy subgroup B (Table 2) revealed significant improvement in sleep quantity and quality in patients after therapy. These findings are in agreement with other reports¹¹.

This study revealed significant increase in the depth of sleep in diabetic patients after VPA therapy. Similar results were reported previously. This is logic because VPA is γ amino butyric acid (GABA) agonist, and GABA is responsible for induction and maintenance of SWS.

There is statistically significant decrease in PLM index in patients after VPA therapy. Meanwhile, previous study¹¹ showed reduction in the number of PLMs index and

in the percentage of arousals associated with it. Thus, these dat

a indicate that VPA has a long-term beneficial effect on sleep consolidation in patients with PLM disorders

REM latency and the duration of the first REM period are significantly increased in patients after VPA therapy. This finding is in agreement with previous reports¹². The delay in

REM latency is possiblely due to increase in the percentage of SWS.

The studying of the effect of CBZ in patients with BAD subgroup A (Table 3); revealed significant improvement in sleep latency and continuity measures as in diabetic neuropathy subgroup.

As regard sleep architecture measurements, the results are similar to those findings in diabetic subgroup except for the unchanged percentage of stage 1NREM sleep.

As for REM sleep, the results are similar to those findings in diabetic neuropathy subgroup except for the delay in the REM latency and unchanged duration of the first REM period in patients with BAD. The delay in REM latency after CBZ in patients with bipolar affective disorders is in agreement with previous reports⁸. The variable effect of CBZ

on REM latency confirms that these changes are disease dependent rather than drug dependent.

The studying of the effect of VPA in patients with BAD subgroup B (Table 4); revealed significant improvement in sleep latency and continuity measures as in diabetic neuropathy subgroup except for the significant reduction in the number of awakening in patients with BAD after VPA therapy. This difference between both group indicates that this change is a result of stabilization of disease, but not due to the effect of the drug.

As regard sleep stages, the results are similar to those findings in diabetic neuropathy subgroup except for the unchanged percentage of stage 1NREM sleep.

As for REM sleep, the results are similar to those findings in diabetic neuropathy subgroup except for the unchanged duration of the first REM period in patients with BAD. This difference between both group indicates that the change is disease related, but not due to the effect of the drug.

CBZ monotherapy produced significant changes in both groups (Table 5). First, it decreases number of awakening, shortens sleep latency, decreases arousal index, and subsequently improves sleep efficiency. This is consistent with the previous reported literature concerning the effect of CBZ on epileptic patients as well as in healthy

volunteers. Although this effect may be due to improvement of parathesia in diabetic patients, or mood stabilizing effect in patients with mood disorders, and improvement of epilepsy in epileptic patients. However, similar results are also observed in healthy volunteers. The university of these changes would strongly suggest another mechanism, it may be due to increased dopamine turnover by CBZ at therapeutic doses previous reported by¹³. Kanabayashi et al.¹⁴ reported that a reduction of dopamine activity seems to facilitate

sleep and reduce behavioral responsiveness. Also, shorten sleep latency may be due to its serotonergic mechanism. Pharmacological evidence suggested that serotonin may have a role in sleep induction¹⁵. Second, CBZ appears to increase SWS in epileptic patients as well

as non epileptics and healthy volunteers. Also, this study revealed shorter SWS latency after CBZ. These findings are possiblely due to its serotonin releasing effect by direct action on serotonergic nerve terminals. Serotonin was implicated in SWS induction and maintenance. Also, increased SWS increase sleep efficiency. Third, CBZ appears to decrease PLM in diabetic. Since, a genetic factor may be present in some cases of restless leg syndrome (RLS) and PLM disorder, that causes an imbalance in serotonin, which causes a free play of nerve impulses that are normally suppressed¹⁶, CBZ may be of benefit due to its serotonergic

releasing effect. Fourth, CBZ has no effect on REM sleep percentage and REM periods. On the other hand, CBZ increases REM latency on patients with BAD. Meaning that this effect is due to its mood stabilizing effect rather than due to its direct action on sleep.

VPA monotherapy for one month has also a unique effect on both groups (Table 6). First, sleep stabilizes (shorter sleep latency, decrease in arousal index, and subsequently improves sleep efficiency) after therapy. Although the effect might be secondary to improving symptomatology. Yet the effect of valproate on GABA may have also modulate sleep directly as well as indirectly by modulating and stabilizing excitatory neurotransmitters. The shortens sleep latency may be due to its serotonergic mechanism. Second, there is significant increase in SWS and shorter latency to SWS in both groups after therapy. This is probably due to increase in central serotonergic neurotransmission previously

reported by Maes et al.¹⁷ after subchronic treatment with valproate in manic patients.

Also, valproate is GABA agonist. Serotonin and GABA are responsible for induction and maintenance of SWS. Increase SWS lead to increase in sleep efficiency. Third, VPA appears to decrease PLM in diabetic patients. Together with the previous reports¹¹, VPA,

most probably has primary effect in consolidation of sleep and decrease the quantity of PLM in patients with PLM disorders whether primary or secondary. Fourth, VPA appears to increase REM latency in both group. It may be related to increase cholinergic sensitivity after VPA therapy as previous reported by DeMet and Sokolski¹⁸ who reported increase papillary

sensitivity to pilocarpine in manic patients after VPA therapy. Acetylcholine is implicated in REM sleep.

Lastly, we can conclude that CBZ and VPA have a primary effect on sleep stabilization and consolidation and can be used in certain conditions associated with sleep disorders as in pain conditions, especially chronic pain conditions that was treated in the past by sedatives and sleep inducing drugs such as phenobarbital and tricyclic antidepressant. But these drugs cause changes in sleep patterns, such as loss of REM sleep. Since the 1960, carbamazepine has been found useful for certain pain syndromes, such as neuropathic pain and trigeminal neuralgia. This study suggest that there may be a more beneficial, or less deleterious, effect of CBZ and VPA on sleep architecture than the previously popular tricyclic antidepressant and sedative hypnotics. For example, benzodiazepines tend to decrease SWS, and the longer varieties also suppress REM sleep, whereas CBZ and VPA increase SWS and shorten latency to SWS and have no effect on the percentage of REM sleep. Also, opioids are used for the treatment of RLS and PLM disorders, especially primary type, but these drugs can increase the risk of drug abuse. In addition, they affect sleep by decreasing REM sleep and increasing arousal.

Several benzodiazepines, including clonazepam, lorazepam, and temazepam, were used to treat RLS and PLM and were shown to reduce the quantity of leg movements and to improve the quality of nocturnal sleep. However, benzodiazepine are potent CNS depressants and that may induce or aggrevate the sleep apnea syndrome, especially in elderly patients. This study suggest that CBZ and

VPA are more beneficial in treatment of RLS and PLM than other drugs mentioned above.

To conclude, one can accept the premise that the majority of AEDs give rise to a stabilization of sleep (directly stabilizing sleep architecture) in non-epileptic , and can be used independently to improve sleep quality and quantity in other neuropsychiatric disorders such as pain, depression. Also, in certain primary sleep disorder such as RLS and PLM disorder.

REEFRENCES

1. Chokroverty S. Sleep Disturbance in Other Medical Disorders. In: Sleep Disorders medicine: basic science, technical considerations and clinical aspects. Chokroverty S(ed). Boston:Butterworth-Heinemann 1999;587-617.

2. Hanna MM, Moreno RA, Tavares SM, Teixeira V, and Aloe F. Polysomnographic features of manic patients. Sleep 2000 ;23:353.

3. Asaad T and Kahla O. Psychometric sleep assessments instruments: An Arabic version for sleep evaluation. Elnahda, El- Fagala. Egypt 2001.

4. Shouse MN, Martins da Silva A, and Sammaritano M. Circadian rhythm, sleep and epilepsy. Journal of Clinical Neurophysiology 1995;13:32-50

5. Sammaritano MR, Levtova VB, and Samson-Dollfus D. Modification of sleep architecture in patients with temporal lobe epilepsy. Epilepsia 1994;35(suppl 8):124.

6. Touchon J, Badely-Moulinier M, and Billiard M. Sleep organization and epilepsy. Epilepsy Res 1991(supp2);73-81

7. El–Khayat N. A Comprehensive Evaluation of Nocturnal Polysomnographic Recording in Epileptic Patients. M.D. thesis 1999. Deparment of Neurology. Ain Shams University Egypt.

8. Riemann D, Gann H, Hohagen F, Bahro M, Muller WE, and Berger M. The effect of carbamazepine on endocrine and sleep variables in a patient with a 48-hour rapid cycling, and healthy controls. Neurophysiology 1993; 27:163-170.

9. Wetter TC and Pollmacher T. Restless legs and periodic leg movements in sleep syndromes. J Neurol 1997; 244(4 Suppl 1): S37-45.

10. Bonanni E, Masetani R, and Galli R . A quantitative study of daytime sleepiness induced by carbmazepine and add-on vigabatrin in epileptic patients. Acta Neurolgica Scandanevin 1997;95:193-196

11. Ehrenberg BL, Eisensehr I, Corbett KE, Crowley PF, and Walters AS. Valproate for sleep consolidation in periodic limb movement disorder. J Clin Psychopharmacol 2000; 20:574-578.

12. Drake ME, Pakalnis A, and Pamada H. Sleep spindles in epilepsy. Clini EEG Electroencephalogr 1991;22:144-149.

13. Okada M, Hirano T, Mizuno K, Chiba T, Kawata Y, Kiryu K, Wada K, Tasaki H, And Kaneko S. Biphasic effects of carbamazepine on the dopaminergic system in rat striatum and hippocampus. Epilepsy Research 1997; 28:143-153.

14. Kanabayashi T,Madokoro S, Ihara H, Umenzawa Y,Murayama J,Kosaka H, Misaki K, and Nakagawa H. Analysis of the human sleep EEG by the correlation dimension.Psychiatry Clin Neurosci 2000;54(3):278-279.

15. Jones BE. Basic mechanisms of sleep-wake state. In Principles and Practice of Sleep Medicine, 3^rd ed.

Kryger MH, Roth T, and Dement WC (eds). Philadelphia:Saunders 2000; 134-155.

16. Simon H. Restless Legs Syndrome. UC Davis Health System 2000.

17. Maes M, Calabrese J, Jayathilake K, and Meltzer HY. Effects of subchronic treatment with valproate on l-5-HTP-induced cortisol responses in mania: evidence for increased central serotonergic neurotransmission. Psychiatry Research 1997;71:67-76

18. DeMet EM and Sokolski KN. Sodium valproate increases pupillary responsiveness to a cholinergic agonist in responders with mania. Biological Psychiatry 1999; 46:432-436

الملخــص العربـــى

يعتبر النوم عملية نشطة وعلي درجة عالية من التنظيم من خلال عوامل عديدة. وهناك العديد من العقاقير التى تؤثر على الجهاز العصبي المركزى. بالأضافه الى ان بعض الأدوية يمكنها مضاعفة اضطرابات النوم الأولية عن طريق غير مباشر. بينما أثبتت أبحاث سابقه تحسن نوعية ومدة النوم مع تناول الأدوية المضادة للصرع في مرضى الصرع. وقد استخلص أثر العلاج بمضادات الصرع على نمط النوم من دراستها في مرضى الصرع. وبما أن مضادات الصرع تستخدم في مرضى التهاب الأعصاب الطرفية والإضطراب الوجدانى ثنائى القطب فقد اتيحت لنا الفرصة لدراسة هذه الأدوية علي مجموعة من المرضى غير المصابين بالصرع.

ولذلك فان الهدف الأساسى من هذا البحث هو تقويم دور مضادات الصرع (الكاربمازيبين والفالبرويت) على نمط النوم في مرضى غير مصابين بالصرع، وإيضاح إذا ما كان لها دور أولي فى تحسين نمط النوم، أو أن دورها ثانوي ينتج عن تحسين نوبات الصرع في مرضي الصرع فقط..

تمت هذه الدراسة على ستين مريضا. تم تقسيمهم الى مجموعتين، المجموعة الأولى شملت ثلاثين مريضا مصاب بالتهاب الأعصاب الطرفية الناتج عن البول السكرى. والمجموعة الثانية، شملت ثلاثين مريضا مصاب بمرض الاضطراب الوجدانى ثنائى القطب. وقد قسمت كل مجموعه الى مجموعتين أصغر. وقد شملت الدراسة أيضا، عشرين شخصا صحيحا (مجموعه ضابطه) مماثلين في العمر والجنس لمجموعه المرضى.

وقد خضع كل المرضى الى بيان تاريخ تفصيلي للمرض مع فحص سريرى كامل، وتاريخ تفصيلي لاضطراب النوم بما فيها الوضع الحالي والوضع السابق. وأجرى لجميع المرضى تخطيط النوم الليلي المتعدد الخاص بمعمل النوم فى وحدة الأمراض العصبية بقسم الأمراض العصبية والنفسية بجامعة عين شمس قبل تناول مضادات الصرع (الكاربمازيبين والفالبرويت)، وتمت إعادته بعد مرور شهر على تناول العقار لتقويم أثر العقار .

وقد أظهرت النتائج ما يلى:

(أ) العلاج بالكاربمازيبين أو الفالبرويت كليهما لمدة شهر فى مرضى التهاب الأعصاب الطرفية أدى الى تقليل الفترة لبداية النوم، مع تقليل معامل التنبه أثناء النوم، وتحسين كفاءة النوم وعمقه، مع تقليل الفترة لبداية النوم العميق، بالإضافة إلي تقليل الحركات الدورية اللإاراديه للأعضاء الطرفية خلال النوم. كلا العقارين كان له أثر على النوم المصاحب بحركة العين السريعة، إذ أن الكاربمازيبين أدى الى زيادة الفترة الأولى من النوم المصاحب بحركة العين السريعة فى حين أن الفالبرويت أدى الى زيادة الفترة لبداية النوم المصاحب بحركة العين السريعة.

(ب) العلاج بالكاربمازيبين أو الفالبرويت كليهما لمدة شهر فى مرضى الاضطراب الوجدانى ثنائى القطب كان له نفس النتيجة بالنسبة لتقليل الفترة لبداية النوم، مع تقليل معامل التنبه أثناء النوم وعدد مرات الاستيقاظ خلال النوم، وتحسين كفاءة النوم وعمقه. مع تقليل الفترة لبداية النوم العميق وزيادة الفترة لبداية النوم المصاحب بحركة العين السريعة.

(ت) العلاج بالكاربمازيبين لمدة شهر فى كلا المجموعتين أدى الى تقليل الفترة لبداية النوم، وتقليل عدد مرات الاستيقاظ خلال النوم مع تقليل معامل التنبه أثناء النوم، وتحسين كفاءة النوم. وهو ما يتفق مع ما أظهرته دراسات أخرى سابقه أجريت على مرضى الصرع وأشخاص أصحاء.

(ث) كان للكاربمازيبين دور فى تحسين عمق النوم. أيضا كان له دور فى تقليل الفترة لبداية النوم العميق فى كلا المجموعتين

(ج) العلاج بالفالبرويت لمدة شهر فى كلا المجموعتين أدى الى تقليل الفترة اللازمة لبداية النوم مع تقليل معامل التنبه أثناء النوم، وتحسين كفاءة النوم.

(ح) أدى عقار الفالبرويت الى زيادة نسبة النوم العميق، وأيضا كان له دور فى تقليل الفترة لبداية النوم العميق فى كلا المجموعتين.

(خ) أدى عقار الفالبرويت الى زيادة الفترة لبداية النوم المصاحب بحركة العين السريعة فى كلا المجموعتين.

وأخيرا، فقد استنتجت هذه الدراسة إن لمضادات الصرع (الكاربمازيبين أو الفالبرويت) دور فى تحسين نوعية النوم ومدته فى المرضى غير المصابين بالصرع. وفى ضؤ ما ذكر يتثنى لنا استخدام مضادات الصرع بمفردها لتحسين نوعية النوم ومدته فى العديد من الأمراض العصبية والنفسية المصاحبة باضطرابات فى النوم مثل الآلام الناتجة عن التهاب الأعصاب، وفى حالات الصداع النصفى، وفى حالات الاضطراب الوجدانى. أيضا، فى حالات اضطرابات النوم الأولية مثل الحركات الدورية اللإاراديه للأعضاء الطرفية خلال النوم