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Withdrawal reaction of carbamazepine after neurovascular decompression for trigeminal neuralgia: A preliminary study
Journal of the Neurological Sciences 338 (2014) 43–45
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Withdrawal reaction of carbamazepine after neurovascular decompression for trigeminal neuralgia: A preliminary study☆ Min-Jie Chen a, Wei-Jie Zhang a,⁎, Zhi-Lin Guo b, Wen-Hao Zhang a, Ying Chai a, Yun-wu Li c a b c
Department of Oral and Maxillofacial Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China Department of Neurosurgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China Department of Pharmacy, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
a r t i c l e
i n f o
Article history: Received 6 September 2013 Received in revised form 29 November 2013 Accepted 4 December 2013 Available online 11 December 2013 Keywords: Carbamazepine Withdrawal reaction Overexcitement Trigeminal neuralgia Microvascular decompression Blood concentration
a b s t r a c t Objective: To evaluate the representations and the relevant factors of carbamazepine-associated withdrawal reaction (CAWR) after microvascular decompression (MVD) to treat trigeminal neuralgia (TN). Methods: The present series included 90 patients who were referred from September 2010 to January 2013 and diagnosed with classical TN. The carbamazepine (CBZ) serum level was tested twice at 24 h pre- and 24 h postoperation by using HPLC analysis. The analysis of correlating selected factors and CAWR was performed. Results: Among 90 patients, 26 (28.9%) suffered from post-operative CAWR for 3 days after MVD. The symptoms of CAWR include overexcitement, e.g. insomnia, dysphoria, hand fremitus, hallucination and severe headache. The history of CBZ therapy before MVD, pre-operative dosage of CBZ, and the D-value of CBZ blood concentrations demonstrated statistic differences between the patients with CAWR and those without CAWR. Patient characteristics such as gender, age, and duration of neuralgia, neuralgia-related factors including neuralgia extent and neurovascular compression severity, and operation conditions including duration of MVD procedure, effect of MVD and complication of MVD had no influence on the occurrence of CAWR. Conclusion: It is strongly suggested that CAWR is dependent on the pre-operative dosage and the changing rate of pre- and post-operative CBZ blood concentrations. © 2013 Elsevier B.V. All rights reserved.
1. Introduction The International Association for the Study of Pain (IASP) defines trigeminal neuralgia (TN) as sudden, usually unilateral, severe, brief, stabbing and recurrent episodes of pain in the distribution of one or more branches of the trigeminal nerve [1,2]. TN is the most common neuralgia. Although approximately 20% of patients who were treated with carbamazepine (CBZ) experience some side effects, CBZ is still the most effective and first line drug for treatment of TN [3,4]. When pharmacotherapy fails to alleviate the pain or if patients experience severe side effects, the surgical approach should be taken into consideration. Microvascular decompression (MVD) is commonly considered as the first neurosurgical option among TN patients with various neurovascular compressions. Most of the patients underwent longterm, high-dosage CBZ therapies before MVD. During pharmacotherapy, the dosage of CBZ should be gradually increased until adequate response level is achieved. It should also be steadily decreased when
☆ Supported by the National Science Foundation of China (No. 81100824) and Foundation of Shanghai Municipal Education Commission (No. 12YZ044). ⁎ Corresponding author at: Department of Oral and Maxillofacial Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhi-zao-ju Road, Shanghai 200011, PR China. Tel.: +86 21 23271699 5388; fax: +86 21 53072423. E-mail address: [email protected] (W.-J. Zhang). 0022-510X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2013.12.013
the pain is completely relieved for at least 2 weeks. However, there is a contradiction that CBZ is always withdrawn rapidly after MVD. Studies concerning on the clinical and electrophysiological changes accompanying CBZ withdrawal have been reported [5,6]. To our knowledge, there is only one report about the conditions following the rapid withdrawal of CBZ after MVD [7]. In this study, a cohort of patients who underwent MVD treatment was observed and evaluated prospectively. Interests are addressed on the following issues: Will the patients present withdrawal symptoms following the rapid withdrawal of CBZ after MVD? What kind of clinical symptoms may arise following the rapid withdrawal of CBZ after MVD? What are the relevant factors leading to CBZ-associated withdrawal reactions (CAWRs)? 2. Materials and methods 2.1. Patients The series included 90 patients who were referred from September 2010 to January 2013 with classical TN (60 women and 30 men; age range, 33 years–80 years; mean age, 57.7 years). Patients did not suffer from imaging abnormalities such as multiple sclerosis, vascular malformation, and tumor. All patients were subjected to MVD under general anesthesia by the same senior neurosurgeon using the same surgical technique. The CBZ serum level was tested twice at 24 h pre- and
44
M.-J. Chen et al. / Journal of the Neurological Sciences 338 (2014) 43–45
24 h post-operation. The ethical approval was given by Shanghai Jiao Tong University's Ethics Committee. We have read the Helsinki Declaration and have strictly followed the guidelines in this investigation. 2.2. Chromatographic procedure Chromatographic analysis was carried out using a microcolumn high performance liquid chromatography (HPLC) device (Waters, USA) with a UV detector, which permitted fixation of the entire absorption spectrum within the range of 190–360 nm. Analytes were detected at a wavelength of 210 nm. The internal standard solution was acetonitrile with acetophenone (5.15 μg/ml). The mobile phase composition was 0.05 M Na2HPO4 with methanol at a ratio of 40:60 (v/v). The flowrate of the mobile phase was 1 ml/min. The serum (200 μl) was added to the internal standard solution (400 μl). The mixture was agitated by hand for 1 min and centrifuged for 10 min. Finally, the supernate (20 μl) was injected for HPLC analysis. 2.3. Statistical analysis Data analysis was performed using the commercially available software SAS version 6.12 (SAS Institute, Cary, NC). Comparisons were performed using the Chi-square test or Fisher's exact test. p b 0.05 was considered as statistically different, while p b 0.01 was considered as statistically significant. 3. Results All patients completely terminated medicine therapy 12 h before MVD. Among 90 patients, 26 (28.9%) suffered from post-operative CAWR for 3 days after MVD. Symptoms of CAWR include overexcitement, e.g. insomnia, dysphoria, hand fremitus, hallucination and severe headache (Table 1). Insomnia lasted for 3 days and could not be relieved by using diazepam. Most of the dysphoria symptoms disappeared 2 days later. 2 patients with severe dysphoria were given 100 mg CBZ via oral loading. Dysphoria symptoms were alleviated several hours later. Hand fremitus lasted for more than 5 days and was relieved gradually. Hallucination symptoms vanished 2 days later. Patients with severe headache were examined to exclude intracranial hemorrhage, pneumatosis and encephaledema. They felt relieved after 5 days by taking CBZ 100 mg/day. Analyses of correlating selected factors and CAWR was performed. The results are listed in details in Table 2. Patient characteristics included gender, age and duration of neuralgia. After data analysis, it was confirmed that patient characteristics did not appear to play a role in the occurrence of CAWR (p = 0.5192, 0.4218 and 0.5462, respectively). Neuralgia-related factors included neuralgia extent and neurovascular compression (NVC). NVC severity was justified by endoscopic findings and classified according to our department [8]. The neuralgia extent and NVC severity had no influence on the incidence of CAWR (p = 0.1162 and 0.1733, respectively). CBZ condition included history of CBZ therapy before MVD, preoperative dosage of CBZ, CBZ blood concentrations tested at 24 h preand 24 h post-operation, and D-value of CBZ blood concentrations. Among the patients with CAWR, there were 25 out of 26 patients Table 1 The representation of CAWR.
Insomnia Dysphoria Hand fremitus Hallucination Severe headache
n/%
Lasting time
9/34.6% 5/19.2% 5/19.2% 3/11.5% 4/15.4%
3 days 2 days 5 days 2 days 5 days
Table 2 Summary of related factors. With CAWR n Sex (n) M F Age b50 years 50–70 years N70 years Duration b2 years 2–6 years N6 years Neuralgia extent (n) 1 division 2 division 3 division NVC severity (n) 0 I II III Medicine therapy before MVD (n) CBZ therapy Other medicine therapy No medicine therapy Pre-operative dose of CBZ (mg) CBZ blood concentrations (μg/ml) 24 h pre-operation 24 h post-operation D-value Duration of MVD (h) Effect of MVD (n) Excellent Good Poor Complication of MVD (%)
Without CAWR
26
64
11 15
19 45
5 16 5
19 38 7
10 8 7
30 15 19
8 17 1
26 28 10
1 13 5 7
3 28 25 8
25 0 1 731
29 12 23 541
p value 0.5192
0.4218
0.5462
0.1162
0.1733
6.29 1.59 4.71 2.21 22 3 1 15.4
4.93 1.60 3.26 2.10 50 5 9 18.8
0.0001a
0.0277a 0.0548b 0.5002 0.0213a 0.9213 0.2796
0.9407
CAWR = CBZ-associated withdrawal reaction; MVD = microvascular decompression; NVC = neurovascular compression. a Statistical difference. b Statistical tendency.
(96.2%) who underwent CBZ therapy before MVD. It was proved to have a significant association with the occurrence of CAWR (p = 0.0001). The pre-operative average dosage of CBZ in the patients with CAWR was 731 mg/day. Comparing with the dosage in the patients without CAWR (541 mg/day), it was demonstrated that high pre-operative dosage of CBZ might lead to a high probability of CAWR (p = 0.0277). CBZ blood concentrations at 24 h post-operation were statistical insignificant (p = 0.5002). Patients with CAWR displayed high CBZ blood concentrations at 24 h pre-operation (average: 6.29 μg/ml), but the calculated value for this data showed only a slight statistical tendency (p = 0.0548). However, the D-value of CBZ blood concentrations showed statistical difference between the patients with CAWR and those without CAWR (p = 0.0213). Operation conditions included duration of MVD procedure, effect of MVD and complication of MVD. According to Kuncz's classification [9], the surgical outcome was graded into 3 groups: excellent, good and poor. During the period of follow-up, no patient died. No intracranial hemorrhage and facial paralysis were found. The complication was numbness (4 patients with CAWR and 9 patients without CAWR), cerebrospinal fluid leak (3 patients without CAWR) and tinnitus (1 patients without CAWR). There was no difference on duration of MVD procedure, effect of MVD and complication of MVD between the patients with CAWR and those without CAWR (p = 0.9213, 0.2796 and 0.9407). 4. Discussion CBZ/Tegretol® is a type of anticonvulsants. Since it was first administered on Scandinavian TN patients in 1962, CBZ has been the popular
M.-J. Chen et al. / Journal of the Neurological Sciences 338 (2014) 43–45
drug for treating TN. Presently, it is still the leading TN drug worldwide, and sometimes called the “gold standard” for treating TN. Its pain-free effects and side effects are dependent on dosage and concentration. When low dosage is insufficient to subsidize the pain, high dosage is suggested to the patients. In clinical practices, carbamazepine is initially given as 50–100 mg daily, and then the dose is titrated by adding 100 mg every other day until an adequate response is achieved or intolerable side effects are encountered. Once the pain is relieved, the same dose is usually continued for at least 2 weeks before slowly and gradually decreasing the dosage. Many studies have examined the clinical and electrophysiological changes accompanying CBZ withdrawal in treating epilepsy [5,6]. Increased seizure frequency, duration and intensity are observed during the CBZ withdrawal period. Since the doses of CBZ to treat TN are always less than that to treat psychiatric disorders or epilepsy, CBZ has not been thought to have any serious withdrawal effects. Reports rarely refer to the withdrawal symptoms of CBZ in treating TN, except for a case with acute psychosis [10] and a case with reversible splenial lesion in the corpus callosum [7]. However, following long-term and high-dosage CBZ therapy, CBZ is usually abruptly discontinued after MVD treatment. The question now lies as: will patients experience withdrawal symptoms during the perioperative period of MVD? From our experience, although all plasma level of CBZ was in stage IV [11], 28.9% TN patients experienced postoperative CAWR for 3 days after MVD if there was no pre-operative intervening measure. CAWR included insomnia, dysphoria, hand fremitus, hallucination and severe headache. The mechanism of CAWR can be discussed with regard to the following aspects. Firstly, the effects of CBZ on the central nervous system (CNS) include: the ability to bind to neuronal membrane sodium channels when they are in the inactivated state; slowing the speed of reactivation and thus reducing the neuron's capacity of high frequency firing; selective interaction with adenosine receptors and modification of the activities of secondary messengers such as cAMP and cGMP; and modification of various neurotransmitter systems [12]. The effects of CBZ on CNS are extensive. In addition, concentrations of CBZ in the brain are about 1.2–1.4 times more than those in blood plasma [12]. Therefore, long-term high-dosage CBZ treatment may result in sedation [3] and neuropsychological side-effects [13]. Once the CBZ concentration in the brain decreases, repressed CNS recovers rapidly, even excessively. The patients then experience hyperactivity symptoms such as insomnia, dysphoria, hand fremitus, and hallucination. Secondly, CBZ targets cation channels and also interacts with antidiuretic hormone (ADH), both of which can influence water balance. Continuous CBZ treatment can lead to a reduction in ADH serum level [14]. Rapid withdrawal of CBZ may result in the rapid increase of ADH, sequentially leading to cerebral edema, which thus brings about severe headache. Thirdly, there is rapid elimination of CBZ and its active metabolites from the brain [15]. Therefore, CAWR occurs almost immediately after MVD. Most CAWR started at the operative day. Data analyses of correlating selected factors and CAWR have to be carefully discussed because their consideration may have practical consequences. Patient characteristics included gender (p = 0.5192), age (p = 0.4218), and duration of neuralgia (p = 0.5462), neuralgiarelated factors included neuralgia extent (p = 0.1162) and NVC severity (p = 0.1733), and operation conditions included duration of MVD procedure (p = 0.9213), effect of MVD (p = 0.2796) and complication of MVD (p = 0.9407). Neither of these factors brought out any statistical difference. Among the patients with insomnia, dysphoria, hand fremitus, hallucination or severe headache, 25 out of 26 (96.2%) underwent CBZ therapy before MVD. By comparison, among the patients without CAWR, 29 out of 64 (45.3%) were subjected to CBZ therapy before
45
MVD. This confirmed the strong correlation between clinical representations and CBZ (p = 0.0001). Furthermore, high pre-operative dosage of CBZ and fast elimination of CBZ on the plasma level can lead to high probability of CAWR (p = 0.0277 and 0.0213, respectively). Therefore, the hypothesis might be that the pre-operative dosage and the changing rate of CBZ concentration in blood plasma are two important determinants of CAWR. In order to avoid CAWR, CBZ should be gradually discontinued before MVD and CBZ dosage should be carefully tapered. In our study, some severe symptoms were relieved by giving 100 mg CBZ via oral loading. To our surprise, CBZ blood concentrations at 24 h pre-operation only showed a slight statistical tendency (p = 0.0548). However, this might be a statistical bias due to sample size. More samples should be taken to test again to confirm this result. 5. Conclusion Rapid withdrawal of CBZ after MVD will result in CAWR. Symptoms of CAWR include insomnia, dysphoria, hand fremitus, hallucination and severe headache. It is strongly suggested that CAWR is dependent on the pre-operative dosage and the changing concentration rate preand post-operation. Conflict of interest There is no conflict of interest. References [1] Merskey H, Bogduk N. Classification of chronic pain. Descriptions of chronic pain syndromes and definitions of pain terms. Seattle: IASP Press; 1994 59–71. [2] Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders, 2nd edition. Cephalalgia 2004;24(Suppl. 1):9–160. [3] Sindrup SH, Jensen TS. Pharmacotherapy of trigeminal neuralgia. Clin J Pain 2002;18:22–7. [4] Liu JK, Apfelbaum RI. Treatment of trigeminal neuralgia. Neurosurg Clin N Am 2004;15:319–34. [5] Bromfield EB, Dambrosia J, Devinsky O, Nice FJ, Theodore WH. Phenytoin withdrawal and seizure frequency. Neurology 1989;39:905–9. [6] Zhou D, Wang Y, Hopp P, Kerling F, Kirchner A, Pauli E, et al. Influence on ictal seizure semiology of rapid withdrawal of carbamazepine and valproate in monotherapy. Epilepsia 2002;43(4):386–93. [7] Mori H, Maeda M, Takanashi J, Kunimatsu A, Matsushima N, Suzuki H, et al. Reversible splenial lesion in the corpus callosum following rapid withdrawal of carbamazepine after neurosurgical decompression for trigeminal neuralgia. J Clin Neurosci 2012;19:1182–4. [8] Chen MJ, Zhang WJ, Yang C, Wu YQ, Zhang ZY, Wang Y. Endoscopic neurovascular perspective in microvascular decompression of trigeminal neuralgia. J Craniomaxillofac Surg 2008;36:456–61. [9] Kuncz A, Vörös E, Barzó P, Tajti J, Milassin P, Mucsi Z, et al. Comparison of clinical symptoms and magnetic resonance angiographic (MRA) results in patients with trigeminal neuralgia and persistent idiopathic facial pain. Medium-term outcome after microvascular decompression of cases with positive MRA findings. Cephalalgia 2006;26:266–76. [10] Darbar D, Connachie AM, Jones AM, Newton RW. Acute psychosis associated with abrupt withdrawal of carbamazepine following intoxication. Br J Clin Pract 1996;50(6):350–1. [11] Weaver DF, Camfield P, Fraser A. Massive carbamazepine overdose: clinical and pharmacological observations in five episodes. Neurology 1988;38:755–9. [12] Albani F, Rivo A, Baruzzi A. Carbamazepine clinical pharmacology: a review. Pharmacopsychiatry 1995;28:235–44. [13] Delcker A, Wilhelm H, Timmann D, Diener HC. Side effects from increased dose of carbamazepine on neuropsychological and posturographic parameters of humans. Eur Neuropsychopharmacol 1997;7:213–8. [14] Stephens WP, Coe JY, Baylis PH. Plasma arginine vasopressin concentrations and antidiuretic action of carbamazepine. Br Med J 1978;1:1445–7. [15] Faigle JW, Feldmann KF. Carbamazepine: biotransformation. In: Levy R, Mattson R, Meldrum B, et al, editors. Antiepileptic drugs. 3rd. ed. New York: Raven Press; 1989. p. 491–504.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Withdrawal reaction of carbamazepine after neurovascular decompression for trigeminal neuralgia: A preliminary study☆ Min-Jie Chen a, Wei-Jie Zhang a,⁎, Zhi-Lin Guo b, Wen-Hao Zhang a, Ying Chai a, Yun-wu Li c a b c
Department of Oral and Maxillofacial Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China Department of Neurosurgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China Department of Pharmacy, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
a r t i c l e
i n f o
Article history: Received 6 September 2013 Received in revised form 29 November 2013 Accepted 4 December 2013 Available online 11 December 2013 Keywords: Carbamazepine Withdrawal reaction Overexcitement Trigeminal neuralgia Microvascular decompression Blood concentration
a b s t r a c t Objective: To evaluate the representations and the relevant factors of carbamazepine-associated withdrawal reaction (CAWR) after microvascular decompression (MVD) to treat trigeminal neuralgia (TN). Methods: The present series included 90 patients who were referred from September 2010 to January 2013 and diagnosed with classical TN. The carbamazepine (CBZ) serum level was tested twice at 24 h pre- and 24 h postoperation by using HPLC analysis. The analysis of correlating selected factors and CAWR was performed. Results: Among 90 patients, 26 (28.9%) suffered from post-operative CAWR for 3 days after MVD. The symptoms of CAWR include overexcitement, e.g. insomnia, dysphoria, hand fremitus, hallucination and severe headache. The history of CBZ therapy before MVD, pre-operative dosage of CBZ, and the D-value of CBZ blood concentrations demonstrated statistic differences between the patients with CAWR and those without CAWR. Patient characteristics such as gender, age, and duration of neuralgia, neuralgia-related factors including neuralgia extent and neurovascular compression severity, and operation conditions including duration of MVD procedure, effect of MVD and complication of MVD had no influence on the occurrence of CAWR. Conclusion: It is strongly suggested that CAWR is dependent on the pre-operative dosage and the changing rate of pre- and post-operative CBZ blood concentrations. © 2013 Elsevier B.V. All rights reserved.
1. Introduction The International Association for the Study of Pain (IASP) defines trigeminal neuralgia (TN) as sudden, usually unilateral, severe, brief, stabbing and recurrent episodes of pain in the distribution of one or more branches of the trigeminal nerve [1,2]. TN is the most common neuralgia. Although approximately 20% of patients who were treated with carbamazepine (CBZ) experience some side effects, CBZ is still the most effective and first line drug for treatment of TN [3,4]. When pharmacotherapy fails to alleviate the pain or if patients experience severe side effects, the surgical approach should be taken into consideration. Microvascular decompression (MVD) is commonly considered as the first neurosurgical option among TN patients with various neurovascular compressions. Most of the patients underwent longterm, high-dosage CBZ therapies before MVD. During pharmacotherapy, the dosage of CBZ should be gradually increased until adequate response level is achieved. It should also be steadily decreased when
☆ Supported by the National Science Foundation of China (No. 81100824) and Foundation of Shanghai Municipal Education Commission (No. 12YZ044). ⁎ Corresponding author at: Department of Oral and Maxillofacial Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhi-zao-ju Road, Shanghai 200011, PR China. Tel.: +86 21 23271699 5388; fax: +86 21 53072423. E-mail address: [email protected] (W.-J. Zhang). 0022-510X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2013.12.013
the pain is completely relieved for at least 2 weeks. However, there is a contradiction that CBZ is always withdrawn rapidly after MVD. Studies concerning on the clinical and electrophysiological changes accompanying CBZ withdrawal have been reported [5,6]. To our knowledge, there is only one report about the conditions following the rapid withdrawal of CBZ after MVD [7]. In this study, a cohort of patients who underwent MVD treatment was observed and evaluated prospectively. Interests are addressed on the following issues: Will the patients present withdrawal symptoms following the rapid withdrawal of CBZ after MVD? What kind of clinical symptoms may arise following the rapid withdrawal of CBZ after MVD? What are the relevant factors leading to CBZ-associated withdrawal reactions (CAWRs)? 2. Materials and methods 2.1. Patients The series included 90 patients who were referred from September 2010 to January 2013 with classical TN (60 women and 30 men; age range, 33 years–80 years; mean age, 57.7 years). Patients did not suffer from imaging abnormalities such as multiple sclerosis, vascular malformation, and tumor. All patients were subjected to MVD under general anesthesia by the same senior neurosurgeon using the same surgical technique. The CBZ serum level was tested twice at 24 h pre- and
44
M.-J. Chen et al. / Journal of the Neurological Sciences 338 (2014) 43–45
24 h post-operation. The ethical approval was given by Shanghai Jiao Tong University's Ethics Committee. We have read the Helsinki Declaration and have strictly followed the guidelines in this investigation. 2.2. Chromatographic procedure Chromatographic analysis was carried out using a microcolumn high performance liquid chromatography (HPLC) device (Waters, USA) with a UV detector, which permitted fixation of the entire absorption spectrum within the range of 190–360 nm. Analytes were detected at a wavelength of 210 nm. The internal standard solution was acetonitrile with acetophenone (5.15 μg/ml). The mobile phase composition was 0.05 M Na2HPO4 with methanol at a ratio of 40:60 (v/v). The flowrate of the mobile phase was 1 ml/min. The serum (200 μl) was added to the internal standard solution (400 μl). The mixture was agitated by hand for 1 min and centrifuged for 10 min. Finally, the supernate (20 μl) was injected for HPLC analysis. 2.3. Statistical analysis Data analysis was performed using the commercially available software SAS version 6.12 (SAS Institute, Cary, NC). Comparisons were performed using the Chi-square test or Fisher's exact test. p b 0.05 was considered as statistically different, while p b 0.01 was considered as statistically significant. 3. Results All patients completely terminated medicine therapy 12 h before MVD. Among 90 patients, 26 (28.9%) suffered from post-operative CAWR for 3 days after MVD. Symptoms of CAWR include overexcitement, e.g. insomnia, dysphoria, hand fremitus, hallucination and severe headache (Table 1). Insomnia lasted for 3 days and could not be relieved by using diazepam. Most of the dysphoria symptoms disappeared 2 days later. 2 patients with severe dysphoria were given 100 mg CBZ via oral loading. Dysphoria symptoms were alleviated several hours later. Hand fremitus lasted for more than 5 days and was relieved gradually. Hallucination symptoms vanished 2 days later. Patients with severe headache were examined to exclude intracranial hemorrhage, pneumatosis and encephaledema. They felt relieved after 5 days by taking CBZ 100 mg/day. Analyses of correlating selected factors and CAWR was performed. The results are listed in details in Table 2. Patient characteristics included gender, age and duration of neuralgia. After data analysis, it was confirmed that patient characteristics did not appear to play a role in the occurrence of CAWR (p = 0.5192, 0.4218 and 0.5462, respectively). Neuralgia-related factors included neuralgia extent and neurovascular compression (NVC). NVC severity was justified by endoscopic findings and classified according to our department [8]. The neuralgia extent and NVC severity had no influence on the incidence of CAWR (p = 0.1162 and 0.1733, respectively). CBZ condition included history of CBZ therapy before MVD, preoperative dosage of CBZ, CBZ blood concentrations tested at 24 h preand 24 h post-operation, and D-value of CBZ blood concentrations. Among the patients with CAWR, there were 25 out of 26 patients Table 1 The representation of CAWR.
Insomnia Dysphoria Hand fremitus Hallucination Severe headache
n/%
Lasting time
9/34.6% 5/19.2% 5/19.2% 3/11.5% 4/15.4%
3 days 2 days 5 days 2 days 5 days
Table 2 Summary of related factors. With CAWR n Sex (n) M F Age b50 years 50–70 years N70 years Duration b2 years 2–6 years N6 years Neuralgia extent (n) 1 division 2 division 3 division NVC severity (n) 0 I II III Medicine therapy before MVD (n) CBZ therapy Other medicine therapy No medicine therapy Pre-operative dose of CBZ (mg) CBZ blood concentrations (μg/ml) 24 h pre-operation 24 h post-operation D-value Duration of MVD (h) Effect of MVD (n) Excellent Good Poor Complication of MVD (%)
Without CAWR
26
64
11 15
19 45
5 16 5
19 38 7
10 8 7
30 15 19
8 17 1
26 28 10
1 13 5 7
3 28 25 8
25 0 1 731
29 12 23 541
p value 0.5192
0.4218
0.5462
0.1162
0.1733
6.29 1.59 4.71 2.21 22 3 1 15.4
4.93 1.60 3.26 2.10 50 5 9 18.8
0.0001a
0.0277a 0.0548b 0.5002 0.0213a 0.9213 0.2796
0.9407
CAWR = CBZ-associated withdrawal reaction; MVD = microvascular decompression; NVC = neurovascular compression. a Statistical difference. b Statistical tendency.
(96.2%) who underwent CBZ therapy before MVD. It was proved to have a significant association with the occurrence of CAWR (p = 0.0001). The pre-operative average dosage of CBZ in the patients with CAWR was 731 mg/day. Comparing with the dosage in the patients without CAWR (541 mg/day), it was demonstrated that high pre-operative dosage of CBZ might lead to a high probability of CAWR (p = 0.0277). CBZ blood concentrations at 24 h post-operation were statistical insignificant (p = 0.5002). Patients with CAWR displayed high CBZ blood concentrations at 24 h pre-operation (average: 6.29 μg/ml), but the calculated value for this data showed only a slight statistical tendency (p = 0.0548). However, the D-value of CBZ blood concentrations showed statistical difference between the patients with CAWR and those without CAWR (p = 0.0213). Operation conditions included duration of MVD procedure, effect of MVD and complication of MVD. According to Kuncz's classification [9], the surgical outcome was graded into 3 groups: excellent, good and poor. During the period of follow-up, no patient died. No intracranial hemorrhage and facial paralysis were found. The complication was numbness (4 patients with CAWR and 9 patients without CAWR), cerebrospinal fluid leak (3 patients without CAWR) and tinnitus (1 patients without CAWR). There was no difference on duration of MVD procedure, effect of MVD and complication of MVD between the patients with CAWR and those without CAWR (p = 0.9213, 0.2796 and 0.9407). 4. Discussion CBZ/Tegretol® is a type of anticonvulsants. Since it was first administered on Scandinavian TN patients in 1962, CBZ has been the popular
M.-J. Chen et al. / Journal of the Neurological Sciences 338 (2014) 43–45
drug for treating TN. Presently, it is still the leading TN drug worldwide, and sometimes called the “gold standard” for treating TN. Its pain-free effects and side effects are dependent on dosage and concentration. When low dosage is insufficient to subsidize the pain, high dosage is suggested to the patients. In clinical practices, carbamazepine is initially given as 50–100 mg daily, and then the dose is titrated by adding 100 mg every other day until an adequate response is achieved or intolerable side effects are encountered. Once the pain is relieved, the same dose is usually continued for at least 2 weeks before slowly and gradually decreasing the dosage. Many studies have examined the clinical and electrophysiological changes accompanying CBZ withdrawal in treating epilepsy [5,6]. Increased seizure frequency, duration and intensity are observed during the CBZ withdrawal period. Since the doses of CBZ to treat TN are always less than that to treat psychiatric disorders or epilepsy, CBZ has not been thought to have any serious withdrawal effects. Reports rarely refer to the withdrawal symptoms of CBZ in treating TN, except for a case with acute psychosis [10] and a case with reversible splenial lesion in the corpus callosum [7]. However, following long-term and high-dosage CBZ therapy, CBZ is usually abruptly discontinued after MVD treatment. The question now lies as: will patients experience withdrawal symptoms during the perioperative period of MVD? From our experience, although all plasma level of CBZ was in stage IV [11], 28.9% TN patients experienced postoperative CAWR for 3 days after MVD if there was no pre-operative intervening measure. CAWR included insomnia, dysphoria, hand fremitus, hallucination and severe headache. The mechanism of CAWR can be discussed with regard to the following aspects. Firstly, the effects of CBZ on the central nervous system (CNS) include: the ability to bind to neuronal membrane sodium channels when they are in the inactivated state; slowing the speed of reactivation and thus reducing the neuron's capacity of high frequency firing; selective interaction with adenosine receptors and modification of the activities of secondary messengers such as cAMP and cGMP; and modification of various neurotransmitter systems [12]. The effects of CBZ on CNS are extensive. In addition, concentrations of CBZ in the brain are about 1.2–1.4 times more than those in blood plasma [12]. Therefore, long-term high-dosage CBZ treatment may result in sedation [3] and neuropsychological side-effects [13]. Once the CBZ concentration in the brain decreases, repressed CNS recovers rapidly, even excessively. The patients then experience hyperactivity symptoms such as insomnia, dysphoria, hand fremitus, and hallucination. Secondly, CBZ targets cation channels and also interacts with antidiuretic hormone (ADH), both of which can influence water balance. Continuous CBZ treatment can lead to a reduction in ADH serum level [14]. Rapid withdrawal of CBZ may result in the rapid increase of ADH, sequentially leading to cerebral edema, which thus brings about severe headache. Thirdly, there is rapid elimination of CBZ and its active metabolites from the brain [15]. Therefore, CAWR occurs almost immediately after MVD. Most CAWR started at the operative day. Data analyses of correlating selected factors and CAWR have to be carefully discussed because their consideration may have practical consequences. Patient characteristics included gender (p = 0.5192), age (p = 0.4218), and duration of neuralgia (p = 0.5462), neuralgiarelated factors included neuralgia extent (p = 0.1162) and NVC severity (p = 0.1733), and operation conditions included duration of MVD procedure (p = 0.9213), effect of MVD (p = 0.2796) and complication of MVD (p = 0.9407). Neither of these factors brought out any statistical difference. Among the patients with insomnia, dysphoria, hand fremitus, hallucination or severe headache, 25 out of 26 (96.2%) underwent CBZ therapy before MVD. By comparison, among the patients without CAWR, 29 out of 64 (45.3%) were subjected to CBZ therapy before
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MVD. This confirmed the strong correlation between clinical representations and CBZ (p = 0.0001). Furthermore, high pre-operative dosage of CBZ and fast elimination of CBZ on the plasma level can lead to high probability of CAWR (p = 0.0277 and 0.0213, respectively). Therefore, the hypothesis might be that the pre-operative dosage and the changing rate of CBZ concentration in blood plasma are two important determinants of CAWR. In order to avoid CAWR, CBZ should be gradually discontinued before MVD and CBZ dosage should be carefully tapered. In our study, some severe symptoms were relieved by giving 100 mg CBZ via oral loading. To our surprise, CBZ blood concentrations at 24 h pre-operation only showed a slight statistical tendency (p = 0.0548). However, this might be a statistical bias due to sample size. More samples should be taken to test again to confirm this result. 5. Conclusion Rapid withdrawal of CBZ after MVD will result in CAWR. Symptoms of CAWR include insomnia, dysphoria, hand fremitus, hallucination and severe headache. It is strongly suggested that CAWR is dependent on the pre-operative dosage and the changing concentration rate preand post-operation. Conflict of interest There is no conflict of interest. References [1] Merskey H, Bogduk N. Classification of chronic pain. Descriptions of chronic pain syndromes and definitions of pain terms. Seattle: IASP Press; 1994 59–71. [2] Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders, 2nd edition. Cephalalgia 2004;24(Suppl. 1):9–160. [3] Sindrup SH, Jensen TS. Pharmacotherapy of trigeminal neuralgia. Clin J Pain 2002;18:22–7. [4] Liu JK, Apfelbaum RI. Treatment of trigeminal neuralgia. Neurosurg Clin N Am 2004;15:319–34. [5] Bromfield EB, Dambrosia J, Devinsky O, Nice FJ, Theodore WH. Phenytoin withdrawal and seizure frequency. Neurology 1989;39:905–9. [6] Zhou D, Wang Y, Hopp P, Kerling F, Kirchner A, Pauli E, et al. Influence on ictal seizure semiology of rapid withdrawal of carbamazepine and valproate in monotherapy. Epilepsia 2002;43(4):386–93. [7] Mori H, Maeda M, Takanashi J, Kunimatsu A, Matsushima N, Suzuki H, et al. Reversible splenial lesion in the corpus callosum following rapid withdrawal of carbamazepine after neurosurgical decompression for trigeminal neuralgia. J Clin Neurosci 2012;19:1182–4. [8] Chen MJ, Zhang WJ, Yang C, Wu YQ, Zhang ZY, Wang Y. Endoscopic neurovascular perspective in microvascular decompression of trigeminal neuralgia. J Craniomaxillofac Surg 2008;36:456–61. [9] Kuncz A, Vörös E, Barzó P, Tajti J, Milassin P, Mucsi Z, et al. Comparison of clinical symptoms and magnetic resonance angiographic (MRA) results in patients with trigeminal neuralgia and persistent idiopathic facial pain. Medium-term outcome after microvascular decompression of cases with positive MRA findings. Cephalalgia 2006;26:266–76. [10] Darbar D, Connachie AM, Jones AM, Newton RW. Acute psychosis associated with abrupt withdrawal of carbamazepine following intoxication. Br J Clin Pract 1996;50(6):350–1. [11] Weaver DF, Camfield P, Fraser A. Massive carbamazepine overdose: clinical and pharmacological observations in five episodes. Neurology 1988;38:755–9. [12] Albani F, Rivo A, Baruzzi A. Carbamazepine clinical pharmacology: a review. Pharmacopsychiatry 1995;28:235–44. [13] Delcker A, Wilhelm H, Timmann D, Diener HC. Side effects from increased dose of carbamazepine on neuropsychological and posturographic parameters of humans. Eur Neuropsychopharmacol 1997;7:213–8. [14] Stephens WP, Coe JY, Baylis PH. Plasma arginine vasopressin concentrations and antidiuretic action of carbamazepine. Br Med J 1978;1:1445–7. [15] Faigle JW, Feldmann KF. Carbamazepine: biotransformation. In: Levy R, Mattson R, Meldrum B, et al, editors. Antiepileptic drugs. 3rd. ed. New York: Raven Press; 1989. p. 491–504.