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Keywords:

  • adverse events;
  • complex partial seizures;
  • evoked potential;
  • infantile spasms;
  • intramyelinic edema;
  • magnetic resonance imaging;
  • refractory epilepsy;
  • review;
  • vigabatrin

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Adverse event profile
  5. Intramyelinic edema
  6. Neuropsychiatric and cognitive effects
  7. Conclusions
  8. Conflicts of interest
  9. Acknowledgments
  10. References

Walker SD, Kälviäinen R. Non-vision adverse events with vigabatrin therapy. Acta Neurol Scand: 2011: 124 (Suppl. 192): 72–82. © 2011 John Wiley & Sons A/S.

Vigabatrin is an effective antiepileptic drug (AED) for the treatment of refractory complex partial seizures (rCPS) and infantile spasms (IS). In clinical trials, vigabatrin was generally well-tolerated with an adverse event profile similar to that of other AEDs. The most common treatment-related adverse events were central nervous system effects, including drowsiness, dizziness, headache, and fatigue, with adjunctive vigabatrin in adults with rCPS, and sedation, somnolence, and irritability with vigabatrin monotherapy in infants with IS. Vigabatrin had little effect on cognitive function, mood, or behavior in a battery of neuropsychologic tests for rCPS. In placebo-controlled clinical trials, the incidence of depression and psychosis, but not other psychiatric adverse events, was greater with vigabatrin than placebo. Intramyelinic edema (IME) was initially identified in rats and dogs and led to a temporary suspension of clinical trials in the United States. IME was subsequently correlated with delays in evoked potential (EP) and increased T2-weighted signals on magnetic resonance imaging (MRI). Clinical trials of vigabatrin were allowed to resume after IME was not detected by neuropathologic assessments of autopsy and neurosurgical specimens or by serial EP or MRI assessments in older children and adults receiving vigabatrin. Subsequently, MRI abnormalities characterized by increased T2 intensity and restricted diffusion were identified in infants treated with vigabatrin for IS. These abnormalities generally resolved with discontinuation of vigabatrin and, in some cases, during continued therapy. The benefit of improved seizure control must be balanced against the potential risks associated with vigabatrin, including abnormal MRI changes and other vigabatrin-related safety issues.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Adverse event profile
  5. Intramyelinic edema
  6. Neuropsychiatric and cognitive effects
  7. Conclusions
  8. Conflicts of interest
  9. Acknowledgments
  10. References

Vigabatrin is an irreversible inhibitor of γ-aminobutyric acid (GABA) transaminase, which was specifically designed to increase central nervous system (CNS) concentrations of GABA to decrease epileptogenic circuits and decrease seizure frequency (1–3). The effectiveness of vigabatrin in the treatment of refractory epilepsies, notably refractory complex partial seizures (rCPS) and infantile spasms (IS), has been established in randomized, placebo-controlled, parallel-group or crossover trials (4–21). These studies — which are reviewed by other articles in this supplement (22–24) — also demonstrated that vigabatrin was generally well-tolerated as adjunctive therapy for adult patients with rCPS who have responded inadequately to several alternative treatments and as monotherapy for pediatric patients aged 1 month–2 years with IS, with an adverse event profile comparable to that of other antiepileptic drugs (AEDs) (25). In these trials, the most common treatment-related adverse events were drowsiness, dizziness, headache, and fatigue with adjunctive vigabatrin in adults with rCPS and sedation, somnolence, and irritability with vigabatrin monotherapy in infants with IS.

Vigabatrin was initially licensed in the United Kingdom and Ireland in 1989. During the next decade, it became an accepted part of the armamentarium for treating adult and pediatric patients in more than 50 countries (25). The development of vigabatrin had a rockier path in the United States. Clinical trials were temporarily suspended in 1983 after intramyelinic edema (IME) was observed in rats and dogs, but studies were allowed to resume in 1990 after such toxicity was not demonstrated in humans. In 1998, the drug was deemed to be unapprovable by the Food and Drug Administration based upon concerns about visual field defects (25, 26). The approval of vigabatrin by the US Food and Drug Administration in 2009 was accompanied by implementation of a comprehensive Risk Evaluation and Mitigation Strategy, which is administered through the Lundbeck Inc. Support, Help And Resources for Epilepsy (SHARE) program. In Europe, restrictions on the use of vigabatrin have been in place since 1998, after a specific pattern of bilateral, mainly asymptomatic, visual field defects were described (27). This article describes the non-visual field adverse event profile of vigabatrin in rCPS and IS, including a review of IME and neuropsychiatric effects. Peripheral visual field defects, the main safety issue for vigabatrin, are discussed in detail in other articles in this supplement (28, 29).

Adverse event profile

  1. Top of page
  2. Abstract
  3. Introduction
  4. Adverse event profile
  5. Intramyelinic edema
  6. Neuropsychiatric and cognitive effects
  7. Conclusions
  8. Conflicts of interest
  9. Acknowledgments
  10. References

Refractory complex partial seizures

The safety profile of vigabatrin as adjunctive therapy for adult patients with rCPS who have responded inadequately to several alternative treatments is illustrated by results from two randomized controlled trials conducted in the United States (12, 15). Both studies enrolled patients aged 18–60 years who did not have adequate seizure control despite receiving one to two AEDs. The first study compared vigabatrin vs placebo in 182 patients, most of whom were receiving two concomitant AEDs (12). Vigabatrin was titrated from 1 g/day to 2.5 g/day during a 4-week titration period, and then the dosage was increased to 3 g/day during a 12-week maintenance period. The most common treatment-related adverse events (vigabatrin vs placebo) were drowsiness (29.3% vs 13.3%), light-headedness (21.7% vs 14.4%), headache (21.7% vs 16.7%), fatigue (19.6% vs 13.3%), and tremor (13.0% vs 4.4%). Seven of 84 patients (8.3%) in the vigabatrin group compared with two of 89 (2.2%) in the placebo group discontinued because of adverse events, mostly CNS-related. In the physician’s overall assessment of tolerability, treatment was rated as “fairly well-tolerated” or better for 90% of vigabatrin-treated patients and 98% of placebo-treated patients.

In the second study, 174 patients were randomized to receive vigabatrin 1, 3, or 6 g/day or placebo (15). This study included a 6-week titration period, during which the dosage of vigabatrin was increased twice weekly in 0.5-g/day increments until the assigned dosage was achieved and was followed by a 12-week maintenance period. Fatigue (33.1% vs 20.0%), drowsiness (26.2% vs 26.7%), and dizziness (20.0% vs 11.1%) were the most common treatment-related adverse events. The incidence tended to increase with dosage of vigabatrin. Discontinuations owing to adverse events were dosage-related: 6.5%, 11.4%, and 18.2% in the 1-, 3-, and 6-g/day vigabatrin groups, respectively, compared with 2.2% in the placebo group. The physician’s overall assessment of tolerability declined significantly with increasing vigabatrin dosage (< 0.001). The percentages of patients who tolerated the drug well or better were 84%, 75%, and 47% for the vigabatrin 1-, 3-, and 6-g/day groups, respectively, compared with 85% for the placebo group. Adverse events occurring in >10% of patients treated with vigabatrin 3 g/day (both studies combined) or 6 g/day are shown in Table 1 (30). CNS events were also the most common adverse events in other adjunctive clinical trials of vigabatrin (6, 9, 31). During long-term treatment, CNS adverse events were occasionally observed, but they were typically mild and transient and caused little subjective disturbance (32).

Table 1.   Treatment-emergent adverse events occurring in >10% of patients with rCPS in any treatment group (30)
Adverse event (preferred term)Vigabatrin 3 g/daya (= 134) n (%)Vigabatrin 6 g/day (= 43) n (%)Placeboa (= 135) n (%)
  1. rCPS, refractory complex partial seizures.

  2. aCombined data from two randomized clinical trials.

Headache44 (33)11 (26)42 (31)
Dizziness32 (24)11 (26)23 (17)
Fatigue31 (23)17 (40)21 (16)
Somnolence29 (22)11 (26)18 (13)
Tremor20 (15)7 (16)11 (8)
Nasopharyngitis19 (14)4 (9)14 (10)
Vision blurred18 (13)7 (16)7 (5)
Nystagmus17 (13)8 (19)12 (9)
Diarrhea14 (10)7 (16)10 (7)
Arthralgia14 (10)2 (5)4 (3)
Nausea13 (10)1 (2)11 (8)
Irritability10 (7)10 (23)10 (7)
Coordination abnormal10 (7)7 (16)3 (2)
Pharyngolaryngeal pain10 (7)6 (14)7 (5)
Diplopia9 (7)7 (16)4 (3)
Memory impairment9 (7)7 (16)4 (3)
Weight increased8 (6)6 (14)4 (3)
Gait disturbance8 (6)5 (12)9 (7)
Depression8 (6)6 (14)4 (3)
Confusional state5 (4)6 (14)1 (1)
Cough3 (2)6 (14)9 (7)

Several other adverse events occurring less commonly with adjunctive vigabatrin therapy are noteworthy, including weight gain, anemia, and peripheral neuropathy. Weight gain is often seen during the first 12 months of treatment, but then tends to stabilize with dietary control measures needed in some cases (32). In a pooled analysis, the mean weight change for vigabatrin-treated patients was 3.5 kg compared with 1.6 kg for placebo-treated patients (30). Anemia has been associated with vigabatrin therapy, but rarely has it resulted in discontinuation of treatment (three of 4,855 patients [0.06%]) (30). In the North American controlled clinical studies, 16 of 280 patients (5.7%) receiving vigabatrin compared with three of 188 patients (1.6%) given placebo had adverse events of anemia and/or met criteria for potentially clinically important hematology changes involving hemoglobin, hematocrit, and/or red blood cell indices (30). Mean decreases in hematocrit of approximately 3% were observed in vigabatrin-treated patients in US controlled trials (30). Finally, signs and/or symptoms of peripheral neuropathy were reported for four of 280 vigabatrin-treated patients (1.4%) in the North American controlled trials vs none in the placebo group. With uncontrolled studies included in the analysis, the incidence of peripheral neuropathy with vigabatrin was 4.2% (30). The clinical studies did not include a systematic analysis of peripheral neuropathy. Therefore, it is not known whether symptoms were related to duration of treatment or cumulative dosage or whether they were completely reversible upon treatment discontinuation.

Other adverse events such as sexual dysfunction, altered fertility, or bone fracture, seen with some AEDs, are not associated with vigabatrin use. Epilepsy itself and some AEDs used to treat it can alter hormone concentrations, which may be manifested as sexual dysfunction and reduced fertility, and AEDs that induce the cytochrome P450 (CYP) 3A4 system decrease the efficacy of oral contraceptives (33). Vigabatrin has not been associated with sexual or reproductive adverse effects (34). Because it does not induce CYP 3A4, vigabatrin has not been associated with risk of failure of oral contraceptives (35). Epilepsy patients are at two- to six-fold greater risk of fracture than the general population, in part owing to seizure-related falls and coexisting neurologic deficits, and in part owing to the adverse impact of CYP-inducing AEDs (e.g., phenobarbital, carbamazepine, oxcarbazepine) on vitamin D metabolism leading to reduced bone mineral density (36). Vigabatrin has not been significantly associated with increased risk of fracture (36).

Infantile spasms

The safety profile of vigabatrin monotherapy as treatment for IS was characterized in a multicenter, randomized, single-blind study spanning 14–21 days, followed by an open-label extension of up to 3 years (21). In this study, patients were randomly assigned to treatment with low-dosage (18–36 mg/kg/day) or high-dosage (100–148 mg/kg/day) vigabatrin and included 222 children in the safety population — the largest cohort of vigabatrin-treated patients with IS evaluated to date. The patients had a mean age of 7 months. The etiology of IS was cryptogenic in 25.8%, symptomatic tuberous sclerosis in 17.2%, and symptomatic from other causes in the remaining 57.0%. Following the single-blind phase, dosage adjustments were made at the investigator’s discretion. The mean vigabatrin dosages during the open-label phase were 126.8 and 144.6 mg/kg/day in the groups initially randomized to low-dosage and high-dosage vigabatrin, respectively.

During the entire study, 115 patients (51.8%) experienced adverse events considered to be related to vigabatrin, most commonly sedation (16.7%), somnolence (13.5%), irritability (9.9%), insomnia (6.3%), sleep disorder (4.5%), constipation (3.6%), lethargy (3.6%), decreased appetite (3.2%), and hypotonia (2.3%). Most events were mild or moderate, with only 2.3% considered severe. Nineteen patients (8.6%) discontinued vigabatrin therapy because of adverse events. In five cases (2.3%), the adverse event was considered to be related to vigabatrin therapy (vomiting, pneumonia, respiratory tract infection, convulsion, and IS, respectively). During the blinded phase, 58 patients (50.9%) in the low-dosage group and 52 patients (48.1%) in the high-dosage group experienced at least one adverse event. Treatment-emergent adverse events, without regard to relationship to vigabatrin therapy, are shown in Table 2 (37). No clear connection between dosage and incidence of adverse events was observed.

Table 2.   Treatment-emergent adverse events occurring in >10% of patients with IS in either treatment group (37)
Adverse event, %Low-dosage vigabatrin (= 114)High-dosage vigabatrin (= 108)
  1. IS, infantile spasms.

Upper respiratory tract infection5146
Otitis media4430
Fever2919
Viral infection2019
Sedation1917
Somnolence1719
Irritability1623
Vomiting1420
Constipation1412
Diarrhea1312
Pneumonia1311
Nasal congestion134
Insomnia1012
Rash811
Ear infection714

The United Kingdom Infantile Spasms Study randomized 110 patients in a 1:1:2 ratio to treatment with prednisolone, tetracosactide, or vigabatrin (18). Patients were evaluated at 14 days and then every 3 months until a final assessment at 14 months of age. The dosage of vigabatrin was titrated from 50 to 100 mg/kg/day after the first 24 h and then to 150 mg/kg/day if spasms continued after 4 days. The study cohort had a median age of 6 months and had spasms for a median of 1 month. The infants treated with vigabatrin had a greater rate of drowsiness (14% vs 6%) but lesser rates of irritability (2% vs 19%) and increased appetite (1% vs 7%) compared with hormonal therapy (i.e., prednisolone or tetracosactide). Gastrointestinal adverse events occurred at similar rates (11% vs 12%). No difference in neurodevelopmental outcomes at 14 months was observed between vigabatrin and hormonal therapy (19).

Intramyelinic edema

  1. Top of page
  2. Abstract
  3. Introduction
  4. Adverse event profile
  5. Intramyelinic edema
  6. Neuropsychiatric and cognitive effects
  7. Conclusions
  8. Conflicts of interest
  9. Acknowledgments
  10. References

Animal studies

Intramyelinic edema (IME) was initially reported in toxicology studies in rats and dogs given high dosages of vigabatrin (38, 39). Consequently, clinical trials in the United States were temporarily suspended in 1983 (25). Microvacuoles, typically 10–100 μm in diameter, were found on histopathologic analysis in specific brain regions, most commonly in the cerebellum, reticular formation, and optic tract of rats and in the hypothalamus, thalamus, optic tract, and fornix columns of dogs (38–40). Of note, IME was not identified in vigabatrin-treated monkeys, even after dosages of 50 or 100 mg/kg/day for 6 years (39). Moreover, lesions were not identified in the spinal cord or peripheral nervous system of any species (39, 40).

Electron microscopic examination revealed that the microvacuolation resulted from fluid accumulation and separation of the outer lamellar sheaths of myelin along the intraperiod line (38), and immunohistochemical analyses indicated that the IME was generally associated with reactive astrocytosis and microglial activation (40). IME developed over a period of several weeks, even at high dosages, and plateaued over a 6- to 12-month period with continued exposure (39, 40). It then disappeared within weeks after vigabatrin was stopped, without any residual effects in dogs, although rats still had swollen axons and microscopic mineralized bodies in the cerebellum (39, 41). IME did not appear to progress to demyelination in any species (39). However, delayed myelination was observed in immature rats administered vigabatrin 50 mg/kg/day for up to 9 weeks (42).

Subsequently, IME observed in rats and dogs was correlated with delays in evoked potential (EP) (43, 44) and with increased T2-weighted signals on magnetic resonance imaging (MRI) (45, 46). Mild damage to central myelinated pathways may lead to delays in EP latency, whereas more significant damage would be expected to block impulse conduction, leading to reductions in EP amplitude (40). In dogs given vigabatrin 300 mg/kg/day, increases in the latencies of the cortical visual EP and somatosensory EP were evident at 6 weeks and reached statistical significance at 8 and 10 weeks, respectively (44). Both parameters returned to baseline by 5 weeks after vigabatrin was ceased. No changes in brainstem auditory EP or in peripheral or spinal conduction were observed.

The correlation between IME and MRI is illustrated by a study conducted in dogs given vigabatrin 300 mg/kg/day (47). T2 intensity was increased in the hypothalamus after 4 weeks and in the thalamus and fornix after 7 weeks. Both T2 intensity and microvacuolation continued to increase during the 12-week treatment course, and then both decreased after vigabatrin was discontinued. By 16 weeks after vigabatrin was halted, histopathology had returned to normal, and there was a marked trend for reversal of the T2 intensity changes. A study conducted several years later employed both T2-weighted and diffusion-weighted MRIs to evaluate changes in rat brain during exposure to vigabatrin 275 mg/kg/day for 12 weeks (48). Significant increases in T2 intensity were observed in the frontal and occipital cortices and in the cerebellar white matter, with the latter lesions more clearly distinguishable on diffusion-weighted images than by T2 contrast alone. After vigabatrin was stopped, the hyperintensity in the cerebellar white matter greatly decreased over a 12-week period.

Clinical evaluations

Magnetic resonance imaging scans conducted during the first randomized controlled US trial of adjunctive vigabatrin for rCPS did not show any clinically important changes nor any evidence suggestive of IME (12). Prolongations ≥15% in either visual or somatosensory EP latency were reported for six patients (6.5%) receiving vigabatrin compared with nine patients (10.0%) receiving placebo, but none of the latency prolongations were associated with symptoms suggestive of IME. Neuropathologic examinations did not detect IME in 62 patients with refractory epilepsy who received vigabatrin for a mean of 28 months either before undergoing neurosurgery for epilepsy or before death (49). Most patients in this series received vigabatrin at dosages of 2–4 g/day. Similarly, case reports or small case series did not identify changes suggestive of microvacuolization, myelin separation, or demyelination in brain tissue obtained at surgery or at autopsy from patients treated with vigabatrin (50–52). A review of more than 400 adults and more than 200 children treated with vigabatrin for CPS, which involved serial MRIs, multimodality EPs, and neurologic examinations, found no evidence suggestive of IME (Lundbeck Inc., data on file).

A subsequent comprehensive review was conducted to identify adolescent and adult patients who had developed clinical abnormalities that may have been related to IME (40). The review included the global clinical trials database, worldwide post-marketing surveillance, and all published literature covering a period of more than 15 years through March 1997. Medical consultants unrelated to the corporate sponsor reviewed items relevant to potential IME and asked patients meeting selection criteria to undergo a 2-day follow-up reassessment that included EP, MRI, and neurologic examination. All information was also reviewed by an additional group of independent medical consultants. The databases comprised an estimated 350,000 patient-years of exposure to vigabatrin (i.e., approximately 175,000 patients exposed for 2 years at an average dosage of 2 g/day). The consultants found no trends in EP latency over time suggestive of IME, no evidence of IME on T2-weighted axial and coronal MRI, and no trends in clinical neurologic findings nor any associations with abnormal EP or MRI changes suggestive of IME. In summary, no cases of IME were identified in this comprehensive analysis. On the basis of these results, it was concluded that if IME occurs in humans, it is an extremely rare and reversible event, which does not result in clinically significant sequelae.

Since the comprehensive review in adolescents and adults was conducted, several reports have been published suggesting that use of vigabatrin to treat IS may produce transient MRI abnormalities consistent with IME (Fig. 1) (53–55). After identifying an index case of a 13-month-old infant who developed new T2-weighted hyperintensity while receiving vigabatrin for IS, Pearl et al. (53) retrospectively evaluated databases at two children’s hospitals to identify patients who underwent MRI testing while receiving vigabatrin. Including the index case, increased T2 intensity was identified in eight of 23 patients (34.8%) treated with vigabatrin for IS. The T2-weighted images from the index case before vigabatrin, during treatment, and following discontinuation are shown in Fig. 2. Locations of T2 hyperintensity included the thalamus (= 7), midbrain (= 7), globus pallidus (= 6), cerebellar dentate nucleus (= 6), dorsal medulla (= 4), medial longitudinal fasciculi (= 4), and corpus callosum (= 1). The median age at time of MRI was 11 months (range, 9–18 months), median dosage of vigabatrin was 170 mg/kg/day (range, 83–220 mg/kg/day), and median duration of vigabatrin therapy was 3 months (range, 1–11 months). The T2 abnormalities were accompanied by increased signal on diffusion-weighted images, with apparent diffusion coefficient maps consistent with restricted diffusion. The MRI abnormalities completely resolved following withdrawal of vigabatrin in all patients except for minimal residual pallidal brightness in one patient. No MRI abnormalities were found in 56 other patients with IS who were not treated with vigabatrin.

image

Figure 1.  Incidence of MRI abnormalities with vigabatrin for infantile spasms. aMedian value. MRI, magnetic resonance imaging.

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image

Figure 2.  Index case of MRI abnormalities with vigabatrin in a 13-month-old boy. Panel A: normal T2-weighted image prior to vigabatrin. Panel B: Increased signal intensity in thalami (arrows) after patient was on vigabatrin (83 mg/kg/day) for 4 months. Panel C: Apparent diffusion coefficient map shows restricted diffusion while on vigabatrin. Panel D: Resolution at 4 months following discontinuation of vigabatrin. MRI, magnetic resonance imaging. Cerebral MRI abnormalities associated with vigabatrin therapy, Pearl P, et al. Copyright © 2009 Epilepsia. Reproduced with permission of John Wiley & Sons, Inc.

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Wheless and coauthors (54) retrospectively reviewed the medical records and cranial MRIs of 205 infants who received treatment for IS. MRI abnormalities — predefined as any hyperintensity on T2-weighted or fluid-attenuated inversion recovery sequences not readily explained by a well-characterized pathology — were identified significantly more frequently for infants treated with vigabatrin than in those who had not received vigabatrin (22% vs 4%; < 0.001). MRI abnormalities were observed for four of 32 patients (12.5%) treated with low-dosage vigabatrin (<125 mg/kg/day) and for 13 of 44 patients (29.5%) treated with high-dosage vigabatrin (≥125 mg/kg/day) (Fig. 1). The pattern of MRI abnormalities was consistent with the observations made by Pearl et al. (53) for 13 patients. The remaining four patients had either focal or multifocal abnormalities that differed from this pattern and presumably reflected processes other than drug toxicity. Nine patients had at least one additional MRI evaluation, and MRI abnormalities resolved for six of these nine patients (66.7%), including two who continued to receive vigabatrin. In this study, MRI images from 668 children and adults with CPS were re-reviewed, but no difference in MRI abnormalities was detected between vigabatrin-exposed and vigabatrin-naïve patients.

Milh et al. (56) retrospectively evaluated MRI images from 22 infants with epilepsy (including 13 with IS) who were treated with vigabatrin. MRI hyperintensity on T2- and diffusion-weighted images increased transiently beginning 1 month after the start of treatment, peaked at 3–6 months, and then returned to low values after 12 months of treatment. The number of obvious hyperintense areas paralleled this time course and mostly involved the globi pallidi, posterior part of the pons, and mesencephalum. The duration or type of epilepsy, and the presence of seizures were not associated with the MRI hyperintensity.

Dracopoulos et al. (55) evaluated 107 patients with IS, who were grouped based on when they had MRI scans and whether they received therapy with vigabatrin ≥120 mg/kg/day. Group I patients (= 81) had MRI scans during but not before vigabatrin therapy. Of these, 25 (30.9%) had MRI signal abnormalities, mostly in the globus pallidus (= 24), brainstem (= 14), dentate nucleus (= 8), or thalamus (= 6). Fifteen Group I patients with MRI abnormalities had follow-up MRIs. Resolution of the abnormalities was observed for 13 patients, including 11 patients who discontinued vigabatrin and two who continued to receive the drug. The two patients who still had abnormalities had discontinued vigabatrin for 3–4 weeks before the second MRI was conducted. Group II patients (= 14) had MRI scans before and during vigabatrin therapy. All had normal MRIs before vigabatrin was started, and four (28.6%) patients demonstrated new MRI signal intensity changes after starting vigabatrin. Reversal of MRI abnormalities was observed for two patients who discontinued vigabatrin and one patient who continued to receive the drug. The other patients still had abnormalities while being weaned off of vigabatrin. Group III patients (= 12) did not receive vigabatrin and had no detectable MRI abnormalities (Fig. 1).

Recently, diffusion tensor imaging was conducted for six patients with IS who were treated with vigabatrin and had abnormal T2- and/or diffusion-weighted images (57). The results suggested that axonal abnormalities play a greater role in the abnormal MRI findings than do changes in myelination. Together, these studies suggest that asymptomatic MRI abnormalities consistent with IME occur in 22–35% of infants treated with vigabatrin for IS. The MRI changes are more common at greater dosages of vigabatrin and appear to be transient in most cases. Reversal of MRI abnormalities was observed for most patients following discontinuation of vigabatrin, and, in some cases, even with continuation of the drug. These changes are likely to be age-dependent, as they are not evident for older children or adults. One case report has been published describing an infant with preexisting white matter abnormalities who received vigabatrin for IS at 9 months of age in combination with topiramate and then immediately had severe deterioration in neurologic function and died 3 weeks later (58). At autopsy, neuropathologic examination revealed white matter vacuolation and myelin splitting at the intraperiod line, consistent with the abnormalities observed in rats and mice. Imaging was not performed during the period of toxicity. This is the first reported case of histologically confirmed, vigabatrin-induced IME in humans.

In a recently published review, Iyer et al. (59) noted that vigabatrin-induced neurotoxicity in infants preferentially affects deep CNS structures (e.g., thalami, anterior commissure, globus pallidi, dentate nuclei, brainstem, corpus callosum), which is characterized by restricted diffusion and T2/fluid-attenuated inversion recovery high signal in these structures. Because bilateral thalamic involvement was often a prominent feature, they suggested that it raises suspicion for venous thrombosis, acute disseminated encephalomyelitis (ADEM), and tumor. However, they also recognized that patients with vigabatrin-induced changes are often asymptomatic with their seizures under control, mitigating against ischemia or ADEM, and that signal abnormalities were usually reversible on follow-up MRI (53–55, 60). They concluded that the clinical significance of these changes is unknown as they are often discovered incidentally and may resolve spontaneously even if patients remain on vigabatrin (54, 60).

Neuropsychiatric and cognitive effects

  1. Top of page
  2. Abstract
  3. Introduction
  4. Adverse event profile
  5. Intramyelinic edema
  6. Neuropsychiatric and cognitive effects
  7. Conclusions
  8. Conflicts of interest
  9. Acknowledgments
  10. References

Acute neuropsychologic disorders occur more frequently in patients with epilepsy than in the general population (61–63). The frequency of these disorders has been estimated at 2–16%, with greater rates for patients with more severe and intractable epilepsy. Of note, neuropsychologic disorders often develop in a setting where previously intractable patients suddenly become seizure-free.

A battery of neuropsychologic assessments were included in the US randomized controlled trials of vigabatrin in rCPS. The trial that evaluated three different dosages of vigabatrin (1, 3, and 6 g/day) included 11 neurophysiologic tests (with a total of 42 subtests within these vehicles) (15). The battery of tests included Profile of Mood States, Washington Psychosocial Seizure Inventory, Lafayette Grooved Pegboard, Stroop Test, Benton Visual Retention Test, Controlled Oral Word Association, Mood Rating Scale, Symbol Digit Modalities, Rey Auditory-Verbal Learning Test, Wonderlic Personnel Test, and Digit Cancellation Test. Patients completed testing at baseline and at the end of the treatment period. Only the Digit Cancellation Test indicated a significant linear trend with vigabatrin dosage (decreases in average number correct and increases in average number omitted), which suggested a slight and clinically insignificant decrease in cognitive performance (15, 64). However, this effect was not observed with the other cognitive function tests. In the other US randomized controlled trial, vigabatrin 3 g/day produced no definite impairment of mood or cognition (12). In an open-label randomized study comparing vigabatrin monotherapy with carbamazepine monotherapy, vigabatrin had no detrimental effects on cognitive function during a 12-month follow-up period (65). Retrieval from both episodic and semantic memory and flexibility of mental processing improved significantly in patients successfully treated with vigabatrin (= 25) compared with patients treated with carbamazepine (= 24).

Smaller studies have suggested that vigabatrin has little effect on cognitive function, although a statistically significant effect may be observed for one or two tests within a battery of neuropsychologic tests. In a randomized controlled study of 45 patients with refractory partial seizures, add-on vigabatrin 3 g/day produced modest impairment based on a visual memory task and a small but significant reduction in motor speed assessed after 20 weeks of treatment (11). However, significant effects were not observed following a battery of other tests measuring memory, mental speed and flexibility, mood, and behavior. A battery of neuropsychologic tests were also administered to 24 patients with refractory epilepsy after 2, 6, and 12 weeks of adjunctive vigabatrin 2–3 g/day or placebo in a double-blind, randomized crossover study (66). No significant differences were found between vigabatrin and placebo at any time point on any of the objective tests of cognitive function. Patients who responded to vigabatrin were then followed for a mean of nearly 15 months. These patients had improvements in psychomotor, memory, and self-rating scales.

Vigabatrin, like some other second-generation AEDs (e.g., topiramate, tiagabine), has been linked to treatment-emergent depressive symptoms (67), and a recent review suggested that it can cause “depression, psychosis, agitation, irritability, and hyperkinesia” (68). The potential for vigabatrin to induce psychiatric adverse events was raised initially after 14 cases of psychosis were reported for 210 patients with refractory epilepsy following initiation of vigabatrin therapy (69). Nine of these patients had no previous history of psychosis. All cases resolved following withdrawal of vigabatrin.

A systematic analysis of US and non-US, double-blind, placebo-controlled trials was conducted subsequently to determine the frequency of psychiatric adverse events with adjunctive vigabatrin therapy for refractory partial epilepsy (70). Vigabatrin was associated with a greater incidence of adverse events coded as depression (12.1% vs 3.5%; < 0.001) and psychosis (2.5% vs 0.3%; = 0.028) compared with placebo (Fig. 3). No difference between vigabatrin vs placebo was observed for aggressive reaction, manic symptoms, agitation, emotional lability, anxiety, or suicide attempt. The cases of psychosis were generally transient and responded to reduction or discontinuation of vigabatrin or to neuroleptic treatment. Of note, the incidence of psychosis was much less than in the initial report of the 14 cases. Cases of depression were typically mild. However, nine of 49 vigabatrin-treated patients (18.4%) with depression had serious depression, as defined by discontinuation from the study, hospitalization, suicide attempt, or psychotic depression. It was not clear whether a history of psychosis or depression increased risk of these events.

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Figure 3.  Incidence of psychiatric AEs with adjunctive vigabatrin in placebo-controlled clinical trials. AEs, adverse events; CI, confidence interval; OR, odds ratio. Levinson DF, Devinsky O (70), Psychiatric adverse events during vigabatrin therapy, Neurology, Vol. 53, Issue 7, p1503–1511. © 1999. Reprinted with permission.

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Suicidal thoughts and behavior are more common in patients with epilepsy than in the general population, but it has been a matter of debate whether the risk is specifically associated with AED therapy (66). To address this issue, the Food and Drug Administration (FDA) conducted a meta-analysis of AED therapy using data from 199 randomized, placebo-controlled, parallel-group trials regardless of the indication (71). Data for 11 AEDs were included in the analysis. Data for vigabatrin were submitted to the FDA, but were not included because the drug was not approved in the United States at that time. The main analysis included 27,863 patients receiving AED therapy and 16,029 placebo-treated patients. Approximately 25% received AEDs for epilepsy, whereas 27% received these agents for psychiatric indications and 48% received them for other conditions. Four patients had completed suicides (all received AED therapy), and 38 patients had attempted suicide (30 received AED therapy). Most other events were coded as suicidal ideation. The estimated incidence of suicidal behavior or ideation was 0.43% for AED-treated patients compared with 0.24% for placebo-treated patients (odds ratio, 1.80; 95% confidence interval, 1.24–2.66). AED therapy was also associated with risk of suicidal behavior and ideation in the subgroup with epilepsy (odds ratio, 3.53; 95% confidence interval, 1.28–12.10). As a result of this analysis, the FDA requires all manufacturers to include a warning about suicidal behavior and ideation in their product labels.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Adverse event profile
  5. Intramyelinic edema
  6. Neuropsychiatric and cognitive effects
  7. Conclusions
  8. Conflicts of interest
  9. Acknowledgments
  10. References

Many clinical studies, including the pivotal randomized controlled trials in rCPS and IS, demonstrate that vigabatrin is generally well-tolerated, with an overall adverse event profile similar to that of other AEDs. The most common treatment-related adverse events are CNS-related: drowsiness, dizziness, headache, and fatigue with adjunctive vigabatrin in adults with rCPS, and sedation, somnolence, and irritability with vigabatrin monotherapy in infants with IS. Vigabatrin has little effect on cognitive function, mood, or behavior based on assessments made with a battery of neuropsychologic tests. The incidence of depression and psychosis, but not other psychiatric adverse events, occurs at a greater rate with vigabatrin than placebo. Accordingly, a careful assessment of the patient’s psychiatric history may be helpful in identifying whether they should be monitored closely for treatment-emergent symptoms during vigabatrin therapy.

The IME observed in rats and dogs has not been found on pathologic assessment of autopsy or neurosurgical specimens in adolescents or adults treated with vigabatrin for rCPS, nor has it been identified in EP assessments or MRI scans in this population. Consequently, routine MRI surveillance during vigabatrin therapy is not necessary for adults with rCPS (30). In contrast, abnormal MRI signal changes characterized by increased T2 intensity and restricted diffusion have been observed during vigabatrin monotherapy of infants with IS. These lesions generally resolved with discontinuation of vigabatrin. In a few cases, they resolved despite continuing vigabatrin. The potential significance of these MRI findings with respect to long-term clinical sequelae remains to be determined. As with any AED therapy, the benefit of improved seizure control must be balanced against the unknown potential risk associated with these abnormal MRI changes.

Conflicts of interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. Adverse event profile
  5. Intramyelinic edema
  6. Neuropsychiatric and cognitive effects
  7. Conclusions
  8. Conflicts of interest
  9. Acknowledgments
  10. References

Steven D. Walker worked in Medical Affairs at Marion Merrell Dow/Hoechst Marion Roussel/Aventis during clinical development of vigabatrin. Reetta Kälviäinen has received consultancy fees or speaker fees from Algol Pharma, Cephalon, Eisai, GlaxoSmithKline, Johnson & Johnson, Lundbeck Inc, Janssen-Cilag, Orion, Pfizer, and UCB.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Adverse event profile
  5. Intramyelinic edema
  6. Neuropsychiatric and cognitive effects
  7. Conclusions
  8. Conflicts of interest
  9. Acknowledgments
  10. References

Medical writing and editorial assistance were provided by Barry M. Weichman, PhD, of BMW Associates (Skillman, NJ, USA), Robin L. Stromberg, PhD, of Arbor Communications, Inc. (Ann Arbor, MI, USA), and Michael A. Nissen, ELS, of Lundbeck Inc. (Deerfield, IL, USA). This support was funded by Lundbeck.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Adverse event profile
  5. Intramyelinic edema
  6. Neuropsychiatric and cognitive effects
  7. Conclusions
  8. Conflicts of interest
  9. Acknowledgments
  10. References