Anticonvulsant-induced downbeat nystagmus in epilepsy.

We report data from two patients who developed reversible downbeat nystagmus (DBN) while using AEDs within the therapeutic range. All previous reported cases of epilepsy with drug-induced DBN related to toxic levels of AEDs were summarized, and DBN was found mostly occurring in those using a sodium channel blocking AED. We propose that in our cases, the DBN with therapeutic AED levels may be explained by additive effects of sodium channel blockers. Adverse drug effects should be considered as a cause of DBN in people with epilepsy treated with multiple AEDs.

Introduction

Iatrogenic down beat nystagmus (DBN) in people with epilepsy is rare and has been reported in the context of intoxication with antiepileptic drugs (AEDs) [1]. We describe two patients who developed reversible DBN while using AEDs within the therapeutic range.

Case reports

Case 1

A 30-year-old man with refractory epilepsy following perinatal occipital lobe infarction was referred to our center with episodes of oscillopsia 1 h after taking his AEDs (lamotrigine 150 mg bid, valproic acid 600 mg bid, gabapentin 400 mg tid, and carbamazepine 400 mg bid). He noted that oscillopsia while reading could be prevented by keeping his book upward. He had DBN on examination. All AED levels were within the therapeutic range (Table 1). Downbeat nystagmus disappeared immediately after reduction of lamotrigine; subsequently, gabapentin was withdrawn without seizure increase.

Table 1

Summary of previous reported and presented cases with epilepsy and anticonvulsant-induced downbeat nystagmus (DBN).

Age	Sex	Etiology	Specific cause	Medication: total daily dosage (mg)		AED serum levels with, without DBN (μg/ml)		Absence of DBN following AED reduction (R) or withdrawal (W)	Reference
23	F	Unknown		Lorazepam 2Lamotrigine 400	Gabapentin 1200	Lamotrigine 19.9#		Lamotrigine (R)	[4]
34	F	Structural	Meningitis	Lamotrigine 500	Valproic acid 1250	Lamotrigine 27.0#, 18.8		Valproic acid (R)	[4]
31	F	Unknown		Carbamazepine 1200Topiramate 200	Lamotrigine 600	Carbamazepine 9.4	Lamotrigine not assessed	Lamotrigine (R)	[5]
51	M	Structural	Gunshot	Phenytoin 400		Phenytoin 38#, 18		Phenytoin (W)	[6]
54	F	Unknown		Phenytoin 400Phenobarbital 120Primidone 250	Perphenazine 12Thioridazine 200	Phenytoin 27#, 14Phenobarbital 24	Primidone 6.3	Phenytoin (W)	[6]
19	F	Unknown		Phenytoin 150Carbamazepine 800	Primidone 750	Phenytoin 14, 14	Primidone 22#, 15	Phenytoin (R)	[7]
23	F	Structural	Adhesions found in posterior fossa (Meningitis?)	Primidone 750Phenytoin 300Carbamazepine 800	Acetazolamide 1000Methosuximide 600	Phenytoin 20#, 9.8Primidone 6	Carbamazepine 3.5Methsuximide 1.7	Phenytoin (W)	[7]
18	F	Unknown		Carbamazepine 1800		Carbamazepine 9.6, 6.9		Carbamazepine (R)	[8]
44	M	Structural	Concussion	Felbamate (dosage not reported)	Haloperidol 3Benztropine 2	Felbamate 110#		Felbamate (W)	[9]
30	M	Structural	Perinatal occipital lobe infarction	Valproic acid 1200Carbamazepine 1200	Lamotrigine 300Gabapentin 3600	Valproic acid 65, 44Carbamazepine 8.4, 6.8	Lamotrigine 9.08, 6.8Gabapentin 11.5, 3.8	Lamotrigine (R)Gabapentin (W)	This paper
38	F	Structural	Tuberous sclerosis complex; hypothalamic giant cell astrocytoma	Valproic acid 2000Levetiracetam 2000	Lamotrigine 200Lacosamide 200	Valproic acid 74, 53Levetiracetam 19.1, 23.2	Lamotrigine 7.6, 7.1Lacosamide 5.0	Lacosamide (W)	This paper

DBN = downbeat nystagmus, AED = antiepileptic drug, F = female, M = male.

Toxic level.

Case 2

A 38-year-old woman with refractory epilepsy due to tuberous sclerosis complex and a hypothalamic giant cell astrocytoma presented with oscillopsia. She had weekly clusters of predominantly complex partial seizures despite taking multiple AEDs. The complaints started following a change of medication: introduction of lacosamide 100 mg bid and tapering of topiramate. At the time of referral, she used valproic acid, levetiracetam, lamotrigine, and topiramate (Table 1). The oscillopsia was continuous without clear fluctuations following drug intake. Downbeat nystagmus and ataxia were noted at examination. There was no evidence of AED intoxication (Table 1). Lacosamide was discontinued, and the DBN and ataxia disappeared.

Discussion

In these cases, the drug levels were within the therapeutic range, but the temporal relationship between oscillopsia and drug ingestion (Case 1), the response to change to the drug treatment (Case 1 and Case 2), and also the impressive amount of AEDs suggested a drug-related cause. An ultimate proof would require a drug challenge, but this was not feasible in these cases.

Downbeat nystagmus is thought to result from impairment of the vestibulocerebellum, flocculus, or paraflocculus, that serves as the output pathway for information on movement, coordination, and balance from the cerebellar cortex [1-3]. In our two cases, the relevant drugs lamotrigine and lacosamide are both sodium channel blockers. In addition, both subjects were on combination therapy with other AEDs with sodium channel blocking properties (carbamazepine and valproic acid in Case 1, lamotrigine and valproic acid in Case 2). We reviewed the PubMed database (search terms: DBN and epilepsy) and identified nine previously reported cases with epilepsy and drug-induced DBN (Table 1). Most cases were related to toxic AED levels (lamotrigine, phenytoin, and felbamate). In one case, lamotrigine toxicity was likely, but not established; in another case, DBN was associated with therapeutic levels of carbamazepine. As in our cases, all subjects suffered from refractory epilepsy, and most (7 out of 9) were using multiple AEDs. All AEDs that have been associated with DBN (carbamazepine, phenytoin, lacosamide, and lamotrigine) have sodium channel blocking properties except for felbamate.

Voltage-gated sodium channel (Nav) 1.1 and Nav1.6 channels are the primary voltage-activated sodium channel isoforms expressed in cerebellar Purkinje neurons and might explain the association between DBN and sodium channel blocking AEDs [10]. We suggest that the occurrence of DBN within the therapeutic range may be explained by additive effects of sodium channel blockers as in our two cases or by an increased propensity for DBN due to epilepsy etiology (e.g., encephalopathy with cerebellar dysfunction).

Conclusion

Adverse drug effects should be considered as a cause of DBN in people with epilepsy treated with multiple AEDs, particularly those with sodium channel blocking properties even in the absence of toxic levels. Prompt recognition of this adverse effect is important to avoid an incorrect diagnosis.

Ethical standard

We confirm that we have read the Journal's position on issues involved in ethical publication and confirm that this report is consistent with the guidelines.

Conflicts of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.