2005 - Seizures associated with memantine use
Gayle Peltz, Domenica M. Pacific, John A. Noviasky, Ahmed Shatla and Theodore Mehalic
GAYLE PELTZ, M.D., is Resident, Family Medicine Residency Program, St. Elizabeth’s Medical Center (SEMC), Utica, NY.
DOMENICA M. PACIFIC, PHARM.D., is Pharmacy Practice Resident, SUNY Upstate Medical University, Syr-acuse, NY.
JOHN A. NOVIASKY, PHARM.D., is Clinical Pharmacy Coordinator, Department of Pharmacy, SEMC. AHMED SHATLA, M.D., is Neurologist, Shatla Neurology, Utica. THEODORE MEHALIC, M.D., is Attending, Department of Medicine, SEMC.
Address correspondence to Dr. Noviasky at the Department of Pharmacy, St. Elizabeth’s Medical Center, 2209 Genesee Street, Utica, NY 13501 (jnoviask@stemc.org).
Memantine hydrochloride is an N-methyl-D-aspartate (NMDA)-receptor antagonist indicated for the treatment of moderate to severe Alzheimer’s disease.1
The most commonly reported adverse central nervous system events with memantine use are depression, insomnia, increased or decreased motor activity, akathisia, and agitation.2
Seizures occur in patients receiving memantine at the rate of 0.2% (not significantly lower than with placebo in clinical trials)1; however, patients with seizure disorder were excluded from the primary studies.3,4 We report an apparent case of new-onset, generalized tonic–clonic seizure activity associated with memantine use.
A 72-year-old Cau-casian woman was admitted to the hospital with new-onset seizure activity.
Earlier that day, she screamed twice, became rigid, started to fall and shook for approximately 30 seconds, followed by a four- to five-minute period of unconsciousness.
When emergency personnel arrived, the patient was responsive only to painful stimuli. She slowly became more responsive but was confused, becoming alert, and complaining of a headache just before arrival at the hospital.
On admission, she was diagnosed with a generalized tonic–clonic seizure with postictal response.
Her medical problems included Alzheimer’s disease for at least eight years, hypertension, glaucoma, and a history of surgery for uterine cancer, but no history of seizure disorder.
The patient was taking
latanoprost,
amlodipine besylate 5 mg daily,
vitamin B-100 daily,
vitamin E 800 IU twice daily,
aspirin 81 mg daily,
ser-traline hydrochloride 50 mg daily for 10 years
before the seizure,
and ri-vastigmine tartrate 4.5 mg twice daily for 3 years before the seizure.
(She had been receiving donepezil hydrochloride since 1996 and was switched to rivastigmine in 2001 for unknown reasons.)
This patient was
also taking olanzapine 5 mg at bedtime for seven months before the seizure and
me-mantine hydrochloride 15 mg daily.
Memantine had been started on Jan-uary 1, 2004, at a dosage of 5 mg daily, increased to 5 mg twice daily one week later, and increased to 5 mg in the morning and 10 mg in the evening on January 22, 2004. Two days after the last increase, she was admitted for the new-onset seizure described above.
After admission to the hospital,
olanzapine,
sertraline,
rivastigmine, and
memantine
were discontinued.
Computed tomography of the brain showed marked atrophy with mi-crovascular ischemic changes but no recent bleeding or infarct.
All hematol-ogy and blood chemistry values were within normal limits except creatinine clearance, which was low (30–35 mL/ min).
During her hospital stay, no further seizure activity was noted, and an electroencephalogram (EEG) completed two days after admission found no abnormalities.
Magnetic resonance imaging indicated moderate diffuse loss of cerebral volume and diffuse is-chemic white-matter changes, which appeared to have progressed slightly from seven years earlier, but no focal lesions were noted.
By the time she was discharged (three days after admission), she had
resumed
olanzap-ine
and sertraline at previous dosages
and
rivastigmine
and memantine at reduced dosages.
Nine days after discharge,
she had a brief episode of seizure-like activity with shaking of the extremities and was given levetiracetam. She has remained seizure free since.
The Naranjo Adverse Drug Reaction Probability Scale
yielded a score of
6 for
memantine,
sertraline,
and olanzapine,
indicating that these agents may have caused the seizure.
Rivastigmine yielded a score of 5, indicating that it was also a probable cause of the seizure.
Of these agents, memantine was considered most suspect, as it was during upward adjustment of the meman-tine dosage that the seizure occurred.
In addition, the patient had been receiving the other agents long term without any seizure activity.
Memantine use is associated with a lowering of the seizure threshold, but this finding has not been further described.2
A report from clinical trials described seizure activity as "trembling of the whole body from morning until 3:00 pm."6
After me-mantine was discontinued, the disturbance resolved and increased delta waves on the patient’s EEG were improved.
However, this patient had a convulsion during placebo, and investigators felt the activity may have been extrapyramidal rather than a result of the seizure.
In another case, a patient developed "proconvulsive-ness" in an overdose situation, although this term was not further described.6 Animal studies revealed ataxia, unsteadiness, hyperexcitabili-ty, and tremor with high dosages of memantine. In one animal model, memantine caused significant behavioral and motor changes, resulting in the animal’s inability to maintain a standing posture.7
The majority of memantine, 57–82%, is excreted unchanged in the urine.
The drug’s terminal half-life is 60–80 hours.
According to the manufacturer, patients with renal impairment have significantly greater exposure to the drug than patients without kidney disease.
Dosage reduction in patients with moderate renal impairment and drug avoidance in patients with severe renal dysfunction are recommended1 (our patient had borderline severe renal insufficiency).
Indeed, higher serum memantine levels are associated with increased seizure activity with certain other central nervous system drugs.8
On the basis of this information, it seems prudent to use a lower initial dosage of memantine and adjust it slowly in patients with renal dysfunction.
Other medications in this patient’s medication profile that are associated with seizure activity include sertraline and olanzapine.2
However, this patient had been stabilized on these agents for some time without seizure. The combination of meman-tine, sertraline, and olanzapine may have increased the risk of seizure activity, as combination therapy has been identified as a factor for increased seizure susceptibility.8
Conclusion.
New-onset seizure activity in a patient with impaired renal function was associated with me-mantine use.
Footnotes
Straightforward reports of unusual drug experiences are included in this section. While selected references may be cited, the purpose of a Drug Experience report is not to present an extensive review of the literature.
A related section, Grand Rounds, includes papers that are well-documented patient case reports with a thorough review of the important literature to help put the case in perspective.
Authors should report serious adverse drug reactions to the FDA medical products reporting program (MedWatch). Such reporting will not jeopardize the chances that AJHP will publish manuscripts on the same drug reactions.
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