Reversible parkinsonism and cognitive impairment with chronic valproate use

Armon, Carl; Shin, Cheolmin; Miller, Patricia P.; Carwile, Sandra T.; Brown, Eric E.; Edinger, Jack D.; Paul, Rubina

doi:10.1212/wnl.47.3.626

Cited by 152 publications

(78 citation statements)

References 7 publications

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“…A total of 72% improved after discontinuing VPA. 26 Since patients with AD are likely sensitive to other neurotoxic insults 27,28 it is possible that the same potentially neurotoxic effects of divalproex associated with brain volume loss in the first 12 months of this longitudinal study also caused the initial rapid decline in MMSE scores observed here. Notably, analysis of adverse events and laboratory data from the primary ADCS divalproex treatment trial showed no evidence of significant neurotoxicity in any participants during the 24-month study.…”

Section: Discussionmentioning

confidence: 84%

Chronic divalproex sodium use and brain atrophy in Alzheimer disease

et al. 2011

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Objective:We evaluated the effect of the divalproex sodium formulation of valproic acid on brain volumes using MRI in people with mild to moderate Alzheimer disease (AD) and assessed for changes associated with behavioral and cognitive effects.Methods: Eighty-nine of 313 participants randomized to divalproex or placebo in a 24-month, parallel-group trial received MRI scans at baseline and 12 months. Interval MRI annual percent changes in whole brain, ventricular, and hippocampal volumes were the primary outcomes of interest. Change from baseline in clinical outcomes was assessed at 6-month intervals.Results: There were no baseline differences between active treatment and placebo groups in age, education, brain volumes, clinical rating scores, or APOE ⑀4 carrier status. The group treated with divalproex showed a greater rate of decline in left and right hippocampal and brain volumes (Ϫ10.9% and Ϫ12.4% vs Ϫ5.6% and Ϫ6.3%, and Ϫ3.5% vs Ϫ1.4%, respectively), and a greater rate of ventricular expansion (24.5% vs 9.9%) (p Ͻ 0.001). Mini-Mental State Examination scores showed a more rapid decline with divalproex through month 12 (placebo ϭ Ϫ2.0 Ϯ 4.3, divalproex ϭ Ϫ3.9 Ϯ 4.0) (p ϭ 0.037), although there were no changes on other cognitive, behavioral, or functional ratings at 12 and 24 months.

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Section: Discussionmentioning

confidence: 84%

Chronic divalproex sodium use and brain atrophy in Alzheimer disease

et al. 2011

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“…First, cognitive functioning and behavior showed a striking improvement within a few days of reducing VPA dosage, and a repeat MRI performed 5 months after drug discontinuation revealed disappearance of pseudoatrophic changes. Second, an association of VPA with reversible severe cognitive deterioration and pseudoatrophy of the brain has recently been suggested in other patients (5,(7)(8)(9)(10). The possibility that pseudoatrophic changes may be related to LTG comedication cannot be fully excluded.…”

Section: Discussionmentioning

confidence: 99%

“…The finding of normal background EEG activity may be helpful in differentiating this condition from other disorders possibly associated with brain atrophy, even though in the syndrome of reversible dementia associated with parkinsonism a slowing in background EEG activity has been reported (5). Other conditions to be considered for differential diagnosis include VPAinduced stupor (2,13,14) with or without hyperammonemia (3,14), which can be differentiated because of lack of brain atrophy (unless preexistent), impairment of consciousness and, in some stuporous cases, clinical or EEG evidence of increased seizure activity.…”

Section: Discussionmentioning

confidence: 99%

Reversible Pseudoatrophy of the Brain and Mental Deterioration Associated with Valproate Treatment

et al. 1998

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Summary:Purpose: To describe an 11-year-old girl with symptomatic localization-related epilepsy and normal intelligence who developed reversible mental deterioration and pseudoatrophic brain changes while receiving valproate (VPA).Methods; Assessment of mental function using Wechsler Intelligence Scale for Children-I11 (WISC) and Raven's Progressive Matrices (PM), EEG recordings while awake and asleep, and brain magnetic resonance imaging (MRI), were performed at the beginning of VPA therapy, after 2 years and 8 months of treatment and following VPA discontinuation.Results: After 2 years and 6 months on VPA (G26 mg/kg/ day) the girl insidiously developed mental deterioration (loss of I8 IQ points and drop in age-adjusted PM score from the 95th to the 50th percentile) associated with MRI-documented pseudoatrophy of the brain. Onset of severe cognitive impairment coincided with serum VPA concentrations near 100 pglml. There were no other manifestations of drug toxicity or hyperammonemia. Background EEG activity was normal. Reduction of VPA dosage and subsequent discontinuation 4 months later resulted in disappearance of clinical symptoms with a 20-point improvement at IQ testing and recovery of previous PM score. Repeat MRI showed disappearance of pseudoatrophic changes.Conclusions: The striking cognitive improvement and reversal of pseudoatrophic brain changes following VPA discontinuation strongly suggest a drug-induced condition. Based on this and previous reports, the syndrome of VPA-associated mental deterioration and pseudoatrophy of the brain appears to encompass different but possibly related clinical entities, which include parkinsonism with cognitive deterioration, mental deterioration with signs of VPA-toxicity, and isolated mental deterioration, as seen in our patient. A drug-induced effect should be considered whenever cognitive deterioration and imaging findings of brain atrophy occur in VPA-treated patients. Key Words: Valproate-MRI-Brain pseudoatrophy-Mental deterioration.Valproate (VPA) is associated with fewer adverse neurological effects than other antiepileptic drugs ( 1). Severe neurological side effects such as VPA-induced encephalopathy with or without hyperammonemia (2,3), extrapyramidal disorders ( 4 3 , and reversible dementia (6-9) are rare. We report on an 1 I-year-old girl with nonsevere epilepsy, in whom mental deterioration with pseudoatrophy of the brain developed insidiously after 2 years on VPA. The condition was not associated with other signs of toxicity or hyperammonemia and was rapidly reversible upon VPA discontinuation. CASE REPORTThis I I-year-old girl was born with mild perinatal suffering (Apgar score 5-9) after a normal pregnancy. Developmental milestones were normal. At age 6 years Accepted June 6, 1997. Address correspondence and reprint requests to Dr. R. Guerrini at Institute of Child Neurology and Psychiatry, University of Pisa, Via dei Giacinti 2, 56018 Calambrone, Pisa, Italy.she experienced her first, sleep related, brief generalized clonic seizure. The electroen...

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“…Valproate can worsen Parkinsonism and cause cognitive deterioration. Both side effects are reversible upon drug discontinuation [Armon et al 1996]. Zonisamide (25-200 mg/day) has been studied in 15 patients with PG, HS, CE or CS in a noncontrolled and open-label design.…”

Section: Management Of Impulse Control Disordersmentioning

confidence: 99%

Diagnosis and treatment of impulse control disorders in patients with movement disorders

Mestre

Strafella

Thomsen

et al. 2013

Ther Adv Neurol Disord

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Impulse control disorders are a psychiatric condition characterized by the failure to resist an impulsive act or behavior that may be harmful to self or others. In movement disorders, impulse control disorders are associated with dopaminergic treatment, notably dopamine agonists (DAs). Impulse control disorders have been studied extensively in Parkinson's disease, but are also recognized in restless leg syndrome and atypical Parkinsonian syndromes. Epidemiological studies suggest younger age, male sex, greater novelty seeking, impulsivity, depression and premorbid impulse control disorders as the most consistent risk factors. Such patients may warrant special monitoring after starting treatment with a DA. Various individual screening tools are available for people without Parkinson's disease. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease has been developed specifically for Parkinson's disease. The best treatment for impulse control disorders is prevention. However, after the development of impulse control disorders, the mainstay intervention is to reduce or discontinue the offending anti-Parkinsonian medication. In refractory cases, other pharmacological interventions are available, including neuroleptics, antiepileptics, amantadine, antiandrogens, lithium and opioid antagonists. Unfortunately, their use is only supported by case reports, small case series or open-label clinical studies. Prospective, controlled studies are warranted. Ongoing investigations include naltrexone and nicotine.

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Reversible parkinsonism and cognitive impairment with chronic valproate use

Cited by 152 publications

References 7 publications

Chronic divalproex sodium use and brain atrophy in Alzheimer disease

Chronic divalproex sodium use and brain atrophy in Alzheimer disease

Reversible Pseudoatrophy of the Brain and Mental Deterioration Associated with Valproate Treatment

Diagnosis and treatment of impulse control disorders in patients with movement disorders

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