Drug- and Toxin-Induced Opsoclonus - a Systematized Review, including a Case Report on Amantadine-Induced Opsoclonus in Multiple System Atrophy.

Background: Opsoclonus is a rare disorder characterized by conjugate multidirectional, horizontal, vertical, and torsional saccadic oscillations, without intersaccadic interval, resulting from dysfunction within complex neuronal pathways in the brainstem and cerebellum. While most cases of opsoclonus are associated with autoimmune or paraneoplastic disorders, infectious agents, trauma, or remain idiopathic, opsoclonus can also be caused by medications affecting neurotransmission. This review was prompted by a case of opsoclonus occurring in a patient with Multiple System Atrophy, where amantadine, an NMDA-receptor antagonist, appeared to induce opsoclonus. Methods: Case report of a single patient and systematized review of toxic/drug-induced opsoclonus, selecting articles based on predefined criteria and assessing the quality of included studies. Results: The review included 30 articles encompassing 158 cases of toxic/drug-induced opsoclonus. 74% of cases were attributed to bark scorpion poisoning, followed by 9% of cases associated with chlordecone intoxication. The remaining cases were due to various toxics/drugs, highlighting the involvement of various neurotransmitters, including acetylcholine, glutamate, GABA, dopamine, glycine, and sodium channels, in the development of opsoclonus. Conclusion: Toxic/drug-induced opsoclonus is very rare. The diversity of toxics/drugs impacting different neurotransmitter systems makes it challenging to define a unifying mechanism, given the intricate neuronal pathways underlying eye movement physiology and opsoclonus pathophysiology.

Amantadine withdrawal in a patient with spinocerebellar ataxia.

We report a case of a man with spinocerebellar ataxia (SCA) on high-dose amantadine who was admitted for acute on chronic dysphagia secondary to progression of SCA. Four days after oral medications were held due to patient's dysphagia, he developed fever, tachycardia and mild rigidity in extremities and became obtunded. Despite antibiotics treatment, the vitals and mental status changes persisted for 8 days. When amantadine was resumed, the patient's vital signs and encephalopathy improved within 2 days. This is among the first reports of amantadine withdrawal syndrome (AWS) in a patient without Parkinson's disease. Our case reinforces the importance of careful medication review at admission and consideration of pharmacologic side effects with not only medication initiation but also discontinuation.

Amantadine toxicity causing visual hallucinations.

Amantadine is an N-methyl-d-aspartate receptor agonist with secondary dopaminergic activity that is used to treat Parkinson's disease-related dyskinesia and to treat fatigue in multiple sclerosis. It is primarily renally excreted and so impaired kidney function prolongs its half-life and may lead to toxicity. We describe a woman with multiple sclerosis taking amantadine who developed acute renal impairment, which triggered florid visual hallucinations that resolved on stopping the medication.

Amantadine-associated delirium in patients with maintenance dialysis: Insomnia-associated recovery and uneven seasonal distribution.

Amantadine hydrochloride is a risky drug for triggering delirium in dialysis patients; however, it is often administered casually. Furthermore, little is known regarding the recovery and prognosis of dialysis patients with amantadine-associated delirium. Data of this retrospective cohort study were collected from a local hospital database for hospitalizations between January 2011 and December 2020. Patients were divided into 2 cohorts: early recovery (recovery within 14 days) and delayed recovery (recovery more than 14 days). The cases were analyzed together with the intermonth temperature using descriptive statistics. A Kaplan-Meier survival curve and binary logistic regression were applied for the analyses of prognoses and factors. A total of 57 patients were included in this study. The most common symptoms were hallucinations (45.61%) and muscle tremors (43.86%). Early recovery was observed in 63.16% of the patients. Only 3.51% of the cases occurred in local summer (June, July, and August). Better prognoses for survival (hazard ratio [HR] = 0.066, 95% confidence interval [95% CI] = 0.021-0.212) and hospitalization costs (7968.42 ± 3438.43 CNY vs 12852.38 ± 9361.13 CNY, P = .031) were observed in patients with early recovery than in those with delayed recovery. In the multivariate logistic regression adjusted by 1:1 propensity score matching, delayed recovery was independently caused by insomnia (P = .022, = 10.119, 95% CI = 1.403-72.990) and avoided in patients with urine volume over 300 mL (P = .029, = 0.018, 95% CI = 0.006-0.621). The increment (per 100 mg) of cumulative dose (P = .190, = 1.588, 95% CI = 0.395-3.172) tended to be a risk of delayed recovery. The area under curve of the receiver operating characteristic curve was 0.867, with a sensitivity of 90.5% and a specificity of 82.4% at the cutoff point (cutoff = 0.432). For amantadine-associated delirium in dialysis patients with uneven seasonal distribution, early recovery with better prognosis should be the aim of treatment by giving priority to the remedy of insomnia.

A placebo-controlled randomized clinical trial of amantadine hydrochloride for evaluating the functional improvement of patients following severe acute traumatic brain injury.

BACKGROUND: Considering the known derangements in the dopaminergic neurotransmitter systems following traumatic brain injury (TBI), dopamine agonists are used as a pharmacologic option. In this study, we evaluate the effects of amantadine hydrochloride on the functional improvement of severe TBI patients. METHODS: Within a triple-blinded (patients, intervention administrators, and outcome assessors) placebo-controlled randomized clinical trial, we evaluated the effects of amantadine (100 mg BD (twice a day) for 14 days, then 150 mg BD for another 7 days, and 200 mg BD for another 21 days) on outcome measurements of weekly mean Glasgow Outcome Scale (GOS) and Disability Rating Scale (DRS), through six weeks of trial for 57 patients (29 amantadine, 28 placeboes) with severe TBI admitted in our hospital. RESULTS: Although both groups had improvement in their DRS, the change from baseline was significantly better in the amantadine group (10.88±5.24 for amantadine vs. 8.04±4.07 for placebo, P=0.015). No significant difference was observed between groups for GOS (1.04±0.55 for amantadine vs. 1.12±1.05 for placebo, P=0.966). CONCLUSIONS: Based on our findings, amantadine hydrochloride might improve the speed of functional ability improvement in severe TBI patients, evaluated by DRS, and is also well tolerated by patients. Although, there were some limitations in this study, including small sample size, short time interval, not providing a wash-off period and invalidity of GOS for measuring recovery rates in short-term periods.

Safe Use of Memantine in a Pediatric Patient With Catatonia.

Pediatric catatonia is a complex neuropsychiatric syndrome. Benzodiazepines are standard first-line pharmacotherapy. When benzodiazepines do not provide relief of symptoms, electroconvulsive therapy (ECT) is the most proven effective therapy. However, the use of NMDA antagonists (amantadine and memantine) has been reported effective in adult patients as adjuncts and may provide an alternative treatment modality when ECT is not readily accessible. To the author's knowledge there are no prior case reports of memantine used in pediatric catatonia. This case demonstrates the safe use of memantine as an adjunctive agent in an adolescent with catatonia.

Amantadine-induced bilateral corneal edema in a pediatric patient.

Amantadine was originally developed as an antiviral agent for influenza A. However, it also has off-label uses for Parkinson disease, multiple sclerosis, and in the management of extrapyramidal symptoms. The mechanism of action in these conditions has yet to be elucidated. Ocular side effects from systemic amantadine are rare but have been described in three previous reports of amantadine-associated corneal edema in the pediatric population. We present an additional case of amantadine-associated transient visual impairment in a patient, which was associated with significant regression and worsening of his underlying neurodevelopmental status.

A Phase 3, double-blind, placebo-controlled efficacy and safety study of ADS-5102 (Amantadine) extended-release capsules in people with multiple sclerosis and walking impairment.

BACKGROUND: ADS-5102, a delayed-release, extended-release (DR/ER) amantadine, improved walking speed in MS in a Phase 2 trial. OBJECTIVE: The aim of this study was to present primary results of a Phase 3, double-blind, ADS-5102 trial (INROADS) for walking speed. METHODS: Adult participants with MS and walking impairment, not currently using amantadine or dalfampridine, underwent 4-week placebo run-in before randomization 1:1:1 to placebo, 137 or 274 mg/day ADS-5102 for 12 weeks. Primary outcome was the proportion of responders (20% increase in Timed 25-Foot Walk (T25FW) speed) for 274 mg ADS-5102 versus placebo at end of double-blind (Study Week 16). Additional measures included Timed Up and Go (TUG), 2-Minute Walk Test (2MWT), and 12-item Multiple Sclerosis Walking Scale (MSWS-12). RESULTS: In total, 558 participants were randomized and received double-blind treatment. Significantly more participants responded with 274 mg ADS-5102 (21.1%) versus placebo (11.3%). Mean T25FW speed also significantly improved (0.19 ft/s) versus placebo (0.07 ft/s). Other measures were not significant using prespecified hierarchical testing procedure. Adverse events led to discontinuation for 3.8% (placebo), 6.4% (137 mg ADS-5102), and 20.5% (274 mg ADS-5102). CONCLUSION: INROADS met its primary endpoint, showing a significantly greater proportion of participants with meaningful improvement in walking speed for 274 mg ADS-5102 versus placebo. Numeric dose response was seen for some secondary efficacy outcomes and adverse events.

Implications of dopaminergic medication withdrawal in Parkinson's disease.

The trajectory of the use of dopamine replacement therapy (DRT) in Parkinson's disease (PD) is variable and doses may need to be increased, but also tapered. The plan for dose adjustment is usually done as per drug information recommendations from the licensing bodies, but there are no clear guidelines with regards to the best practice regarding the tapering off schedule given sudden dose reductions of drugs such as dopamine agonists may have serious adverse consequences. A systematic literature search was, therefore, performed to derive recommendations and the data show that there are no controlled studies or evidence-based recommendations how to taper or discontinue PD medication in a systematic manner. Most of the data were available on the dopamine agonist withdrawal syndrome (DAWS) and we found only two instructions on how to reduce pramipexole and rotigotine published by the EMA. We suggest that based on the available data, levodopa, dopamine agonists (DA), and amantadine should not be discontinued abruptly. Abrupt or sudden reduction of DA or amantadine in particular can lead to severe life-threatening withdrawal symptoms. Tapering off levodopa, COMT inhibitors, and MAO-B inhibitors may worsen motor and non-motor symptoms. Based on our clinical experience, we have proposed how to reduce PD medication and this work will form the basis of a future Delphi panel to define the recommendations in a consensus.

Efficacy and safety of amantadine as a treatment for apathy after brain injury: Two single-case experimental design studies.

Studies on the efficacy of amantadine as a treatment for apathy after brain injury are scarce and of low quality. We examined the efficacy and safety of amantadine for treatment of apathy in two individuals with brain injury.Two double-blind, randomized, single-case experimental (baseline-amantadine-placebo-withdrawal) design (SCED) studies. Apathy measures included a Visual Analogue Scale (VAS), the Neuropsychiatric Inventory (NPI) apathy subscale and the Behavior Rating Inventory of Executive Function for Adults "Initiate" subscale. Safety measures included a rating scale of possible side effects of amantadine and physical examinations.No difference in apathy symptoms (VAS) between baseline and amantadine phase was found in case 1 (NAP = 0.55). Surprisingly, in case 2, apathy symptoms deteriorated from baseline to amantadine phase (NAP = 0.28, 90% CI = -0.69 to -0.20) and improved from amantadine to placebo phase (NAP = 0.92, 90% CI = 0.60-1.00). This improvement was also found on the NPI apathy subscale. Side effects of amantadine were observed in case 2.In this SCED study, amantadine did not improve apathy symptoms in two individuals with brain injury. However, this study shows that side effects of amantadine can occur which lead to a significant decrease in well-being. More high quality studies are required.

Amantadine treatment and delayed onset of levodopa-induced dyskinesia in patients with early Parkinson's disease.

BACKGROUND AND PURPOSE: Levodopa-induced dyskinesia (LID) is a common motor complication in patients with Parkinson's disease (PD). Although amantadine is indicated for LID treatment, it is uncertain whether early treatment with amantadine reduces the risk of LID in patients with PD. We aimed to evaluate the association between amantadine treatment and LID onset in patients with early-stage PD. METHODS: This was a hospital-based retrospective cohort study that used electronic medical records from January 1, 2009 to October 31, 2016. The effect of amantadine on LID onset was compared with those of anticholinergics and monoamine oxidase type B inhibitors in patients with PD. Propensity-score weighting and landmark analysis were used to reduce potential confounding. The time to LID onset was analyzed using Cox models. Sensitivity analyses were performed to determine the robustness of the results. RESULTS: The analyses included 807, 661, and 518 patients at 6-, 12-, and 18-month landmark points, respectively. Amantadine use was associated with delayed LID onset in the 6- and 12-month landmark analyses, with adjusted hazard ratios of 0.65 (95% confidence interval [CI] = 0.49-0.86) and 0.64 (95% CI = 0.47-0.88), respectively. Sensitivity analysis findings were comparable to those of the main analysis. CONCLUSIONS: Early treatment with amantadine may delay LID onset more than treatment with other symptomatic agents. Further studies are needed to elucidate the mechanism of amantadine in LID onset delay and to validate our findings.

Amantadine Revisited: A Contender for Initial Treatment in Parkinson's Disease?

The best practice for the initiation of symptomatic motor treatment for Parkinson's disease is an ongoing topic of debate. Fueled by interpretation of the results of the LEAP and MED Parkinson's disease studies, many practitioners opt for early initiation of levodopa formulations, avoiding dopamine agonists to circumvent potential deleterious side effects, namely impulse control disorder. Compared with levodopa, monoamine oxidase inhibitors may lack necessary potency. Ignored in this academic debate is another therapeutic option for patients with Parkinson's disease requiring treatment initiation: amantadine. Amantadine was first reported effective in the treatment of Parkinson's disease in 1969 and several studies were published in the 1970s supporting its efficacy. Currently, amantadine is mainly utilized as an add-on therapy to mitigate levodopa-related dyskinesia and, more recently, new long-acting amantadine formulations have been developed, with new indications to treat motor fluctuations. Amantadine has not been reported to cause dyskinesia and is rarely implicated in impulse control disorder.

Delayed amantadine toxicity causing apparent progression of multiple sclerosis.

BACKGROUND: Amantadine is sometimes used to treat fatigue in multiple sclerosis. OBJECTIVES: To report a patient with secondary progressive multiple sclerosis (SPMS) who developed late-onset side effects of amantadine which were initially felt to represent a progression of her SPMS. METHODS: A single retrospective case report. RESULTS: Symptoms of cognitive deterioration, ataxia and hallucinations resolved completely on cessation of the amantadine she had been prescribed several years beforehand. CONCLUSION: Clinicians involved in the management of the symptoms of SPMS should be aware of the potential for cumulative side effects of drugs used to treat symptoms and consider their potential role in precipitating neurological deterioration.

Parkinsonism-hyperpyrexia Syndrome After Amantadine Withdrawal: Case Report and Review of the Literature.

INTRODUCTION: Parkinsonism-hyperpyrexia syndrome (PHS) is a rare and potentially fatal complication of Parkinson disease (PD) characterized by a neuroleptic malignant-like syndrome due to abrupt discontinuation of antiparkinsonian medications. CASE REPORT: A 79-year-old woman with late-stage PD presented at the hospital with neuropsychiatric and uncontrolled parkinsonian motor symptoms. Soon after the abrupt discontinuation of amantadine, the patient suddenly presented with global rigidity, global unresponsiveness, diaphoresis, tachycardia, recurrent hyperpyrexia, and a mildly elevated creatine kinase, which lead to the diagnosis of PHS. Amantadine was then reinitiated and her symptoms resolved within 10 days. CONCLUSIONS: Amantadine is an antiparkinsonian medication scarcely associated with PHS. The few reported cases are further summarized and discussed in this article. This case highlights the importance of early recognition of PHS, which may be caused by changes in other antiparkinson agents such as amantadine, and the need to slowly titrate such agents.