Levodopa-Induced Dyskinesia in Parkinson's disease: Amantadine to Sheath the Double-edged Sword

Parkinson's disease (PD) is a movement disorder and the second most common neurodegenerative disorder in adults over the age of 60 years (1). India is home to an estimated 771 000(95% UI 635 000–919 000)persons living with PD as estimated in 2019 (2). The disease is almost twice as common in men as in women in most populations (3).PD contributes to significant morbidity and healthcare burden (4).

Degeneration of dopaminergic cells in substantia nigra of midbrain and the resulting loss of dopamine and its related neurotransmitter, norepinephrine, leads to the development of motor symptoms such as tremor (trembling I, hands, limbs, head, and jaw), rigidity (stiffness of the trunk and limbs), bradykinesia (slowed movements) and postural instability (impaired balance) alongside non-motor symptoms which include sleep disorders (frequent waking, day time somnolence), autonomic disturbances(orthostatic hypotension, urogenital dysfunction, and constipation), cognitive impairment, mood disorders, and pain.

The medical management of PD patients is challenging, as choices of drugs are limited and levodopa is the mainstay of treatment. Levodopa-induced dyskinesia (LID) is a commonly seen complication in Parkinson's disease (PD) patients treated with levodopa. This side effect is usually encountered after a long duration of treatment, but occasionally, this may be seen even after a few days or months of treatment. The present review aims to present a framework for physicians to tackle this troublesome situation in their clinical practice. Following a brief discussion of the characteristics of LID's, we explore the role of amantadine as an effective treatment strategy in this scenario.

When Therapy Becomes The Problem

Levodopa, the most effective Parkinson's disease medication, is a dopamine precursor that is converted to dopamine in the brain thus acting as a dopamine replacement agent. When levodopa therapy is first instituted, patients with PD typically experience a smooth and prolonged response. However, with long-term use and advancing disease, the effect of levodopa begins to wear off more rapidly. Motor complications of levodopa, in the form of dyskinesia, occur in 30 to 40 percent of patients during the first five years of use and nearly 60 percent or more by 10 years (5). Younger patients are more susceptible earlier in the disease course.

a) Identifying LID's in PD Levodopa-induced dyskinesia refers to abnormal, involuntary movements brought on by chronic use of levodopa. The term encompasses a variety of involuntary movements or postures, from involuntary rapid jerking and twisting, to slow and extended muscle spasms. The severity can range from bothersome to incapacitating.LID can have different clinical phenomenology, but broadly speaking, they are of three types, emerging at various times concerning levodopa dosing: peak-dose dyskinesia, wearing-off (or off-period) dyskinesia, and diphasic dyskinesia, of which peak-dose dyskinesia is the most common and diphasic dyskinesia is least common (6). A patient may have one type of dyskinesia or a combination of two or three types. 

Peak-dose dyskinesia appears after a dose of levodopa when the patient is in the "on" period and is often choreiform in nature.

"Wearing off" dystonia manifest as abnormal spasm of body parts, most commonly affecting foot or leg, emerging during "off" periods. These are particularly common first thing in the morning, before a dose of levodopa.

Diphasic dyskinesia leads to two separate periods of involuntary movement; the first occurring 10-15 min after a levodopa dose preceding an improvement in parkinsonian features for a few hours, followed by recurrence of dyskinesia when levodopa levels begin to decline (6).

Patients should be asked at each visit whether and when they sense jerky movements during a dosing cycle because some patients may confuse dyskinesia and tremor. The main difference is that tremor is rhythmic in its movement, particularly around one joint. Dyskinesia is not only involuntary, it's also usually disordered. Tremor associated with Parkinson's is usually suppressible with movement and activity, while dyskinesia isn't.

b) Breaking down the pathophysiology of LID LIDs result from the changes within the brain circuitry provoked by nigrostriatal degeneration occurring in Parkinson's disease. Typically, dyskinesia is temporally related to rise and fall in plasma levodopa levels. As the disease advances, the same dosage of levodopa required to relieve parkinsonian symptoms may also cause dyskinesia. Several other mechanisms including glutamatergic receptors may also play an important role in the development of LID.

Treatment Options

a) When is treatment required Not all dyskinesia requires treatment. Many patients are unaware of the presence of dyskinetic movements since they prefer being "on" with dyskinesia to being "off." However, severe dyskinesia may take the form of large-amplitude, ballistic movements that interfere with function and become very disturbing to patients and their caregivers. First-line treatment strategies include lowering the dose of levodopa and/or adjunctive dopaminergic therapies, when possible, and the use of medication to help suppress dyskinesia, such as amantadine (7). Surgical options are also being underway with DBS.

b) Role of Amantadine in tackling treatment troubles The discovery of the antiparkinsonian effects of amantadine was serendipitous. The utilization of amantadine in Parkinson's disease became obvious after Schwab and colleagues (8) saw that the symptoms of a Parkinson's patient got better when he took amantadine for influenza and deteriorated after drug discontinuation. This prompted the first clinical trials of amantadine for Parkinson's disease in 1968.

Even though amantadine has now been used for over 50 years, its mechanisms of action are yet to be understood completely. It has a unique combination of antiparkinsonian and anti-dyskinetic properties— two impacts generally viewed as contradictory. Its effects on dopaminergic transmission may explain it antiparkinsonian efficacy, while anti-glutamatergic action is postulated to underlie anti-dyskinetic effects.

Amantadine remains the only drug with proven efficacy in reducing levodopa-induced dyskinesias without worsening of parkinsonism in Parkinson's disease.

A placebo-controlled trial (9) reported a 60% reduction in levodopa-induced dyskinesia for amantadine, with a clear dose-response association, and maintained efficacy up to 1 year (10). Two randomized trials, in which patients with Parkinson's disease receiving chronic immediate-release amantadine therapy was switched to placebo or maintained on immediate-release amantadine, have shown that the drug can be effective over at least several years (11,12).

In practice, it is administered as two or three daily doses of 100 mg each7. It usually does not completely suppress levodopa-induced dyskinesias. According to a meta-analysis (13), the most frequent adverse events of amantadine are visual hallucinations, confusion, blurred vision, leg edema, dry mouth, and constipation—all of which are In clinical practice, two types of adverse events most often lead to amantadine discontinuation: mental status changes (such as confusion or visual hallucinations) and agitational states, which are particularly common in older and cognitively impaired patients. Amantadine should be avoided in patients with a history of drug-induced psychosis and there should be compelling reasons before administering it to cognitively impaired patients without the possibility of close monitoring. There have been rare reports of suicidal attempts in association with amantadine; patients should thus be monitored for mood disorders.

Abrupt withdrawal of amantadine can cause acute worsening of parkinsonism or levodopa-induced dyskinesias, as well as agitation and delirium, hence discontinuation requires a step-wise down-titration.

Conclusion

Dyskinesias complicating Levodopa treatment in Parkinson's disease is a common clinical scenario that needs to be addressed by physicians. Amantadine has stood the test of time for over half a century and its place is firmly established as an anti-dyskinetic medication in levodopa-treated Parkinson's disease.

REFERENCES

1.De Lau LM, Monique MB Breteler Epidemiology of Parkinson's disease. The Lancet Neurology 2006;5(6);525-35

2. The burden of neurological disorders across the states of India: the Global Burden of Disease Study 1990–2019. India State-Level Disease Burden Initiative Neurological Disorders Collaborators.Lancet Glob Health 2021;9: e1129–44Issue 8

3. Van Den Eeden SK, Tanner CM, Bernstein AL, Fross RD, Leimpeter A,Bloch D.A et al. Incidence of Parkinson's disease: Variation by age, gender, and race/ethnicity. Am J Epidemiol 2003;157:1015-22.

4. Lubomski M, Rushworth RL, Tisch S. Hospitalisation and comorbidities in Parkinson's disease: a large Australian retrospective study. J Neurol Neurosurg Psychiatry 2015;86:324-330.

5. Turcano P, Mielke MM, Bower JH,Parisi J.E,Gregory J.K, Ahlkog J.E et al. Levodopa-induced dyskinesia in Parkinson disease: A population-based cohort study. Neurology 2018; 91:e2238.

6. Sanjay Pandey, PrachayaSrivanitchapoom. Levodopa-induced Dyskinesia: Clinical Features, Pathophysiology, and Medical Management. Ann Indian Acad Neurol. 2017 Jul-Sep; 20(3): 190–198

7. Olivier Rascol, MargheritaFabbri, Werner Poewe. Amantadine in the treatment of Parkinson's disease and other movement disorders.Lancet Neurol2021; 20: 1048–56

8. Schwab RS, England AC Jr, Poskanzer DC, Young RR. Amantadine in the treatment of Parkinson's disease.JAMA 1969; 208: 1168–70.

9. VerhagenMetman L, Del Dotto P, van den Munckhof P, Fang J, Mouradian MM, Chase TN. Amantadine as a treatment for dyskinesias and motor fluctuations in Parkinson's disease. Neurology 1998; 50: 1323–26.

10. Metman LV, Del Dotto P, LePoole K, Konitsiotis S, Fang J, Chase TN. Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study. Arch Neurol1999; 56: 1383–86.

11. Wolf, E., Seppi, K., Katzenschlager, R., Hochschorner, G., Ransmayr, G., Schwingenschuh, P., Ott, E., Kloiber, et al. Long-term antidyskinetic efficacy of amantadine in Parkinson's disease. MovDisord2010; 25: 1357–63.

12. Ory-Magne, F., Corvol, J. C., Azulay, J. P., Bonnet, A. M., Brefel-Courbon, C., Damier, P., Dellapina, E., Withdrawing amantadine in dyskinetic patients with Parkinson disease: the AMANDYSK trial. Neurology 2014; 82: 300–07 13. Kong M, Ba M, Ren C, Yu L, Dong S, Yu G, Liang H. An updated meta-analysis of amantadine for treating dyskinesia in Parkinson's disease.Oncotarget2017; 8: 57316–26.   

13. Kong M, Ba M, Ren C, Yu L, Dong S, Yu G, Liang H. An updated meta-analysis of amantadine for treating dyskinesia in Parkinson's disease.Oncotarget2017; 8: 57316–26.