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Amantadine is generally well tolerated. The most common idiosyncratic side effects include livedo reticularis and pedal edema. Livedo reticularis is a mottled bluish-red reticular skin discoloration, which blanches to pressure. It is observed in more than 5% of patients receiving amantadine. It is more common in women (30) and is usually predominant in the lower extremities. The appearance is nonspecific, and skin biopsies of the area are normal (31). Livedo reticularis usually appears after weeks of treatment and it can occur up to one year from initiation of therapy. The etiology of livedo reticularis is unclear, but is believed to be caused by abnormal widespread dilatation of dermal blood vessels due to depletion of catecholamines at the peripheral nerve terminals (32). The cosmetic appearance is usually far more apparent than any physical adverse effects. Pedal edema can also appear idiosyn-cratically, and is independent of either renal or cardiac failure. Its presence has generally been attributed to a redistribution of fluid and does not appear to represent excess fluid. Quinn et al. (33) have reported a few cases of congestive heart failure occurring in association with the use of amantadine, but this appears to be an exception to routine clinical use.

The presence of either livedo reticularis or pedal edema does not always necessitate discontinuation of amantadine. There is no specific treatment for the cosmetic discoloration associated with livedo reticularis. Symptoms are generally expected to resolve with discontinuation of the drug, but may take up to several weeks. Rarely, these conditions may be severe and associated with leg ulceration and peripheral neuropathy (34). A prudent combination of discontinuing the drug and providing appropriate referrals to exclude important secondary causes, such as a superimposed renal failure, cardiac failure, autoimmune or vasculitic livedo, and deep vein thrombosis, must be an important part of continued clinical follow-up for patients on amantadine.

Rimantadine is an alpha-methyl derivative of amantadine. An open-label trial showed the effectiveness of rimantadine in controlling motor symptoms in PD (35). A retrospective study of seven patients with moderate-to-severe PD revealed that rimantadine was an effective alternative to amantadine, in patients experiencing amantadine-induced peripheral side effects such as livedo reticularis and lower limb edema (36). Side effects did not develop on rimantadine and patients showed good clinical efficacy.

Amantadine-induced peripheral neuropathy has been rarely reported (37). It was hypothesized that amantadine transfers the blood supply to the peripheral nerves because of its effect on catecholamine storage (37).

Nonspecific symptoms, such as lightheadedness, insomnia, jitteriness, depression, and concentration difficulties, are potential side effects of amantadine (10). Amantadine also possesses mild anticholinergic properties, which contribute to side effects such as dry mouth, orthostatic hypotension, constipation, dyspepsia, and urinary retention. Therefore, reasonable care should be taken when administering amantadine in conjunction with anticholinergics (38). One report (8) noted cardiac arrhythmias with amantadine. Amantadine is not recommended during pregnancy, as it has more teratogenic potential than the other PD medications (39).

There are reports of ocular side effects, such as corneal lesions and edema, associated with the use of amantadine (40-42). Corneal side effects can occur within a few weeks to a few years after initiation of therapy and are generally reversible within a week of stopping the medication.

Acute toxicity presenting as delirium (18), seizure (43), and psychosis (12) has been reported. Abrupt withdrawal has been described to produce delirium (44), as well as neuroleptic malignant syndrome (45). In many of these cases, patients either had baseline cognitive deficits, psychiatric background, or excess amantadine use beyond clinical recommendations. In general, the cognitive side effects such as confusion and concentration difficulties are more common in those with underlying, pre-existing cognitive dysfunction. In advanced PD, amantadine may even carry comparable propensity for cognitive side effects to levodopa (46). As such, conservative use in the elderly and avoidance of use even in the mildly cognitively impaired patient is necessary.

Because of the renal predominant excretion of amantadine, patients with impaired kidney function carry a higher risk of toxicity. Dosing schedules have been developed for patients with poor renal function according to creatinine clearance (47). It is best to avoid the use of amantadine in patients with poor renal clearance. In the event of suspected toxicity, dialysis is not helpful in decreasing toxic levels, probably due to extensive tissue binding (48).

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