Case Reports Describing Amantadine Intoxication in a Rehabilitation Hospital

ABSTRACT

Background: Amantadine is widely used to improve reduced spontaneity and prevent aspiration pneumonia. There are few reports on cases of amantadine intoxication in the field of rehabilitation. Cases: Case 1 involved an 83-year-old man with a history of a lacunar infarction who was transferred to our rehabilitation hospital after a left femoral neck fracture and a left upper arm fracture. He had mild renal dysfunction. Although he was started on oral amantadine 150 mg/dayto reverse a decline in spontaneity, he could not begin rehabilitation therapy because of hallucinations and myoclonus. Furthermore, he developed aspiration pneumonia as a result of a consciousness disorder. After stopping amantadine, his toxic symptoms disappeared completely. Case 2 involved a 53-year-old man who was transferred to our hospital for rehabilitation after a brain contusion. He was started on oral amantadine 100 mg/day to reverse a decline in spontaneity. After amantadine was increased to 150 mg/day, myoclonus and hallucinations developed. At that time, his renal function was mildly impaired. The concentration of amantadine in his blood serum was found to be 4783 ng/dl. After amantadine was stopped, his spontaneity decline recurred. After restarting amantadine at 50 mg/day, his toxic symptoms did not reappear, and the decline in his spontaneity improved. Discussion: Amantadine is a renally excreted drug that may cause toxic symptoms as a result of decreased renal function. It is necessary to monitor renal function and toxic symptoms when amantadine is administered in rehabilitation hospitals.

INTRODUCTION

Amantadine is an antiviral agent against the influenza A virus and it is also widely used as a therapy for Parkinson’s syndrome and as a cognitive enhancer for patients with head trauma or cerebrovascular disease. It is also useful for the prevention of aspiration pneumonia.¹⁾

In rehabilitation hospitals, amantadine is widely used to improve reduced spontaneity in patients with cerebrovascular disease or head injuries and for the prevention of aspiration pneumonia. However, there are few reports on the symptoms of amantadine intoxication in the field of rehabilitation. The authors here describe two cases of amantadine intoxication as a result of impaired renal function in inpatients in a rehabilitation hospital.

CASES

Case 1

An 83-year-old man was transported to an acute hospital because of traffic injuries and was diagnosed with a left femoral neck fracture and a left humeral fracture. His medical history included a lacunar infarction, atrial fibrillation, and diabetes. He developed aspiration pneumonia after hospitalization and received antibiotic treatment (Table 1). Nasogastric tube nutrition was started. On day 17, he received an artificial head replacement for the left femoral neck fracture, but the left humeral fracture was treated conservatively. On day 38, the patient was transferred to the rehabilitation ward. He was fed by a nasogastric tube. He did not have limb paralysis and could slowly walk a short distance with a walker. However, he lacked spontaneity and lacked facial expression. Mild renal dysfunction was noted with a serum creatinine level of 1.12 mg/dL, a blood urea nitrogen level of 30.7 mg/dL, and an estimated glomerular filtration rate of 48 ml/min/1.73 m². When the patient was transferred to our hospital, he was being treated with sotalol (40 mg orally), rivaroxaban (15 mg orally), azosemide (60 mg orally), spironolactone (25 mg orally), repaglinide (0.5 mg orally), silodosin (8 mg orally), acetaminophen (1200 mg orally), and lansoprazole (15 mg orally)/day. On day 39, a videofluoroscopic swallowing examination was performed, and the patient’s ability to swallow was estimated to be level 7 (easy-to-swallow food is orally ingested in three meals, and no alternative nutrition is given) on the Food Intake LEVEL Scale (FILS).²⁾ He started oral intake. The patient was reluctant to participate in rehabilitation from the time of admission and was suspected to have a tendency to depression. Consequently, an antidepressant was prescribed. On day 90, he was initially treated with oral sulpiride 150 mg/day, but no improvement was seen. On day 95, the antidepressant was changed from sulpiride to escitalopram 10 mg/day. However, the symptoms persisted. On day 103, the patient developed aspiration pneumonia, and antibiotic treatment was administered. He was again fed via a nasogastric tube. At that time, his ability to swallow was estimated to be level 4 (easy-to-swallow food less than the quantity of a meal [enjoyment level] is ingested orally) on the FILS. On day 104, because of the history of lacunar infarction (Fig. 1), oral administration of amantadine 150 mg/day was started to improve his decline in spontaneity. After that, the patient developed disturbance of consciousness, myoclonic jerks in his limbs, and hallucinations, and he was unable to undergo rehabilitation therapy. On day 108, we changed the oral antidepressant from escitalopram to duloxetine 20 mg/day. When the patient restarted oral intake on day 109, his ability to swallow was estimated to be level 5 (easy-to-swallow food is orally ingested in one to two meals, but alternative nutrition is also given) on the FILS. Amantadine intoxication was suspected, so the amantadine was reduced on day 125 and discontinued on day 129. At that time, aspiration pneumonia recurred, and antibiotic therapy was administered. The myoclonus and hallucinations gradually improved, and he was able to start rehabilitation. His swallowing function improved to FILS level 8 (the patient eats three meals by excluding food that is particularly difficult to swallow). He became stable walking with a walker, and he was discharged home on day 194. Informed consent for the publication of this case report was obtained from the patient.

Fig. 1.

T2-weighted image showing lacunar infarction.

Case 2

A 53-year-old man presented with disturbance of consciousness at home and was taken to the emergency room. Initial computed tomography (CT) of the head revealed a brain injury (Fig. 2). His medical history revealed alcoholism. After craniotomy for removal of hematoma and intensive care, he was transferred on day 31 to the convalescent department of our hospital for rehabilitation after brain injury (Table 2). The patient’s renal function was normal, with a blood urea nitrogen level of 11.7 mg/dl, a creatinine level of 0.65 mg/dl, and an estimated glomerular filtration rate of 99 ml/min/1.73 m². The patient exhibited truncal ataxia and needed assistance to walk. He also showed evidence of declining spontaneity. The amount of oral intake was also insufficient, and nutritional supplementation by tube feeding was necessary. At that time, the patient’s ability to swallow was estimated to be level 5 on the FILS. On day 49, he was started on oral amantadine 100 mg/day to ameliorate the decline in spontaneity. On day 56, the dose was increased to 150 mg/day. His spontaneity decline improved, and oral intake was adequate. His swallowing function improved to FILS level 8. However, the patient developed hallucinations and myoclonic jerks in the limbs, and his oral intake was unstable. On day 87, the concentration of amantadine in the blood was 4783 ng/dl. At that time, his kidney function was mildly declining, with a serum creatinine level of 1.09 mg/dL and an estimated glomerular filtration rate of 56 ml/min/1.73 m². On day 89, the patient was treated with intravenous fluids because his oral dietary intake was insufficient. On day 93, oral amantadine was stopped, and the decline in spontaneity recurred. On day 101, he was restarted on a small amount of amantadine, 50 mg/day. The patient’s toxic symptoms did not recur, and the decline in spontaneity improved. The patient was discharged home on day 173. Informed consent for the publication of this case report was obtained from the patient.

Fig. 2.

Initial computed tomography of the head demonstrating traumatic hematoma in the right cerebellar hemisphere (left) and traumatic subarachnoid hemorrhage in the frontal lobe (right).

Table 1. Clinical course and treatment timeline for case 1

Day	1	4	17	38	39	45		103	104		109	129		138	194
Clinical course	Left femoral neck fracture and left humeral fracture. Hospital admission	Aspiration pneumonia		Transferred			Gradual decline in spontaneity	Aspiration pneumonia		Myoclonus and hallucinations gradually appeared		Aspiration pneumonia	Myoclonus and hallucinations gradually improved		Discharged
Location	Acute hospital			Rehabilitation hospital											Home
eGFR (ml/min/1.73 m2)			54	48							54	52
FILS		2	2	2	7	8		4	4	4	5	5	5	8	8
Treatment	Physical, occupational, and speech therapy started	Antibiotic treatment. Tube feeding started	Artificial head replacement of a left femoral neck fracture	Physical, occupational, and speech therapy continued	Tube feeding stopped			Antibiotic treatment. Tube feeding restarted	Amantadine 150 mg/day started			Amantadine stopped. Antibiotic treatment started		Tube feeding stopped
Examination	X-ray, CT				VF			Chest CT				Chest X-ray

eGFR, estimated glomerular filtration rate; FILS, Food Intake LEVEL Scale²⁾; VF, videofluoroscopy examination of swallowing

Table 2. Clinical course and treatment timeline for case 2

Day	1	2		32		49	55	60		87	89	93		102		173
Clinical course	Brain injury. Hospital addmission			Transferred	Decline in spontaneity				Myoclonus and hallucinations gradually appeared	Concentration of amantadine in the blood 4783 ng/dl			Myoclonus and hallucinations gradually improved. Decline in spontaneity reappeared		Decline in spontaneity gradually improved	Discharged
Location	Acute hospital			Rehabilitation hospital												Home
eGFR (ml/min/1.73 m2)				99				68		56
FILS			Improved from 2 to 5	5	5	8	8	8	8	9	6	9	9	9	9	9
Treatment	Intensive care	Craniotomy for removal of hematoma	Physical, occupational, and speech therapy started	Physical, occupational, and speech therapy continued		Amantadine 100 mg/day Started	Amantadine 150 mg/day increased				Transfusion	Amantadine reduced and stopped		Amantadine 50 mg/day restarted
Examination	CT									Blood sampling

eGFR, estimated glomerular filtration rate; FILS, Food Intake LEVEL Scale²⁾

DISCUSSION

Amantadine is often used in rehabilitation hospitals as a therapy for parkinsonism, as a cognitive enhancer, and for the prevention of aspiration pneumonia. However, in the current two cases, amantadine unexpectedly inhibited rehabilitation.

Various side effects of amantadine have been described in previous cases reports. Amantadine overdose mainly affects the cardiovascular and central nervous systems.^3,4,5) Unexpected death as a result of amantadine intoxication has been reported.⁶⁾

In the current two cases, we started oral administration of amantadine to improve motivation for rehabilitation. However, quite the opposite occurred: myoclonus, hallucination, and disturbance of consciousness developed, and the patients became unable to undergo rehabilitation therapy. Furthermore, the patient in case 1 developed aspiration pneumonia as a result of a consciousness disorder caused by amantadine toxicity. The symptoms of amantadine intoxication may adversely affect deglutition disorders. Amantadine should be started at a low dose in patients with impaired renal function.

In case 1, escitalopram could also have been the cause of the patient’s myoclonus and mental symptoms,⁷⁾ because symptoms developed relatively shortly after starting amantadine. However, the symptoms persisted even after changing escitalopram to duloxetine, whereas, the symptoms gradually improved after discontinuing amantadine. Considering this clinical course, the cause of the symptoms was suspected to be amantadine.

In case 2, the patient’s amantadine blood concentration was as high as 4783 ng/dl. Neurotoxicity caused by amantadine has been reported at serum levels >1 µg/dl.³⁾ Amantadine is not actively metabolized in humans and is mainly excreted unchanged in the urine by glomerular filtration and tubular secretion (90% of the ingested dose). Thus, this drug tends to accumulate in patients with impaired renal function.⁸⁾ Amantadine-induced neurotoxicity may occur because of accumulation of the drug as a result of excessive dosing or decreased renal clearance.⁹⁾

In the current two cases, the symptoms of intoxication improved after the reduction or discontinuation of amantadine. There is no antidote for amantadine overdose. Conventional hemodialysis has little effect on amantadine intoxication because of the large distribution volumes, and even peritoneal dialysis can remove only a proportion of the drug.¹⁰⁾ Factors that cause a decrease in renal function include dehydration, infection, drugs, and obstructive urinary tract diseases. In case 2, the patient had normal kidney function at the time of admission, but his renal function declined after hospitalization. The cause of renal dysfunction could have been dehydration as a result of insufficient oral intake. Monitoring kidney function and attention to factors that can impair renal function are essential when administering amantadine.

In conclusion, we described two cases of amantadine administration resulting in toxicity. Amantadine is often used in rehabilitation hospitals, but its effects may result in the interruption of rehabilitation therapy. The authors recommend careful monitoring of renal function and toxic symptoms in patients treated with amantadine to ensure adequate rehabilitation therapy.

CONFLICTS OF INTEREST

The authors declare that there are no conflicts of interest.

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