Amantadine withdrawal in a patient with spinocerebellar ataxia

Abstract

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.

Background

Reconciliation of home medications affects the safety of all admitted patients. This report describes a severe medication withdrawal event that led to a prolonged hospitalisation with multiple transfers, invasive interventions and extensive diagnostic studies. Earlier recognition of the potential for medication withdrawal and quickly establishing alternative medication administration routes can help prevent such complications.

Spinocerebellar ataxia (SCA) is an autosomal dominant disease that typically presents in middle age with over 40 identified subtypes. Each SCA type has its distinguishing feature, but all SCA types present with varying symptoms of cerebellar degeneration, upper motor neuron dysfunction and multisystem atrophy.^{1 2} The symptoms generally worsen over 10 to 20 years, affecting the individual’s lifespan.

Our patient had SCA type 2 (SCA 2), which is typically distinguished by areflexia and slow saccadic eye movements or ophthalmoparesis.³

Investigational gene therapies for SCA have been explored, but treatment is largely supportive. Amantadine hydrochloride, often prescribed for conditions like Parkinson’s disease, also has been used for supportive therapy of SCA.⁴ Though its exact mechanism of action pertaining to SCA is unknown, amantadine has been shown to weakly antagonise N-methyl-D-aspartate receptors and increase dopaminergic transmission.⁵

Case presentation

A man in his early 60s with SCA 2 on supportive therapy with high-dose amantadine (400 mg daily) and riluzole (100 mg daily, off-label use) presented to the emergency department with acute odynophagia and dysphagia after taking his amantadine pills at home. After an initial otorhinolaryngology evaluation, the patient was admitted to the medical intensive care unit for close airway monitoring.

On examination, he was afebrile, tachycardic to 110 beats per minute, normotensive at 124/86 mm Hg, saturating at 95% on room air. He had a hoarse voice, but he was fully alert and oriented; lungs were clear to auscultation. He was otherwise at his neurologic baseline with severe ataxia, dysarthric speech, bilateral dysmetria and dysdiadochokinesia and fixed rightward gaze.

His home oral medications were held on admission. Initially, modified barium swallow study demonstrated dysphagia with all solid consistencies. Nasogastric tube insertion was attempted but discontinued due to patient intolerance. He was consented for percutaneous gastric tube placement, initially scheduled for hospital day 5.

Between hospital day 4 and 5, the patient became febrile to 38.5°C, tachycardic to 130 beats per minute with acute hypoxic respiratory failure requiring 2 L nasal cannula. He was awake but not answering any questions or consistently following commands. He was noted to have mild rigidity in bilateral upper extremity and lower extremities as well as bilateral extremity tremors with movement. Fever and tachycardia persisted through hospital day 13, and he eventually became comatose. Thus, extensive further diagnostic investigation was pursued.

Investigations

Initial investigation began with serial urine, blood and sputum bacterial cultures to evaluate for infection, which did not show any growth. CT pulmonary angiogram was performed on hospital day 5 and hospital day 11 given worsening hypoxia. Neither scan showed evidence of pulmonary emboli but rather a worsening right lower lobe lung consolidation. Given his progression from hypoactive delirium to a coma, head CT and MRI were obtained, which showed severe cerebellar degeneration consistent with SCA 2 but did not show any evidence of acute intracranial pathology (figure 1). Lumbar puncture was performed, which showed normal glucose and protein levels, and cerebral spinal fluid PCR did not detect any organisms and had 0 nucleated cell count. Electroencephalogram did not capture clinical or electrographic seizures. All other serologic metabolic tests were within normal limits.

Figure 1.

MRI brain sagittal view of T1 spoiled gradient recalled echo demonstrates profoundly atrophied cerebellum (*) but did not demonstrate any evidence of stroke.

Differential diagnosis

Given the fever, tachycardia and increasing oxygen requirement, an acute process such as pulmonary embolism was considered, but no pulmonary artery filling defect was detected radiographically. As the patient was at high aspiration risk, sepsis secondary to aspiration pneumonia was supported by the right lung consolidations seen in the CT images. However, the patient’s clinical condition failed to improve with appropriate antibiotic treatment, and there were no other evident sources of infection.

The degree and rapidity of his decline in mental status were unlikely to be directly caused by SCA 2, which is a slow, degenerative process. However, he had severe progression of SCA 2 at baseline, which likely lowered his functional reserve. Given the prolonged hospitalisation, hypoactive delirium was considered. It was thought that due to the patient’s poor functional reserve, provoking factors like potential delirium might cause more significant mental status changes. However, delirium secondary to aspiration pneumonia was not believed to be an adequate explanation for the severity of all the patient’s neurological changes based on the clinical judgement of the providers at the time. Furthermore, an acute process like stroke was ruled out by head imaging as shown in figure 1. Subclinical seizure was also considered, but no epileptiform activity was detected.

None of the differential diagnoses above would explain the mild rigidity noted on patient’s extremities associated with fever, tachycardia and encephalopathy. Neuroleptic malignant syndrome (NMS) was also considered, but on review of home medications, social history and urine toxicology, no agents were identified that might have caused NMS. Therefore, amantadine withdrawal syndrome complicated by aspiration pneumonia was ultimately determined to be the aetiology of his acute decompensation.

Treatment

Treatment included a prolonged course of antibiotics. A third-generation cephalosporin was started on hospital day 5 . The regimen was broadened to a combination of glycopeptide and carbapenem antibiotics on hospital day 12 when chest imaging showed worsening consolidation, accompanied by persistent fever, tachycardia and worsened mental status. In addition, due to the patient’s inability to protect his airway and increasing oxygen requirements, he was intubated and mechanically ventilated by hospital day 12. Notably, his home amantadine dose of 400 mg daily was resumed via orogastric tube on hospital day 12 (figure 2). The antibiotics were then narrowed and discontinued by hospital day 16 with significant improvement in the patient’s clinical status detailed below. As riluzole toxicity can cause depressed mental status and riluzole withdrawal has not been described, only amantadine was resumed.⁶

Figure 2.

Timeline of the patient’s hospital course outlines the acute changes in physical exam between hospital day (HD) 4 and 5. Of note, amantadine was held starting HD 1 after a modified barium swallow study (MBSS). Amantadine was resumed on HD 12, which led to significant improvement in physical exam starting HD 13 .

Outcome and follow-up

Within 1 day of resuming amantadine on hospital day 12, the patient showed significant improvement. He defervesced and his heart rate normalised. Although he was minimally sedated while intubated, he was able to open his eyes, track to vocal stimuli and intermittently follow simple commands. His limb rigidity resolved. He was noted to have new left greater than right wrist myoclonic-like jerks. He was extubated 2 days later, at which point he was reliably following simple commands and moving all four extremities.

Following multiple family discussions, the patient underwent tracheostomy tube and percutaneous endoscopic gastrostomy tube placement. By hospital day 30, the patient was discharged to an acute rehabilitation facility. He had severely dysarthric speech but was now able to state his name. He had normal tone in all extremities and was lifting them antigravity. He also had improvement in the mild intermittent, arrhythmic, low-frequency, low-amplitude myoclonic movements involving his bilateral wrists. He was discharged on a reduced dose of amantadine 300 mg daily.

At a neurology televisit 1 month after hospital discharge, the patient’s family reported that he had been hospitalised multiple times at a different hospital due to various infections. He was still receiving amantadine 300 mg daily via percutaneous endoscopic gastrostomy (PEG) tube. A few weeks later, his family shared that the patient had died at the other hospital, where he was being treated for a complicated urinary tract infection.

Discussion

First described in 1987, amantadine withdrawal syndrome (AWS) is a potentially fatal medication-related adverse event. Risk factors include advanced age, prolonged use of amantadine and underlying dementia.⁷ Most prior reports involved patients with Parkinson’s disease with or without cognitive impairment.^{5 7–13} Similar to NMS, AWS presents with fever, extrapyramidal symptoms, delirium and hallucinations. Symptoms begin at 1–3 days after abrupt disruption of amantadine, and the degree of severity may vary. It typically resolves within days of restarting amantadine, though Fryml et al describe a case of AWS that lasted for weeks, and some patients may have permanent neurologic sequelae.¹¹ In addition, withdrawal of other dopaminergic medications commonly used for the treatment of Parkinson’s disease has been described as Parkinsonism-hyperpyrexia syndrome, which presents like NMS.¹⁴

The exact mechanism of AWS is not well understood, but sudden discontinuation of dopaminergic agents like amantadine likely depletes central dopamine level abruptly, causing temperature dysregulation and motor symptoms similar to that of Parkinsonism.⁵ This hypothesis would correlate with postulated mechanism for NMS caused by central dopaminergic blockage or dopamine depletion.¹⁵ Miyasaki et al also hypothesised that the delirium component may be related to the glutamatergic system.¹⁰ However, further investigation is still needed to understand the exact pathophysiology of AWS.

To our knowledge, there have been only two prior reports of AWS in patients who do not have Parkinson’s disease.^{7 12} Murray et al described a case of patient with SCA who presented with amantadine toxicity first with agitation and hallucination and then with hypoactive delirium consistent with AWS.⁷ The patient had a full neurologic recovery after resuming amantadine. Our case also demonstrated characteristic features of AWS in a patient with SCA and recovery after reintroduction of amantadine. Unlike most of the previous case reports, he did not make full recovery from hypoactive delirium and had new persistent motor symptoms of myoclonic-like jerks on his wrists. We suspect that the lack of full recovery from delirium may be partially explained by the patient’s low functional reserve prior to admission. It is unclear what led to the persistent motor symptoms. Therefore, our case is unique in describing AWS in a patient with advanced SCA 2 that led to significant morbidity and persistent neurologic sequelae.

Multiple factors contributed to the inpatient discontinuation of amantadine, including dysphagia secondary to progression of SCA 2, patient intolerance to nasogastric tube, delay in PEG tube placement and lack of intravenous formulation of amantadine outside of preliminary clinical trials.¹⁶ However, the biggest contributor was the lack of awareness of AWS and early consideration of medication discontinuation in the differential diagnosis of fever, rigidity and encephalopathy. Our case highlights the importance of slowly tapering dopaminergic medications to avoid adverse consequences of acute discontinuation and diagnostic confusion. In addition, if a dopaminergic medication needs to be held before a procedure or for other reasons, it should be reinitiated as soon as possible, and the patient should be closely monitored for signs and symptoms resembling NMS. This will help prevent significant morbidity and death associated with this condition. Further investigation is needed in understanding the pathophysiology of AWS and implementing a quality improvement system for medication reconciliation of high-risk medications for vulnerable patient populations.

Learning points.

• Our case of amantadine withdrawal syndrome (AWS) highlights the importance of careful medication reconciliation at admission to avoid complications, extensive workup and invasive procedures.

• Always consider potential adverse effects with not only medication initiation but also discontinuation.

• Recognise toxicity and withdrawal effects of dopaminergic medications and slowly taper if they need to be discontinued.

• If a dopaminergic medication needs to be held temporarily, then reinitiate it as soon as possible and closely monitor for signs and symptoms resembling neuroleptic malignant syndrome.

Ethics statements

Patient consent for publication

Consent obtained from next of kin.