What could be the reason for a poor Glasgow Coma Scale (GCS) score in a bed-bound patient with parkinsonism, fever, and elevated C-reactive protein (CRP), despite negative cultures, after withdrawal of Amantadine (amantadine) and Trihexiphenidyl (trihexyphenidyl)?

Likely Causes of Poor GCS in This Clinical Scenario

The most likely cause of this patient's poor GCS of 6 is neuroleptic malignant syndrome (NMS) or parkinsonism-hyperpyrexia syndrome triggered by abrupt withdrawal of amantadine and trihexyphenidyl, complicated by an underlying urinary tract infection. 1

Primary Consideration: Drug Withdrawal Syndrome

Neuroleptic Malignant Syndrome (NMS) / Parkinsonism-Hyperpyrexia Syndrome

Abrupt discontinuation of amantadine in Parkinson's disease patients can precipitate a life-threatening syndrome characterized by fever, altered consciousness, and autonomic dysfunction. 1

• The FDA label for amantadine explicitly warns that "abrupt discontinuation may also precipitate delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression and slurred speech" 1
• Sporadic cases of NMS have been reported specifically in association with dose reduction or withdrawal of amantadine therapy 1
• NMS is characterized by fever or hyperthermia, altered consciousness, muscle rigidity, and autonomic dysfunction—all potentially present in this patient 1
• The syndrome typically manifests with decreased GCS, intermittent fever spikes (as seen in this case), and can occur even when cultures are negative 1

Trihexyphenidyl Withdrawal

• The FDA label for trihexyphenidyl warns that "abrupt withdrawal of treatment for parkinsonism may result in acute exacerbation of parkinsonism symptoms" and "may result in neuroleptic malignant syndrome (NMS)" 2
• Simultaneous withdrawal of both medications compounds the risk 1, 2

Contributing Factor: Urinary Tract Infection

UTI as a Confounding Element

• The presence of 50 pus cells in urine and elevated CRP (10) suggests an active urinary tract infection 3
• In bed-bound, elderly patients with parkinsonism, UTI commonly causes delirium and decreased consciousness, but typically not to GCS 6 in isolation 3
• The negative cultures may reflect early sampling, inadequate culture technique, or partially treated infection 3

Differential Diagnosis Considerations

What Has Been Ruled Out

• MRI Brain normal: excludes acute stroke, intracranial hemorrhage, or mass lesion 3
• CSF normal: excludes bacterial meningitis or encephalitis (though viral encephalitis with normal early CSF remains possible) 3
• Electrolytes normal: excludes metabolic encephalopathy from hyponatremia, hypernatremia, or other electrolyte disturbances 3

Remaining Possibilities Beyond Drug Withdrawal

• Sepsis-associated encephalopathy: CRP of 10 with pyuria suggests systemic inflammation, which can cause profound encephalopathy in vulnerable patients 3
• Non-convulsive status epilepticus: not excluded without EEG, though less likely given the clinical context 3
• Toxic-metabolic encephalopathy: from accumulated uremic toxins or medication effects in the setting of chronic immobility 3

Critical Management Approach

Immediate Actions Required

The emergency team's decision to stop amantadine and trihexyphenidyl was likely the precipitating factor and should be reversed immediately. 1

• Reinstitute amantadine and trihexyphenidyl at previous doses to reverse the withdrawal syndrome 1, 2
• Research evidence demonstrates that in two patients who developed severe hyperthermia after amantadine withdrawal, reintroduction of amantadine led to resolution of hyperthermia within four days 4
• The FDA label emphasizes that "patients should be observed carefully when the dosage of amantadine hydrochloride is reduced abruptly or discontinued" 1

Supportive Management

• Intensive symptomatic treatment and medical monitoring as recommended for NMS management 1
• Treat the urinary tract infection aggressively with appropriate antibiotics based on local resistance patterns 3
• Consider dopamine agonists such as bromocriptine and muscle relaxants such as dantrolene, though their effectiveness in NMS has not been demonstrated in controlled studies 1
• Maintain adequate hydration and monitor for rhabdomyolysis (check CPK, myoglobin) 1

Diagnostic Workup to Complete

• Obtain creatine phosphokinase (CPK) level: elevated CPK supports NMS diagnosis 1
• Check for myoglobinuria and serum myoglobin: additional markers of NMS 1
• Perform EEG: to exclude non-convulsive status epilepticus 3
• Repeat blood cultures: if fever persists despite antibiotic therapy 3

Critical Pitfalls to Avoid

Common Errors in This Scenario

• Never abruptly discontinue antiparkinsonian medications in patients with Parkinson's disease, as this can precipitate parkinsonian crisis or NMS 1, 2
• Do not attribute all symptoms to infection alone when drug withdrawal is temporally related 1
• Avoid administering long-acting sedatives or paralytics before the clinical picture is clear, as this masks neurological deterioration 5
• Do not make irreversible decisions before 72 hours unless there is clear clinical deterioration or brain death criteria are met 5

Prognostic Considerations

• The GCS of 6 at day 2 is concerning, but neurological prognosis in drug-induced encephalopathy differs fundamentally from structural brain injury 6
• Serial GCS assessments provide substantially more valuable clinical information than a single determination 5
• Failure to show neurological improvement within 72 hours after reinstituting medications would be a negative prognostic factor requiring reassessment 5

Timeline and Expected Recovery

• If this is primarily drug withdrawal syndrome, improvement should begin within 24-96 hours of reinstituting medications 4
• The research evidence shows that hyperthermia from amantadine withdrawal resolved within 4 days of reintroduction 4
• Continue close monitoring with serial GCS assessments every 1-2 hours initially 5, 3