What are the differential diagnoses for an elderly male patient with a history of essential tremors, orthostatic hypotension, currently experiencing repeated falls, hyponatremia, and hypokalemia, and taking zonisamide (Anticonvulsant) 300mg/day?

Differential Diagnoses for Elderly Male with Falls, Hyponatremia, Hypokalemia, and Orthostatic Hypotension on Zonisamide

The most likely diagnosis is zonisamide-induced electrolyte disturbances causing falls, as zonisamide is a carbonic anhydrase inhibitor that can precipitate hyponatremia, hypokalemia, and worsen orthostatic hypotension in elderly patients with pre-existing autonomic dysfunction. 1

Top 10 Differential Diagnoses (Ranked by Likelihood)

1. Zonisamide-Induced Electrolyte Disturbances and Orthostatic Hypotension

• Zonisamide acts as a carbonic anhydrase inhibitor, which increases risk of metabolic acidosis and electrolyte abnormalities 1
• The drug can worsen pre-existing orthostatic hypotension through multiple mechanisms including volume depletion and altered autonomic compensation 2, 1
• Hyponatremia and hypokalemia directly increase fall risk (OR 1.751 and 2.209 respectively) 3
• Critical pitfall: Anticonvulsants are frequently overlooked as causes of orthostatic hypotension in elderly patients 4

2. Polypharmacy-Related Orthostatic Hypotension with Electrolyte Depletion

• Elderly patients on multiple medications face compounded risk, with effects exacerbated by age-related loss of peripheral autonomic tone 4
• The combination of zonisamide with any other medications (diuretics, antihypertensives, antipsychotics) creates synergistic hypotensive effects 4, 2
• Age-related reductions in thirst, sodium/water preservation, and baroreceptor response predispose to volume depletion 4, 2

3. Primary Aldosteronism

• Prevalence of 8-20% in resistant hypertension populations, commonly presents with hypokalemia and muscle weakness 4
• Can cause both hypertension (supine) and orthostatic hypotension simultaneously 4
• Screen with plasma aldosterone/renin ratio under standardized conditions after correcting hypokalemia 4
• Key feature: Spontaneous or diuretic-induced hypokalemia with muscle cramps strongly suggests this diagnosis 4, 5

4. Neurogenic Orthostatic Hypotension from Parkinson's Disease

• Essential tremor can be misdiagnosed; Parkinson's disease commonly presents with orthostatic hypotension and falls in elderly patients 6, 7
• Neurogenic orthostatic hypotension results from failure of cardiovascular sympathetic fibers to increase peripheral vascular resistance upon standing 2
• Diagnostic approach: Examine for bradykinesia, rigidity, postural instability beyond what essential tremor would cause 6, 8
• Orthostatic vital signs should be measured immediately in lying, sitting, and standing positions 6

5. Drug-Induced Parkinsonism with Autonomic Dysfunction

• Dopamine antagonists, antipsychotics, antihistamines can cause parkinsonism that mimics idiopathic disease 6
• These same medications precipitate syncope and orthostatic hypotension in elderly patients 4
• Requires comprehensive medication review and withdrawal of offending agents rather than dopaminergic therapy 6

6. Syndrome of Inappropriate Antidiuretic Hormone (SIADH) from Zonisamide

• Anticonvulsants are well-known causes of SIADH leading to hyponatremia 9
• Hyponatremia in elderly leads to cognitive impairment, falls, and fractures even when mild and chronic 9
• Correction of hyponatremia can improve cognitive performance and postural balance 9

7. Diuretic-Induced Electrolyte Depletion with Volume Depletion

• Diuretics are among the most common medications causing orthostatic hypotension in elderly patients 4, 2
• Severe volume depletion from excessive diuresis is a common reversible cause of orthostatic hypotension 2
• Beta-blockers, calcium antagonists, ACE inhibitors, and nitrates have more pronounced effects in elderly due to altered pharmacokinetics 2, 5

8. Autonomic Dysfunction from Diabetes Mellitus

• Diabetic autonomic neuropathy commonly causes neurogenic orthostatic hypotension 2, 7
• Patients with diabetes should be screened for orthostatic hypotension due to autonomic neuropathy risk 2
• Age-related autonomic dysfunction is compounded by diabetic neuropathy 2, 6

9. Hypothyroidism

• Prevalence <1% but presents with hyponatremia, muscle weakness, delayed reflexes, and cold intolerance 4
• Screen with thyroid-stimulating hormone and free thyroxine 4
• Can contribute to falls through multiple mechanisms including muscle weakness and cognitive slowing 4

10. Multifactorial Falls Syndrome in Elderly

• Annual incidence of falls in elderly is 30%, with up to 30% of falls due to syncope 4
• Multiple origins of syncope and orthostatic hypotension frequently coexist in elderly patients 4, 2
• Key contributing factors include polypharmacy, multiple coexisting diseases, carotid sinus hypersensitivity, postprandial hypotension, cardiovascular deconditioning, and gait disorders 4, 2
• Orthostatic hypotension is associated with 64% increase in age-adjusted mortality and increased falls/fractures 2

Critical Immediate Actions

Stop or reduce zonisamide immediately while monitoring tremor control, as this is the most likely culprit given the temporal relationship and mechanism 1

• Correct electrolyte abnormalities urgently, as both hyponatremia and hypokalemia independently increase fall risk 3, 4
• Measure orthostatic vital signs after 5 minutes supine rest, then at 1 and 3 minutes after standing (orthostatic hypotension defined as ≥20 mmHg systolic or ≥10 mmHg diastolic drop) 4, 2
• Review complete medication list for other contributors: diuretics, antihypertensives, antipsychotics, tricyclic antidepressants, antihistamines, dopamine agents, narcotics, and alcohol 4, 2
• Screen for primary aldosteronism with plasma aldosterone/renin ratio after correcting hypokalemia 4
• Perform focused neurological examination to distinguish essential tremor from Parkinson's disease, looking specifically for bradykinesia, rigidity, and postural instability 6, 8