What are the differential diagnoses for a 25-year-old male with a 6-month history of hyperhidrosis (excessive sweating) of hands, feet, and groin, accompanied by dizziness, and who has a past medical history of presumed seizure and migraine, currently taking Keppra (levetiracetam), Depakote (valproate), and Sumatriptan (sumatriptan)?

Differential Diagnoses for Hyperhidrosis with Dizziness in a Young Male on Antiepileptic Medications

The most likely diagnoses are medication-induced adverse effects (particularly from levetiracetam causing dizziness and asthenia, or sumatriptan causing dizziness and sweating), primary focal hyperhidrosis with concurrent orthostatic intolerance, or autonomic dysfunction secondary to an underlying neurological condition. 1, 2, 3

Medication-Induced Causes (Highest Priority)

Levetiracetam (Keppra) commonly causes dizziness, asthenia (weakness), and somnolence as documented adverse effects occurring in 9% and 15% of patients respectively. 3 While hyperhidrosis is not a direct side effect of levetiracetam, the dizziness component is clearly medication-related. 1, 3

Sumatriptan causes dizziness as a common adverse effect (>2% incidence) and can produce "warm or cold feeling" sensations, though frank hyperhidrosis is not typically listed. 2 However, the FDA label warns about serotonin syndrome when combined with other serotonergic agents, which presents with sweating, mental changes, and autonomic instability. 2

• Critical drug interaction concern: The combination of sumatriptan with other medications metabolized by cytochrome P450 can rarely cause "serotonergic syndrome" characterized by headache, nausea, sweating, and dizziness in mild cases. 4 Valproate (Depakote) can interact through this pathway. 4

Primary Focal Hyperhidrosis

Primary focal hyperhidrosis affects approximately 4.8% of the US population and typically presents with bilateral, symmetric excessive sweating of palms, soles, axillae, and craniofacial areas—matching this patient's distribution (hands, feet, groin). 5

• The 6-month duration and focal distribution (hands, feet, groin) strongly suggest primary focal hyperhidrosis rather than secondary causes. 5, 6
• Primary focal hyperhidrosis stems from autonomic nervous system dysfunction causing neurogenic overactivity of eccrine sweat glands, controlled by the hypothalamus for thermoregulatory sweating and limbic system for emotional sweating. 7, 8
• This diagnosis does NOT explain the dizziness, which must be addressed separately. 5

Orthostatic Intolerance Syndromes

Orthostatic intolerance presents with dizziness, palpitations, and sweating as cardinal features when standing, and must be evaluated with formal orthostatic vital signs. 4, 9

• Measure blood pressure and heart rate lying flat, then at 1 and 3 minutes after standing to identify:

  • Orthostatic hypotension: Drop >20 mmHg systolic or >10 mmHg diastolic 4
  • Postural Orthostatic Tachycardia Syndrome (POTS): Heart rate increase >30 bpm without hypotension 4, 9

• Antiepileptic medications (particularly valproate) can contribute to orthostatic hypotension through multiple mechanisms. 4

Secondary Autonomic Dysfunction

Small fiber sensory polyneuropathy (SFSN) presents with autonomic and somatic C fiber involvement, manifesting as abnormal sweating and circulatory instability. 4

• Autonomic testing (heart rate variability, sudomotor function testing) can identify parasympathetic and sympathetic dysfunction. 4
• Skin biopsy to measure intraepidermal nerve fiber density is validated for diagnosing SFSN. 4
• However, this is less likely in a 25-year-old without diabetes, connective tissue disease, or other predisposing conditions. 4, 6

Secondary Hyperhidrosis Causes to Exclude

Secondary generalized hyperhidrosis requires exclusion of underlying systemic diseases before diagnosing primary hyperhidrosis. 5, 6

Essential laboratory evaluation includes:

• Thyroid function tests (hyperthyroidism causes generalized sweating with heat intolerance) 6, 10
• Fasting glucose (diabetes-related autonomic neuropathy) 4
• Complete blood count (infections, lymphoproliferative disorders) 6
• Chest radiograph if constitutional symptoms present (tuberculosis, lymphoma) 6

Seizure-Related Autonomic Phenomena

Ictal or post-ictal autonomic symptoms including sweating can occur with temporal lobe seizures, particularly if the "presumed seizure" diagnosis is incorrect or seizures are poorly controlled. 1

• Review whether witnessed seizure activity occurred or if diagnosis was based solely on clinical suspicion
• Consider EEG if seizure control is uncertain 1

Critical Diagnostic Algorithm

1. Obtain 12-lead ECG immediately to exclude arrhythmias causing dizziness (SVT, conduction abnormalities). 9, 11

2. Measure orthostatic vital signs (lying, 1 minute standing, 3 minutes standing) to identify orthostatic hypotension or POTS. 4, 9

3. Review medication timing: Does dizziness correlate with medication administration? Consider dose reduction or alternative agents if medication-induced. 1, 3

4. Obtain thyroid function, fasting glucose, and CBC to exclude secondary hyperhidrosis causes. 6, 10

5. If orthostatic vital signs and basic labs are normal, diagnose primary focal hyperhidrosis with medication-induced dizziness as separate issues. 5

6. If autonomic testing abnormalities are found, consider referral to neurology for autonomic function testing and possible skin biopsy. 4

Common Pitfalls to Avoid

Do not attribute dizziness with sweating to "just anxiety" without excluding cardiac arrhythmia first—arrhythmias are the most common cardiac cause of these combined symptoms. 9

Do not assume primary hyperhidrosis without excluding secondary causes, particularly hyperthyroidism, which is easily treatable. 5, 6

Do not overlook serotonin syndrome when multiple serotonergic medications are prescribed together (sumatriptan with potential interactions). 4, 2

Do not order brain or cervical spine imaging for isolated dizziness without neurological red flags—diagnostic yield is <1% for CT and 4% for MRI. 11