What are the differential diagnoses and appropriate evaluation for chronic morning nausea accompanied by intermittent phantosmia of a rotten‑vegetable odor?

Chronic Morning Nausea with Phantosmia: Differential Diagnosis and Evaluation

The most likely diagnosis is cyclic vomiting syndrome (CVS), which characteristically presents with stereotypical episodes of nausea occurring predominantly in early morning hours, and you must obtain a detailed cannabis use history to distinguish this from cannabinoid hyperemesis syndrome (CHS). 1

Primary Differential Diagnoses

The morning-predominant pattern strongly suggests CVS, as most episodes tend to occur in the early morning hours. 1 CVS has a prevalence of approximately 2% in US adults and is characterized by stereotypical episodes of acute-onset vomiting that can occur at specific times of day. 1

Key diagnostic considerations include:

• Cyclic Vomiting Syndrome: Stereotypical episodic vomiting resembling CVS in terms of onset, with frequency 3 or more times annually. 2 Prodromal symptoms lasting approximately 1 hour before vomiting onset occur in 65% of CVS patients. 1

• Cannabinoid Hyperemesis Syndrome: CHS should be suspected in patients with chronic nausea and vomiting and cannabis use. 2 Duration of cannabis use more than 1 year before symptom onset and frequency more than 4 times per week are diagnostic criteria. 2 Hot-water bathing was reported in 71% of patients with CHS. 2

• Functional Dyspepsia: Defined by Rome IV criteria as bothersome epigastric pain, burning, postprandial fullness, or early satiation without structural disease. 3 However, when vomiting is prominent, this likely represents the gastroparesis end of the spectrum. 3

• Gastroparesis: Delayed gastric emptying occurs in 25-40% of functional dyspepsia patients. 3 Symptoms correlate poorly with degree of gastric emptying delay. 3

The Phantosmia Component

The intermittent phantosmia (rotten vegetable smell) is an unusual feature that warrants specific attention. Olfactory disturbances can occur with:

• COVID-19 infection: Anosmia as a presenting symptom has been well-documented, though this typically involves loss rather than distorted smell. 2

• Neurologic causes: Central nervous system tumors can cause nausea through increased intracranial pressure, and increased intracranial pressure typically causes other neurologic signs. 3 If phantosmia persists or is accompanied by other neurologic symptoms, brain imaging should be considered. 2

• Sinonasal disease: Psychophysical olfactory testing can help differentiate between potential causes for inflammatory olfactory loss. 2

Essential Diagnostic Workup

Cannabis use history is critical and must be obtained directly:

Ask specifically about frequency, duration, and any hot water bathing behaviors for symptom relief. 1 Missing cannabis use history is critical for distinguishing CHS from CVS, as cannabis use augments hot water bathing behavior. 3 Resolution of symptoms after a period of abstinence from cannabis use for at least 6 months, or at least equal to the total duration of 3 typical vomiting cycles, is required for CHS diagnosis. 2

Inquire about CVS triggers and prodromal symptoms:

Ask about triggers including stress, sleep deprivation, hormonal fluctuations, travel, motion sickness, infections, surgery, fasting, or intense exercise. 1 Prodromal symptoms may include impending sense of doom, panic, inability to communicate, fatigue, mental fog, restlessness, anxiety, headache, bowel urgency, diaphoresis, flushing, or shakiness occurring before vomiting episodes. 1

Initial laboratory testing should include:

Complete blood count, electrolytes, glucose, liver function tests, lipase, and urinalysis. 3 Testing for H. pylori infection should be performed. 3

Upper endoscopy is essential:

Upper endoscopy is essential to exclude mechanical obstruction, peptic ulcer disease, and malignancy before diagnosing a functional or motility disorder. 1 Mechanical obstruction must be ruled out with upper endoscopy before diagnosing functional or motility disorders. 3

If upper endoscopy is normal and vomiting persists:

Perform gastric emptying scintigraphy for at least 4 hours (gold standard for gastroparesis diagnosis). 1 The test should be performed for at least 2 hours, with 4-hour testing providing higher diagnostic yield and accuracy. 3 Normal gastric retention at 4 hours is <10%; gastroparesis is confirmed when retention is >10% at 4 hours. 3

Critical Pitfalls to Avoid

Do not rely solely on symptoms to distinguish between conditions. Gastroparesis is indistinguishable from functional dyspepsia based on symptoms alone, and both may represent the same spectrum of pathological gastric neuromuscular dysfunction. 3

Ensure proper gastric emptying test conditions. Medications that influence gastric emptying should be withdrawn for 48-72 hours prior to testing, and blood glucose should be maintained in normal range during the test. 3 Shorter gastric emptying test durations (<2 hours) are inaccurate for determining gastroparesis. 3

Do not overlook psychiatric comorbidity. Psychiatric comorbidity, younger age, and tobacco use are associated with CVS. 1

Initial Management Approach

If CVS is suspected:

Educate the patient about recognizing prodromal symptoms and triggers, as early intervention during the prodromal phase has higher probability of aborting episodes. 1 For long-term management, counseling to achieve marijuana cessation and tricyclic antidepressants, such as amitriptyline, are the mainstay of therapy, with the minimal effective dose being 75–100 mg at bedtime. 2

For acute symptom relief:

Antiemetic agents such as phenothiazines or 5-HT3 receptor antagonists can be used for symptomatic relief. 1 Topical capsaicin may improve symptoms by activation of transient receptor potential vanilloid type 1 receptors. 2 Opioids should be avoided due to worsening of nausea and high risk of addiction. 2

Start empirical high-dose PPI therapy while awaiting endoscopy to address potential acid-related pathology. 1