Abstract Introduction Unexplained dyspnea with normal imaging and pulmonary function testing poses a diagnostic challenge, particularly in patients with connective tissue disease (CTD). Systemic, metabolic, and mitochondrial disorders can mimic primary pulmonary pathology, leading to diagnostic uncertainty. We describe a case of a woman with undifferentiated CTD and persistent exertional dyspnea despite a normal cardiopulmonary evaluation, ultimately found to have a metabolic disturbance secondary to medication effect. Case Presentation A 36-year-old woman with undifferentiated CTD and a history of minocycline-induced lupus presented with progressive exertional dyspnea and fatigue beginning in early 2024. Her history was notable for chronic migraines and hemicrania continua treated with topiramate. She denied smoking or environmental exposures. High-resolution computed tomography (HRCT) of the chest and transthoracic echocardiography revealed no interstitial lung disease (ILD), pulmonary hypertension, or diaphragmatic dysfunction. Spirometry, total lung capacity and DLCO measurements were normal but reduced maximal inspiratory (MIP) and expiratory pressures (MEP) were observed, suggestive of respiratory muscle weakness. . Resting arterial blood gas analysis revealed chronic metabolic acidosis (serum bicarbonate 17 mmol/L) with respiratory compensation. Neurological evaluation noted normal limb strength but raised suspicion for subtle neuromuscular or mitochondrial dysfunction as this could cause chronic metabolic acidosis. Creatinine phosphokinase (CPK) levels, sniff test, and nerve conduction studies were normal, and the concern for neuromuscular disease was then ruled out by neurology. Nephrology attributed the acidosis to a proximal renal tubular acidosis, likely secondary to topiramate’s carbonic anhydrase inhibition. Sodium bicarbonate supplementation normalized serum bicarb level and improved symptoms. Following multidisciplinary discussion, topiramate was tapered and alternative migraine therapies pursued. Discussion This case underscores the complexity of evaluating dyspnea in CTD when conventional investigations—HRCT, PFTs, and echocardiography—are unrevealing. Metabolic acidosis caused by carbonic anhydrase inhibitors can provoke compensatory hyperventilation and contribute to dyspnea. In this patient, normalization of bicarbonate levels led to symptom improvement, emphasizing the importance of systemic assessment. A multidisciplinary approach is essential to identify overlapping systemic, neuromuscular, and metabolic contributors to dyspnea in patients with confounding CTD. This case highlights how medication effects, particularly those with multisystem impact, should be reviewed across specialties. In patients with CTD and unexplained dyspnea, diagnostic evaluation should extend beyond ILD to include metabolic, mitochondrial, and neuromuscular causes. Recognition of these subtler etiologies can guide targeted management and improve patient outcomes. This abstract is funded by: None
Gul et al. (Fri,) studied this question.