Comb‐Like EEG Pattern as an Early Diagnostic Clue in Maple Syrup Urine Disease ( MSUD ): A Systematic Review

Maple syrup urine disease (MSUD) is a life‐threatening inborn error of amino acid metabolism that often presents in the neonatal period with nonspecific symptoms such as poor feeding, lethargy, and seizures. Although newborn screening (NBS) enables early identification, false‐negative results and delays in reporting may lead to missed or delayed diagnosis, resulting in severe neurologic injury. A characteristic EEG finding, the “comb‐like rhythm,” consisting of central‐ or frontocentral‐predominant, sharply contoured 4–7 Hz theta bursts has been reported in MSUD. However, its diagnostic utility has not been systematically evaluated. Therefore, we aimed to investigate the comb‐like rhythm as a diagnostic clue for MSUD. A systematic literature search was conducted in accordance with PRISMA guidelines using MEDLINE and Embase databases up to May 18, 2026. Studies evaluating EEG findings in individuals with MSUD were included. Data on clinical presentation, biochemical findings, brain imaging, and EEG features were extracted and synthesized qualitatively. In addition, two neonatal cases from our institution were included. Associations of the comb‐like EEG rhythm with patient age at EEG (neonatal vs. non‐neonatal) and plasma leucine concentrations were evaluated using Fisher's exact test and the Mann–Whitney U test. A total of 113 records were screened, and 18 studies were included, comprising 24 symptomatic cases including our two patients. Abnormal EEG findings were reported in 21 of 24 (88%). A comb‐like pattern was exclusively observed in neonates with acute metabolic crisis (13/15 neonates [86.7%] vs. 0/9 non‐neonates [0%], p < 0.0001). The comb‐like rhythm was associated with higher plasma leucine concentrations (median, 3545 vs. 1782 μmol/L, p = 0.0033). The pattern often diminished or resolved following treatment or clinical stabilization. In our two patients, the comb‐like rhythm contributed to raising diagnostic suspicion despite initially normal NBS results. The comb‐like rhythm may serve as an adjunctive EEG marker that raises suspicion for acute MSUD, given its strong association with neonatal metabolic crisis and severe hyperleucinemia. Further studies are needed to clarify its pathophysiological basis and determine the clinical utility of EEG in MSUD crisis.