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Pure/predominant upper motor neuron (pUMN) and lower motor neuron (pLMN) diseases have significantly better prognosis compared to amyotrophic lateral sclerosis (ALS), but their early differentiation is often challenging. We therefore tested whether a multimodal characterization approach embedding clinical, cognitive/behavioral, genetic, and neurophysiological data may improve the differentiation of pUMN and pLMN from ALS already by the time of diagnosis. Dunn’s and chi-squared tests were used to compare data from 41 ALS, 34 pLMN, and 19 pUMN cases with diagnoses confirmed throughout a 2-year observation period. Area under the curve (AUC) analyses were implemented to identify the finest tools for phenotypes discrimination. Relative to ALS, pLMN showed greater lower limbs weakness, lower UMN burden, and progression rate (p < 0.001–0.04). PUMN showed a greater frequency of lower limbs onset, higher UMN burden, lower ALSFRS-r and MRC progression rates (p < 0.001–0.03), and greater ulnar compound muscle action potential (CMAP) amplitude and tibial central motor conduction time (CMCT) (p = 0.05–0.03). The UMN progression rate was the finest measure to identify pLMN cases (AUC = 90%), while the MRC progression rate was the finest tool to identify pUMN (AUC = 82%). Detailed clinical and neurophysiological examinations may significantly improve MNDs differentiation, facilitating prognosis estimation and ameliorating stratification strategies for clinical trials enrollment.

Late-onset Rasmussen encephalitis (LoRE) is a rare unihemispheric progressive inflammatory disorder causing neurological deficits and epilepsy. The long-term radiological evolution has never been fully described. We retrospectively analyzed the MR images of 13 LoRE patients from a total of 136 studies, and searched for focal areas of volume loss or signal intensity abnormality in grey matter or white matter. Each subject had a median of nine MRI studies (IQR 7–13). Frontal and temporal lobes were the most affected regions (13/13 and 8/13, respectively) and showed the greatest worsening over time in terms of atrophic changes (9/13 and 5/8, respectively). A milder cortical atrophy was found in the insular and parietal lobes. The caudate nucleus was affected in seven patients. Hyperintensities of grey matter and white matter on T2-WI and FLAIR images were observed in all patients, and transiently in eight patients. In two cases out of the latter patients, these transient alterations evolved into atrophy of the same region. Disease duration was significantly associated with signal abnormalities in the grey matter at last follow-up. LoRE MRI alterations are milder, and their progression is markedly slower compared to radiological findings described in the childhood form.