Patient #1 and #2 suffered from MSA-C, while patient #3 had MSA-P + C. Patients #1 and #2 also had moderate RBD, scoring a maximum of 2 on a scale ranging from 0 (no symptom) to 4 (most severe symptoms). Regarding positive findings, both patients with RBD described relief of RBD symptoms after three to four weeks (Supplementary Fig. 1) following treatment initiation. However, the negative outcome was that all three patients had worsening of gait and balance symptoms after two to three weeks on the full dosage-approximately four weeks after treatment initiation-leading to snap-like falls in Patient #1. This deterioration was accompanied by a subjective sense of overall health decline (Supplementary Fig. 2). These serious side effects necessitated discontinuation of the ADLL (Tanganil™) treatment only a few weeks after baseline evaluation. As the treatment period was considered too short to allow for any potential disease-modifying effects, the planned 6 months follow-up assessments were not conducted (see Supplementary Results for details). Upon cessation of ADLL (Tanganil™), gait and balance symptoms improved within two weeks in two of the three patients. In parallel, the RBD phenotype reappeared at its pre-ADLL therapy level of severity (Supplementary Tables 1, 2).
Patient #3 presented with very advanced MSA-P + C at baseline and had additional severe infections with slow recovery during the follow-up period. As a result, this patient’s self-reported data could not be reliably analysed. Patient # 2 was institutionalized at the beginning of our clinical follow-up period, precluding consistent self-reporting and observation by a constant external observer. Only self-reported data from Patient #1, with the assistance of his wife (a board-qualified nurse), could be considered reliable for analysis.
UMSARS scores at neurological evaluation and weekly self-assessed by the patients, remained largely unchanged throughout the follow-up period (see Supplementary Results for details). It is important to note that the UMSARS is designed for physician-administered evaluations and may not be well-suited for self-assessment. Furthermore, its scoring system—ranging from 0 (absence of symptoms) to 4 (most severe symptoms)—may lack the sensitivity required to detect subtle, yet clinically significant changes. These limitations likely contributed to the lack of utility of the self-ratings during the follow-up. Additionally, the severity of the patients’ disease made regular follow-up visits at the Department of Neurology at UMR impractical.
Patient #1
The patient is a 71-year-old retired business administrator whose treatment regimen consisted of duloxetine, ramipril, allopurinol, prucalopride, and a nasal corticosteroid, along with physiotherapy and occupational therapy at home.
The patient’s symptoms first emerged at age 65, beginning with instability while walking, followed by slurred speech. Initially, these symptoms were thought to be age-related. However, as the instability worsened rapidly and his speech further deteriorated, the symptoms became socially debilitating. Consequently, three years later, at age 68, he was diagnosed with clinically established MSA-C and had also developed RBD.
Given his condition, he now uses a wheelchair when outside his home and a rollator indoors. As his other MSA symptoms dominated, sleep disturbances became less of a concern. Four weeks after beginning of ADLL (Tanganil™) therapy, he noticed improvements in sleep quality and a calmer sleep pattern. His wife reported no longer hearing him shout during night sleep. However, concurrently, after two to three weeks on ADLL (Tanganil™) 5 g daily – approximately four weeks after treatment initiation- he lost the ability to stand unassisted and could no longer walk, even with the guidance of his wife, who is a nurse. He experienced repeated falls, collapsing to the floor without warning and with a high risk to injure himself, and was unable to get up without emergency assistance. Consequently, he discontinued ADLL (Tanganil™) and opted not to restart the treatment. Following discontinuation, RBD symptoms worsened, while gait gradually improved over two weeks, returning to pre-treatment levels.
Patient #2
The patient is a 56-year-old engineer. He began experiencing symptoms of MSA at the age of 49, initially presenting with balance disturbances. He noticed increasing “clumsiness”, which progressively worsened. By age 53, and following extensive assessments, he was diagnosed with clinically established MSA-C. His condition has since deteriorated, leading to a loss of autonomy and requiring institutional care. For the past two years, he has also required a urinary catheter. His further medical history consisted of a thyroidectomy. At the start of the observational period with ADLL therapy, the patient was undergoing twice-weekly physiotherapy, speech therapy, and weekly occupational therapy. His medication regimen included baclofen to reduce nocturnal cramps, pramipexole 3.75 mg extended-release, and levodopa 100 mg extended-release in the evening. He had developed restless legs syndrome around age 50, which was alleviated with pramipexole and levodopa. Due to the severity of his other symptoms and the loss of autonomy, the patient considered his RBD symptoms to be of lesser concern. However, he had adapted his environment to protect himself during violent RBD episodes, which occurred nightly, with falls out of bed approximately once a week. Over the past 2–3 years, he had noticed a decrease in the severity of his RBD symptoms, although he still considered himself at risk of falling in the absence for protective measures.
Four weeks after initiating ADLL (Tanganil™) therapy, the patient experienced worsening balance, resulting in a fall and marked exacerbation of his pre-existing Pisa syndrome with a pronounced sensation of his trunk being strongly pulled to the right. Unlike patient #1, he did not report sudden, snap-like falls of similar intensity. The worsening of his impaired balance and of his Pisa syndrome necessitated the discontinuation of ADLL (Tanganil™). Interestingly, his RBD symptoms had nearly completely regressed within the first four weeks of therapy. Two weeks after stopping ADLL (Tanganil™), his balance gradually improved, but the RBD symptoms worsened again. To determine if the worsening was due to ADLL (Tanganil™), the therapy was reintroduced at a lower dose one month later. However, after three days of taking 3 tablets of 500 mg daily, his balance issues resurfaced, leading to the final decision to discontinue ADLL (Tanganil™). Two weeks after completely stopping ADLL-therapy, his balance returned to its prior state.
Patient #3
The patient is a 46-year-old teacher diagnosed with clinically established MSA-P + C. Diagnosis was done only three years earlier, as for the first six years of disease progression, the diagnosis was incorrectly attributed to a psychosomatic cause. He has no significant medical history. His first symptoms appeared at age 37, beginning with erectile dysfunction. By age 40, he reported bladder dysfunction, necessitating the use of a urinary catheter, and then progressively developed an extrapyramidal syndrome. These symptoms became severely disabling, eventually leading to the loss of his ability to walk. Additionally, he frequently suffered from recurrent infections, particularly pulmonary and urinary, which each time exacerbated his MSA symptoms. When he presented to our study, he had advanced-stage MSA, was confined to a wheelchair, and had been institutionalised due to recurrent infections and worsening of MSA symptoms. Upon starting ADLL therapy, the patient also developed a severe pulmonary infection. His RBD symptoms began at age 39 and were particularly pronounced during the two years following their onset. By the time of the study, he no longer noticed RBD symptoms, although he reported that his sleep was insufficiently restorative. With ADLL therapy, he reported sudden awakenings about three hours following sleep onset, feeling as if his body was preparing to start the day. After falling back asleep, he had a particularly calm and deep sleep, with fewer dreams and difficulty waking up. However, two weeks following ADLL instauration, his trunk stability deteriorated, and his existing Pisa syndrome worsened significantly. He could no longer sit upright on the edge of the bed, as his trunk was pulled forward and to the left. He also reported episodes of severe rigidity while on ADLL, rendering him unable to move and requiring assistance on two occasions. The discontinuation of ADLL led to an improvement in symptoms, returning them to baseline levels, and the patient’s sleep patterns reverted to their previous state. (see Supplementary Results for details). During the observation period, he first developed severe pulmonary, followed by urinary, infections with a prolonged recovery over several weeks. Therefore, it remains unclear whether his truncal ataxia was attributable to ADLL (Tanganil™) therapy, or whether it was related to his concurrent infections with slow recovery.