Multiple System Atrophy Presenting Research Articles

Clinically Probable Multiple System Atrophy Presenting Ptosis as an Early Manifestation

Many ocular features were found in patients with multiple system atrophy (MSA), which include dry eye, blepharospasm, eye movement problems, and blink reflex dysfunction. Some of these symptoms are associated with autonomic dysfunctions seen in MSA. We report a young clinically-probable MSA patient with bilateral ptosis at an early disease stage. Although there is no clear evidence that ptosis, in this case, was caused by abnormalities in the sympathetic cholinergic system, the selective impairment of sudomotor function implied an injured sympathetic cholinergic system secondary to MSA pathology. Ocular manifestations need more attention in clinical examinations of patients with MSA.

Sex-related differences in the clinical presentation of multiple system atrophy

PurposeTo investigate sex-related differences in the clinical presentation of multiple system atrophy (MSA) through a literature review and an analysis of a retrospective cohort.MethodsThe PubMed database was searched for articles including sex-related information in MSA. In a retrospective Innsbruck cohort, we investigated the baseline to last available follow-up clinical-demographic differences between men and women with MSA in a univariate fashion, followed by multivariable binary regression analysis.ResultsThe literature search yielded 46 publications with sex-related information in MSA. Most studies found comparable survival rates between the sexes, while some recent reports suggested a potential survival benefit for women, possibly due to initial motor onset and overall less severe autonomic failure compared to men. The retrospective Innsbruck MSA cohort comprised 56 female and 60 male individuals with a comparable median follow-up of 27 months. At baseline, female sex was independently associated with depression (odds ratio [OR] 4.7; p = 0.007) and male sex with severe orthostatic hypotension (OR 5.5; p = 0.016). In addition, at last follow-up, female sex was associated with the intake of central nervous system-active drugs (OR 4.1; p = 0.029), whereas male sex was associated with the presence of supine hypertension (OR 3.0; p = 0.020) and the intake of antihypertensive medications (OR 8.7; p = 0.001). Male sex was also associated with initiation of antihypertensive medications over the observation period (OR 12.4; p = 0.004).ConclusionThe available literature and findings of the present study indicate sex-related differences in the clinical presentation of MSA and its evolution over time, highlighting the importance of considering sex in symptom exploration, therapeutic decision-making, and future clinical trial design.

Diagnosing Premotor Multiple System Atrophy: Natural History and Autonomic Testing in an Autopsy-Confirmed Cohort.

Nonmotor features precede motor symptoms in many patients with multiple system atrophy (MSA). However, little is known about differences between the natural history, progression, and prognostic factors for survival in patients with MSA with nonmotor vs motor presentations. We aimed to compare initial symptoms, disease progression, and clinical features at final evaluation and investigate differences in survival and natural history between patients with MSA with motor and nonmotor presentations. Medical records of autopsy-confirmed MSA cases at Queen Square Brain Bank who underwent both clinical examination and cardiovascular autonomic testing were identified. Clinical features, age at onset, sex, time from onset to diagnosis, disease duration, autonomic function tests, and plasma noradrenaline levels were evaluated. Forty-seven patients with autopsy-confirmed MSA (age 60 ± 8 years; 28 men) were identified. Time from symptom onset to first autonomic evaluation was 4 ± 2 years, and the disease duration was 7.7 ± 2.2 years. Fifteen (32%) patients presented with nonmotor features including genitourinary dysfunction, orthostatic hypotension, or REM sleep behavior disorder before developing motor involvement (median delay 1-6 years). A third (5/15) were initially diagnosed with pure autonomic failure (PAF) before evolving into MSA. All these patients had normal supine plasma noradrenaline levels (332.0 ± 120.3 pg/mL) with no rise on head-up tilt (0.1 ± 0.3 pg/mL). Patients with MSA with early cardiovascular autonomic dysfunction (within 3 years of symptom onset) had shorter survival compared with those with later onset of cardiovascular autonomic impairment (6.8 years [5.6-7.9] vs 8.5 years [7.9-9.2]; p = 0.026). Patients with early urinary catheterization had shorter survival than those requiring catheterization later (6.2 years [4.6-7.8] vs 8.5 years [7.6-9.4]; p = 0.02). The survival of patients with MSA presenting with motor and nonmotor symptoms did not differ (p > 0.05). Almost one-third of patients with MSA presented with nonmotor features, which could predate motor symptoms by up to 6 years. Cardiovascular autonomic failure and early urinary catheterization were predictors of poorer outcomes. A normal supine plasma noradrenaline level in patients presenting with PAF phenotype is a possible autonomic biomarker indicating later conversion to MSA.

Clinicopathologic and genetic features of multiple system atrophy with Lewy body disease.

Background: Abnormal aggregates of α‐synuclein are pathologic hallmarks of multiple system atrophy (MSA) and Lewy body disease (LBD). LBD sometimes coexists with MSA, but the impact of co‐pathology, particularly diffuse LBD, on presentation of MSA has not been studied. We aimed to determine the frequency and clinicopathologic features of MSA with LBD (MSA+LBD). Methods: Using hematoxylin & eosin and α‐synuclein‐immunostained slides, we assessed the distribution and severity of LBD in 230 autopsy‐confirmed MSA patients collected from 1998 to 2018. Alzheimer‐type pathology was assessed to assign the likelihood of clinical presentations of dementia with Lewy body (DLB) using the consensus criteria for DLB. We reviewed medical records to characterize clinicopathologic features of MSA+LBD. Genetic risk factors for LBD, including APOE ε4 allele and mutations in GBA, SNCA, LRRK2, and VPS35, were analyzed. Results: LBD was observed in 11 MSA patients (5%); seven were brainstem type, three were transitional type, and one was diffuse type. The latter four had an intermediate or high likelihood of DLB. Three of the four had an antemortem diagnosis of Parkinson’s disease with dementia (PDD) or clinically probable DLB. Two patients had neuronal loss in the substantia nigra, but not in striatal or olivocerebellar systems with widespread glial cytoplasmic inclusions, consistent with minimal change MSA. In these cases, LBD was considered the primary pathology, and MSA was considered coincidental. APOE ε4 allele frequency was not different between MSA+LBD and MSA without LBD. Two of nine MSA+LBD patients had a risk variant of GBA (p.T408M and p.E365K). Conclusions: Although rare, MSA with transitional or diffuse LBD can develop clinical features of PDD or DLB. Minimal change MSA can be interpreted as a coincidental, but distinct, α‐synucleinopathy in a subset of patients with diffuse LBD.

Progression and prognosis in multiple system atrophy presenting with REM behavior disorder.

To investigate (1) the prevalence of REM sleep behavior disorder (RBD) as mode of disease onset in a cohort of patients with multiple system atrophy (MSA) and (2) disease progression and prognosis in patients with MSA with RBD predating (pre-RBD) and following (post-RBD) disease onset. We retrospectively identified all patients with a clinical diagnosis of MSA evaluated at least once a year during the disease course. Type of onset was defined by the first reported motor or autonomic symptom/sign related to MSA. The occurrence of symptoms/signs and milestone of disease progression, and their latency from disease onset, were collected. Survival data were calculated. RBD was confirmed by video-polysomnography. Of a total of 158 patients, pre-RBD represented the mode of disease onset in 27% of patients, preceding disease onset according to the international criteria with a median of 3 (2-5) years. Comparing pre-RBD and post-RBD patients, the first group showed an increased prevalence of autonomic onset of disease, a reduced prevalence of parkinsonism, an earlier onset of stridor, pyramidal signs, symptomatic orthostatic hypotension, urinary dysfunction, severe dysphagia, and wheelchair dependency. The risk of death was higher in patients with pre-RBD. In our MSA cohort, RBD represented the most frequent mode of disease presentation. A more rapid progression of disease was observed in the pre-RBD group. These findings suggested a careful assessment of sleep disorders to early recognize RBD and a closer follow-up of autonomic dysfunction and stridor in patients with pre-RBD.

Bladder dysfunction as the initial presentation of multiple system atrophy: a prospective cohort study.

Multiple system atrophy (MSA) is a disease that combines autonomic (orthostatic or bladder) with motor [parkinsonian (MSA-P) or cerebellar (MSA-C)] dysfunction. While bladder dysfunction may occur earlier than motor disorders, thus far no prospective study has been available to determine how often and how early bladder autonomic dysfunction predates motor dysfunction in MSA. Therefore, we present data from detailed history-taking in patients with MSA. This is a prospective cohort study. Detailed history-taking was performed and a questionnaire administered in 121 MSA patients (73 MSA-C, 48 MSA-P; 74 men, 47 women; age, 58 ± 8.0years; initial recruitment period, 5years; follow-up, 6.5 ± 4.0years). Among the patients with MSA-C, 40 patients (55%) suffered motor dysfunction first, 22 (30%) suffered autonomic dysfunction first, and 11 (15%) initially suffered both simultaneously. Among the patients with MSA-P, 22 patients (46%) suffered motor dysfunction first, 22 (46%) suffered autonomic dysfunction first, and two (8%) initially suffered both simultaneously. Among the 'autonomic-first' subgroup of MSA-C patients, five suffered orthostatic dysfunction first, 13 suffered urinary dysfunction first, and four initially suffered both simultaneously. Among the 'autonomic-first' subgroup of MSA-P patients, six suffered orthostatic dysfunction first, nine suffered urinary dysfunction first, and seven initially suffered both simultaneously. Urinary symptoms were further preceded by erectile dysfunction in men. Overall, 18.2% of patients suffered only urinary symptoms initially, and the mean interval from the onset of urinary to the onset of motor symptoms was 2.8years (range 1-7years). In MSA patients, 18.2% presented with bladder dysfunction as the sole initial manifestation, and the mean interval from the onset of urinary to the onset of motor symptoms was 2.8years. It is clinically important to avoid unnecessary prostatic surgery when MSA patients see urologists before neurologists.

Multiple System Atrophy Presenting as Motor Neuron Disease (P6.069)

Multiple System Atrophy Presenting as Motor Neuron Disease (P6.069)

POTS (postural orthostatic tachycardia syndrome) in a young patient: An unusual presentation of MSA (multiple system atrophy) type P

Abstract A young patient presented with gradually progressive gait imbalance and fall with episodic dizziness and features suggestive of parkinsonism. On autonomic testing, he was found to have POTS (postural orthostatic tachycardia syndrome) as unusual presenting feature of multiple system atrophy.

人工声帯をもちいた実験的声帯外転障害−多系統萎縮症における非侵襲的陽圧換気療法の圧設定−

Non-invasive positive pressure ventilation (NPPV) has recently been applied to the patients with multiple system atrophy (MSA) with various respiratory complications including vocal cord abduction impairment and respiratory disturbance by the central origin. Any consensus guidelines on setting up the inspiratory positive airway pressure (IPAP) and expiratory one (EPAP), however, have not been raised yet. To investigate this problem, we made the upper airway tract model with moderately and severely narrow glottis using a training/test lung and the artificial vocal cord which was developed for a humanoid talking robot in Waseda University. The artificial vocal cord was molded out of a high performance thermoplastic rubber in imitation of the human larynx. Previous studies using with a high-speed camera and a sound analyzer showed that the artificial vocal cord resembled human larynx closely both morphologically and functionally. The opening and closing movements of the artificial vocal cord were observed fiberscopically under various conditions of IPAP (4-20 cmH2O) and EPAP (4-10 cmH2O). The maximal glottic width during inspiration and expiration were measured by a pair of calipers on the video-monitored display. Both of the moderately and the severely narrow artificial vocal cords without non-paralytic factors showed typical paradoxical movement showing adduction in inspiration and abduction in expiration, which is characteristic to vocal cord abductor impairment seen in MSA. In the model with moderately severe narrow glottis, this paradoxical movement was released under any positive pressures of continuous (CPAP) and bilevel (Bilevel PAP) modes. In the model with severely narrow glottis, however, there existed a threshold in setting up the optimal EPAP to release the paradoxical movement. In conclusion, EPAP-leading procedure seems to be preferable to IPAP-leading procedure to dilate the narrow glottis as a pneumatic splint in the managements of the patients with MSA presenting with a paralytic type of vocal cord abductor impairment.

Multiple system atrophy presenting with language impairment

Multiple system atrophy (MSA) typically presents with parkinsonism, cerebellar ataxia, corticospinal dysfunction, and autonomic failure.1 We describe a case of pathologically confirmed MSA with semantic language impairment. A 55-year-old right-handed psychiatrist presented with language difficulties since age 50. He had shrinking vocabulary, spelling, and reading difficulties, loss of foreign language skills, and difficulty with comprehension of complex conversations. His speech was fluent, grammatically correct, with occasional anomic pauses and substitution of low-frequency words with general words (e.g., “thing” and “it”). He had hyperreflexia in the right arm and leg, right-sided Babinski, writer's cramp, and mildly impaired fine motor skills in the right hand. Neuropsychological evaluation revealed anomia (Boston Naming Test [BNT] score 35/60, <1%), intact verbal fluency (FAS 88%), surface dysgraphia (“curteus” instead of “courteous,” “medeval” instead of “medieval”), surface dyslexia (could not read “subtlety”), and moderate retrieval-type verbal memory deficit. His receptive vocabulary skills were below expectation given his advanced education (Peabody Picture Vocabulary Test, 48%). His performance …

Vocal cord abductor paralysis evaluated by laryngoscopy in multiple system atrophy

Objectives: Multiple system atrophy (MSA) is a chronic neurological disorder characterized by atypical parkinsonism and autonomic dysfunction. Sudden death during sleep is common among MSA patients. Sleep laryngoscopy demonstrates the restriction of abduction of vocal cords with a markedly reduced size of the glottic chink. Vocal cord abductor paralysis (VCAP) is considered to be an important predisposing factor of sudden death in MSA. The aim of this study was to elucidate the effects of VCAP on sleep and the utility of awake and sleep laryngoscopy in MSA. Methods: We recruited 14 patients with MSA presenting with snoring (4 men and 10 women; mean age, 54.6 years; disease duration, 4.2 years; International Cooperative Ataxia Rating Scale [ICARS], 46.9). After performing arterial blood gas analysis, spirometry, and polysomnography (PSG), awake and sleep laryngoscopy were performed. Results: Sleep laryngoscopy revealed that 7 patients exhibited VCAP and 7 patients did not. Between these 2 groups, there were no significant difference in the following findings: sex, disease duration, ICARS, findings of daytime blood gas analysis and PSG findings (mean SpO2 during sleep, AI, AHI and arousal index). Five of 7 patients who exhibited VCAP also showed bilateral arytenoidal tremor on awake laryngoscopy. Conclusion: These findings suggest that MSA should be followed by sleep laryngoscopy, however, it is difficult to perform sleep laryngoscopy as a routine evaluation. Since early diagnosis of VCAP is difficult to make on awake laryngoscopy, arytenoidal tremor may be useful as a sign to predict VCAP.

The symptomatic treatment of multiple system atrophy.

Multiple system atrophy (MSA) is a neurodegenerative disease of undetermined aetiology that occurs sporadically and manifests itself as a combination of parkinsonian, autonomic, cerebellar and pyramidal signs. Despite the lack of any effective therapy to reverse this condition, some of the symptoms may be, at least temporarily, improved with adequate symptomatic therapies. Medical treatment is largely aimed at mitigating the parkinsonian and autonomic features. The therapeutic results of levodopa therapy in cases of MSA are difficult to interpret because of their variability. Nevertheless, the statement that patients with MSA are non or poorly levodopa-responsive is misleading. Clinical and pathologically proven series document about 40-60% levodopa efficacy in patients with MSA presenting with predominant parkinsonian features. Unfortunately, other antiparkinsonian compounds (dopamine agonists, amantadine) are not more effective than levodopa. Orthostatic hypotension (OH) can be suspected from the patient's history and subsequently documented in the clinic by measuring lying and standing blood pressure. The diagnosis ideally should be confirmed in the laboratory with additional tests to determine the cause and evaluate the functional deficit, so as to aid treatment. A variety of pharmacological agents with different mechanisms of action have been used in MSA to reduce OH when this is symptomatic. OH can also be alleviated by avoiding aggravating factors, such as the effects of food, micturition, exposure to a warm environment and physiological diurnal changes and by using other non-pharmacological strategies. The treatment of the very common genito-urinary symptoms (incontinence, retention, impotence) should also be considered in order to improve the quality of life of these patients.

Cerebellar presentation of multiple system atrophy.

Early diagnosis of multiple-system atrophy (MSA) is important in patients presenting with late-onset cerebellar ataxia because it has a less favourable prognosis than other degenerative ataxic disorders. We report cerebellar presentation of MSA in a series of 16 patients, 3 of whom later developed parkinsonism. Two-thirds of them had early evidence of impaired postural reflexes with a history of recurrent falls. Some of these had a narrow-based, unsteady gait, unlike the more classic broad-based gait ataxia of cerebellar disease. On review of the patients' histories, genitourinary dysfunction (particularly impotence) was present at the onset of, or preceding, cerebellar ataxia in 60% of patients, but this had often been attributed to age, or to urological or gynaecological causes. External striated anal or urethral sphincter electromyography (EMG) demonstrated features of chronic denervation and reinnervation in 14 (93%) of 15 patients, consistent with degeneration in Onuf's nucleus as occurs in MSA. Autonomic function tests were abnormal in 9 (64%) of 14 patients. Our data suggest that close enquiry into genitourinary function and analysis of the gait disorder can be useful pointers to a diagnosis of MSA in patients with an unexplained adult-onset progressive cerebellar syndrome, and that sphincter EMG is the most useful investigation in this context.

Multiple system atrophy presenting as parkinsonism: clinical features and diagnostic criteria.

To evaluate the possibility that parkinsonian signs may be the only presenting feature of multiple system atrophy (MSA), parkinsonian patients were studied who had no atypical clinical signs and had no symptoms of autonomic dysfunction, but who reported that they had not experienced the anticipated good response to dopaminergic treatment. These stringent criteria identified 20 patients from a series of 298 consecutive parkinsonian outpatients. The following clinical pointers were analysed: (a) rate of disease progression; (b) symmetry of parkinsonian symptoms and signs; (c) occurrence of resting tremor during the first three years from onset. In addition, all patients underwent (d) acute and chronic challenge with dopaminergic drugs; (e) cardiovascular reflex autonomic function tests; (f) high field MRI. Rapid progression of disease was seen in 45% of patients, onset was symmetric in 25%, tremor was absent at onset in 70%, response to dopaminergic drug challenges was inadequate in 40%, abnormal cardiovascular reflexes occurred in 50%, and some abnormal MRI finding occurred in 35% of cases. Each of these features was equally weighted by giving to each patient a 0 to 6 point score corresponding to the number of abnormal findings. Fifteen patients scoring higher than 1 were considered at risk for having MSA: five of them were classified as clinically possible (score 2), six as clinically probable (score 3-4), and four patients were classified as clinically definite multiple system atrophy (score 5). The six pointers considered were variably combined in each patient, none of them being universally abnormal in patients with high scores. The patients were followed up for a mean 2.1 (SEM 0.65) years. All but one of the 10 patients prospectively classified as probable or definite MSA developed unequivocal clinical signs of fully symptomatic MSA. A receiver operator characteristic cure was plotted for the prospective score based on follow up diagnosis. The best compromise for trade off between sensitivity and specificity was a cut off value at a score of 3. The sensitivity and specificity of the individual pointers considered to predict fully symptomatic MSA varied considerably, and no single item could predict whether patients presenting with just parkinsonian signs went on during the two year follow up period to develop fully symptomatic MSA. Instead, the number of abnormalities offered a predictive value for the clinical prognosis of these parkinsonian patients.

Laryngeal electromyography with separated surface electrodes in patients with multiple system atrophy presenting with vocal cord paralysis.

When recording the activity of the posterior cricoarytenoid muscle (PCA) with surface electrodes, there is contamination from the surrounding muscles such as the cricopharyngeal muscle. We therefore devised a new oesophageal catheter electrode of the separate type, having three individual surface electrodes for the PCA, cricopharyngeal muscle and diaphragm. The records obtained with this catheter demonstrated satisfactory separation between PCA and cricopharyngeal muscle activities. We used this catheter in patients with multiple system atrophy presenting with vocal cord paralysis, who were awake or asleep. There were two interesting electromyographical findings, which were inspiratory activity of the adductor muscle (the thyroarytenoid muscle) and fade-out of the abductor muscle, that is, PCA activity during sleep. Although vocal cord paralysis is one of the most serious life-threatening complications, the precise mechanism has not been clarified. We believe that our catheter may be useful in investigating the mechanism of vocal cord paralysis which could cause sudden death in neurodegenerative disorders, including multiple system atrophy.