Non-pharmacological and drug treatment of autonomic dysfunction in multiple system atrophy: current status and future directions.

Multiple system atrophy (MSA) is a sporadic, fatal, and rapidly progressive neurodegenerative disease of unknown etiology that is clinically characterized by autonomic failure, parkinsonism, cerebellar ataxia, and pyramidal signs in any combination. Early onset and extensive autonomic dysfunction, including cardiovascular dysfunction characterized by orthostatic hypotension (OH) and supine hypertension, urinary dysfunction characterized by overactive bladder and incomplete bladder emptying, sexual dysfunction characterized by sexual desire deficiency and erectile dysfunction, and gastrointestinal dysfunction characterized by delayed gastric emptying and constipation, are the main features of MSA. Autonomic dysfunction greatly reduces quality of life and increases mortality. Therefore, early diagnosis and intervention are urgently needed to benefit MSA patients. In this review, we aim to discuss the systematic treatment of autonomic dysfunction in MSA, and focus on the current methods, starting from non-pharmacological methods, such as patient education, psychotherapy, diet change, surgery, and neuromodulation, to various drug treatments targeting autonomic nerve and its projection fibers. In addition, we also draw attention to the interactions among various treatments, and introduce novel methods proposed in recent years, such as gene therapy, stem cell therapy, and neural prosthesis implantation. Furthermore, we elaborate on the specific targets and mechanisms of action of various drugs. We would like to call for large-scale research to determine the efficacy of these methods in the future. Finally, we point out that studies on the pathogenesis of MSA and pathophysiological mechanisms of various autonomic dysfunction would also contribute to the development of new promising treatments and concepts.

Unravelling the etiology of sporadic late-onset cerebellar ataxia in a cohort of 205 patients: a prospective study.

BACKGROUND: Despite recent progress in the field of genetics, sporadic late-onset (> 40 years) cerebellar ataxia (SLOCA) etiology remains frequently elusive, while the optimal diagnostic workup still needs to be determined. We aimed to comprehensively describe the causes of SLOCA and to discuss the relevance of the investigations. METHODS: We included 205 consecutive patients with SLOCA seen in our referral center. Patients were prospectively investigated using exhaustive clinical assessment, biochemical, genetic, electrophysiological, and imaging explorations. RESULTS: We established a diagnosis in 135 (66%) patients and reported 26 different causes for SLOCA, the most frequent being multiple system atrophy cerebellar type (MSA-C) (41%). Fifty-one patients (25%) had various causes of SLOCA including immune-mediated diseases such as multiple sclerosis or anti-GAD antibody-mediated ataxia; and other causes, such as alcoholic cerebellar degeneration, superficial siderosis, or Creutzfeldt-Jakob disease. We also identified 11 genetic causes in 20 patients, including SPG7 (n = 4), RFC1-associated CANVAS (n = 3), SLC20A2 (n = 3), very-late-onset Friedreich's ataxia (n = 2), FXTAS (n = 2), SCA3 (n = 1), SCA17 (n = 1), DRPLA (n = 1), MYORG (n = 1), MELAS (n = 1), and a mitochondriopathy (n = 1) that were less severe than MSA-C (p < 0.001). Remaining patients (34%) had idiopathic late-onset cerebellar ataxia which was less severe than MSA-C (p < 0.01). CONCLUSION: Our prospective study provides an exhaustive picture of the etiology of SLOCA and clues regarding yield of investigations and diagnostic workup. Based on our observations, we established a diagnostic algorithm for SLOCA.

Spinal Cord Stimulation Improved Freezing of Gait and Hypokinetic Dysarthria of a Patient with Dopamine-Resistant Multiple System Atrophy-Parkinsonian Type.

Background: Multiple system atrophy parkinsonian type (MSA-P) patients with resistance to dopamine have highly limited treatment options. This calls for further study of spinal cord stimulation (SCS) as a potential nondopaminergic therapy to improve motor and speech functions of patients with dopamine-resistant parkinsonism. Case Presentation: A 58-year-old male with MSA-P had hypokinetic dysarthria, freezing of gait (FOG), and spinal disc herniation with refractory back pain. SCS was used to treat his refractory back pain. Serendipitously, after the surgery, the patient reported not only a reduction in pain but also rapid improvement of FOG and hypokinetic dysarthria. Conclusion: SCS has been found in some cases to improve FOG and hypokinetic dysarthria. It is necessary to further study the potential of and the mechanism behind SCS as a potential nondopaminergic therapy to improve motor and speech functions of patients with dopamine-resistant parkinsonism.

Pharyngolaryngeal semiology and prognostic factors in multiple system atrophy.

INTRODUCTION: Multiple system atrophy (MSA) is a rare degenerative neurological disorder in adults. It induces parkinsonian and/or cerebellar syndrome associated with dysautonomia. Pharyngolaryngeal symptoms are common. Our aim is to describe the Pharyngolaryngeal semiology on one hand, and to ascertain whether the presence of these symptoms represents a prognostic factor for MSA on the other. METHODS: Thus, we carried out a retrospective, single-centre study, on a cohort receiving care at the centre of reference for MSA. The patients were referred for otorhinolaryngology assessment. The data was collected over the year 2020 with the help of computer software from the university hospital centre (UHC). Firstly, we described the Pharyngolaryngeal semiology specific to MSA by questioning patients, and by the results of nasofibroscopic examinations and swallowing tests. We then used multivariate analysis of variance to describe the prognostic factors of MSA progression (in UMSARS I and II points per month of progression) and survival (number of years between the first symptoms and death). RESULTS: This study included a hundred and one patients and made it possible to define a Pharyngolaryngeal semiology profile of MSA, which is: a reduction in laryngeal mobility (primarily vocal cord abduction defects), abnormal movements (particularly at rest or when initiating a movement) and a defect in the protection mechanisms of the upper airways. The swallowing difficulties are moderate and the main mechanisms are delayed pharyngeal swallow and/or an oro-pharyngeal transport defect. In the multivariate analyses, the contributing factors are laryngeal anomalies, modification of solid food to fluid food and nutritional complication. CONCLUSION: ENT specialists should pay close attention to problems in the Pharyngolaryngeal dynamic and then consider a neurological cause. They can also itemize the clinical factors that could have a negative effect on the prognosis of the patient with MSA. Indeed, early detection makes it possible to provide care for respiratory and nutritional complications.

Neuroleptic malignant-like syndrome associated multiple system atrophy: report on three cases.

BACKGROUND: Multiple system atrophy (MSA) associated with neuroleptic malignant-like syndrome (NMLS) is rare and few cases have been described in the literature. CASE PRESENTATION: In the present study, three patients with MSA associated with NMLS were analyzed from January 2012 to January 2020 to characterize their clinical presentations. Data collected from the patients for analysis included general patient history, the fluctuation and severity of disease symptoms, the indicated therapies and disease progression at follow-up. All patients had histories of sudden withdrawal or reduction of levodopa prior to the onset of symptoms. Clinical presentations were characterized by hyperthermia, autonomic dysfunction, worsening of extrapyramidal symptoms, and elevated serum creatine kinase (CK) levels. During hospitalization, one patient rapidly progressed and died, while the other two patients were successfully treated. CONCLUSIONS: Early diagnosis and treatment are very important for patient outcomes in NMLS. Notably, the correct dose and time of administration of dopaminergic medication may be key in treating NMLS.

Parkinsonism and dysautonomia with anti-CV2/CRMP5 associated paraneoplastic neurological syndromes mimicking multiple system atrophy: a case report.

BACKGROUND: Paraneoplastic neurological syndromes (PNSs) are broad-spectrum disorders that can affect any part of the nervous system varying in core symptoms. Onconeural antibodies, including Hu, Yo, Ri, anti-CV2, amphiphysin, Ma2, and Tr are well-characterized and commonly used for the diagnosis of definite PNS. Generally, anti-CV2 antibodies have usually been associated with cerebellar ataxia, chorea, peripheral and autonomic neuropathies, myelopathy, optic neuritis, and retinitis. However, Parkinsonism has not been reported as the core symptom in patients with anti-CV2 antibodies. CASE PRESENTATION: We report a patient with anti-CV2 antibody manifested as Parkinsonism and autonomic dysfunction, which may lead to the diagnosis of multiple system atrophy with predominant Parkinsonism (MSA-P). A lumbar puncture examination was undergone to find a positive anti-CV2 antibody in cerebrospinal fluid. PET-CT showed no tumor. Immunotherapy was adopted and the symptoms were relieved for 5 months. However, with no evidence of tumor, he died after 8 months. CONCLUSIONS: Our findings indicate that PNS with anti-CV2 antibody can be shown as MSA-P mimic. Considering that MSA is a neurodegenerative disease with a poor prognosis, screening for other treatable or controllable factors like PNS presented in this case is necessary when encountering a rapid progressive MSA-mimic patient.

Opsoclonus Following Downbeat Nystagmus in Absence of Visual Fixation in Multiple System Atrophy: Modulation and Mechanisms.

We report atypical opsoclonus in a patient with multiple system atrophy and propose a mechanism based on the patterns of modulation by visual, vestibular, and saccadic and vergence stimulation. Firstly, the 6-Hz opsoclonus mostly in the vertical plane occurred only after the development of downbeat nystagmus in darkness without visual fixation. Even after a substantial build-up, visual suppression of the opsoclonus was immediate and complete. Furthermore, the latency for re-emergence of opsoclonus in darkness was greater when the duration of preceding visual fixation was longer. Secondly, the effect of preceding downbeat nystagmus on the development of opsoclonus was evaluated by changing the head position. The opsoclonus did not occur in the supine position when the downbeat nystagmus was absent. After horizontal head shaking, the opsoclonus in the vertical plane gradually evolved into horizontal plane and resumed its vertical direction again after vertical head shaking. Thirdly, any opsoclonus was not triggered by imaginary saccades in the supine position. Lastly, combined vergence and saccadic eye movements during the Müller paradigm did not induce opsoclonus. From these findings of modulation, we suggest that the opsoclonus observed in our patient was invoked by vestibular signals. When the function of the omnipause neurons and saccadic system was impaired, the centrally mediated vestibular eye velocity signals may activate the saccadic system to generate opsoclonus. These atypical patterns of opsoclonus, distinct from the classic opsoclonus frequently observed in para-neoplastic or para-infectious disorders, may be an unrevealing sign of degenerative brainstem or cerebellar disorders.

Transplantation of Adipose-Derived Stem Cells Alleviates Striatal Degeneration in a Transgenic Mouse Model for Multiple System Atrophy.

Patients with multiple system atrophy (MSA), a progressive neurodegenerative disorder of adult onset, were found less than 9 years of life expectancy after onset. The disorders include bradykinesia and rigidity commonly seen in Parkinsonism disease and additional signs such as autonomic dysfunction, ataxia, or dementia. In clinical treatments, MSA poorly responds to levodopa, the drug used to remedy Parkinsonism disease. The exact cause of MSA is still unknown, and exploring a therapeutic solution to MSA remains critical. A transgenic mouse model was established to study the feasibility of human adipose-derived stem cell (ADSC) therapy in vivo. The human ADSCs were transplanted into the striatum of transgenic mice via intracerebral injection. As compared with sham control, we reported significantly enhanced rotarod performance of transgenic mice treated with ADSC at an effective dose, 2 × 105 ADSCs/mouse. Our ex vivo feasibility study supported that intracerebral transplantation of ADSC might alleviate striatal degeneration in MSA transgenic mouse model by improving the nigrostriatal pathway for dopamine, activating autophagy for α-synuclein clearance, decreasing inflammatory signal, and further cell apoptosis, improving myelination and cell survival at caudate-putamen.

Morbidity and mortality in orthostatic hypotension.

This review summarizes the current literature on the epidemiology of orthostatic hypotension (OH) in the elderly and in patients with autonomic impairment also known as neurogenic OH (nOH); these two conditions have distinct pathophysiologies and affect different patient populations. The prevalence of OH in the elderly varies depending on the study population. In community dwellers, OH prevalence is estimated at 16%, whereas in institutionalized patients, it may be as high as 60%. The prevalence of OH increases exponentially with age, particularly in those 75 years and older. Multiple epidemiological studies have identified OH as a risk factor for all-cause mortality and cardiovascular disease including heart failure and stroke. Real-world data from administrative databases found polypharmacy, multiple co-morbid conditions, and high health-care utilization as common characteristics in OH patients. A comprehensive evaluation of medications associated with OH is discussed with particular emphasis on the use of anti-hypertensive therapy from two large clinical trials on high-intensive versus standard blood pressure management. Finally, we also review the epidemiology of nOH based on the underlying neurodegenerative disorder (either Parkinson's disease or multiple system atrophy), and the presence of co-morbid conditions such as hypertension and cognitive impairment.

Acute Postoperative Bilateral Vocal Fold Paralysis After Posterior Spinal Correction for Dropped Head Syndrome.

BACKGROUND: Acute bilateral vocal fold paralysis is a life-threatening complication that can occur during spinal surgery but has almost exclusively occurred with anterior approaches. Bilateral vocal fold paralysis after posterior spinal surgery has been exceedingly rare. CASE DESCRIPTION: We present a case of acute postoperative dyspnea due to vocal fold paralysis requiring intubation and surgical intervention after posterior spinal correction for the treatment of dropped head syndrome. The patient had had a previous diagnosis of atypical Parkinson disease but was later diagnosed with multiple system atrophy. CONCLUSIONS: We suggest that multiple system atrophy can result in an increased risk of bilateral vocal fold paralysis during surgical intervention of dropped head syndrome. Thus, our report could be of interest for those who perform spinal surgery in patients with neurological conditions.

Skin Biopsy May Help to Distinguish Multiple System Atrophy-Parkinsonism from Parkinson's Disease With Orthostatic Hypotension.

BACKGROUND: The differential diagnosis between multiple system atrophy parkinsonism type (MSA-P) and Parkinson's disease with orthostatic hypotension (PD+OH) is difficult because the 2 diseases have a similar clinical picture. The aim of this study is to distinguish MSA-P from PD+OH by immunostaining for abnormal phosphorylated α-synuclein at serine 129 (p-syn) in cutaneous nerves. METHOD: We recruited 50 patients with parkinsonism and chronic orthostatic hypotension: 25 patients fulfilled the diagnostic criteria for MSA-P and 25 patients for PD+OH. The patients underwent a skin biopsy from the cervical area, thigh, and leg to analyze somatic and autonomic skin innervation and p-syn in skin nerves. RESULTS: Intraneural p-syn positivity was found in 72% of patients with MSA-P, mainly in distal skin sites. More important, p-syn deposits in MSA-P differed from PD+OH because they were mainly found in somatic fibers of subepidermal plexi, whereas scant autonomic fiber involvement was found in only 3 patients. All patients with PD+OH displayed widely distributed p-syn deposits in the autonomic skin fibers of proximal and distal skin sites, whereas somatic fibers were affected only slightly in 4 patients with PD+OH. Skin innervation mirrored p-syn deposits because somatic innervation was mainly reduced in MSA-P. Sympathetic innervation was damaged in PD+OH but fairly preserved in MSA-P. CONCLUSIONS: The p-syn in cutaneous nerves allows the differentiation of MSA-P from PD+OH; MSA-P mainly shows somatic fiber involvement with relatively preserved autonomic innervation; and by contrast, PD+OH displays prevalent abnormal p-syn deposits and denervation in autonomic postganglionic nerves. © 2020 International Parkinson and Movement Disorder Society.

Altered resting-state voxel-level whole-brain functional connectivity in multiple system atrophy patients with cognitive impairment.

OBJECTIVE: There is increasing evidence of cognitive impairment (CI) frequently occurring in patients with multiple system atrophy (MSA); however, the neurobiological mechanisms underlying CI in patients with MSA remain unclear. METHODS: We enrolled 61 patients with probable MSA and 33 healthy controls (HC). We used degree centrality (DC) analysis to assess changes in the centrality level of MSA-CI related brain nodes. We conducted a secondary seed-based functional connectivity (FC) analysis to investigate dysfunctions in cognitive networks related to MSA. Further, we analysed the correlation between clinical symptoms and acquired connectivity measures. RESULTS: Compared with HC, patients with MSA-CI and those with MSA with normal cognition (MSA-NCI) exhibited lower DC values in the left calcarine and right postcentral regions and higher DC values in the bilateral caudate and left precuneus. There were significant differences in the DC values in the right middle prefrontal gyrus between the MSA-CI and MSA-NCI groups. The mean DC values in the right middle prefrontal gyrus (RMPFG) were correlated with clinical cognitive severity. Consequently, we used this brain region as a seed in secondary seed-based FC analysis and observed FC changes within the right precuneus, inferior parietal lobe, and right insula. CONCLUSIONS: Decreased middle prefrontal cortex activity and its altered functional connectivity with the precuneus, inferior parietal lobe, and insula are possible biomarkers of cognitive dysfunction in patients with MSA-CI. SIGNIFICANCE: Cognitive impairment in MSA is associated with alterations in the dorsolateral prefrontal cortex network.

Systemic lupus erythematosus in a patient with multiple system atrophy: A case report.

RATIONALE: Multiple system atrophy is a late-onset rare neurodegenerative movement disorder which results in debilitating disease. Fever frequently ensues in the context of infections which can be associated with significant morbidity and mortality, but among alternative diagnostic possibilities neoplasms and autoimmune disorders should be considered. PATIENT CONCERNS: We describe a case of a prolonged febrile syndrome in a 55-year-old female patient with onset of multiple system atrophy two years before presentation. Patient history and symptoms were not contributive to guide the diagnostic work-up. DIAGNOSIS: Initial evaluation provided no specific findings. Repeat testing of auto-antibodies revealed positive antinuclear and anti-ds DNA antibodies coupled with low complement which in conjunction with renal biopsy substantiated the diagnosis of systemic lupus erythematosus flare. INTERVENTION: Pending the biopsy result, treatment with hydroxychloroquine and corticosteroids was initiated. Due to failure to achieve remission, azathioprine was added, but symptoms persisted. Following the diagnosis of lupus nephritis, azathioprine was discontinued and induction treatment with cyclophosphamide in accordance with the Euro-Lupus regimen was initiated and upon completion followed by maintenance therapy with mycophenolate mofetil. OUTCOMES: The patient achieved remission after cyclophosphamide was added to treatment with corticosteroids and has not experienced new flares during the next two years. The neurological syndrome has remained stable during this period. LESSONS: To our knowledge, we report the first case of concurrent systemic lupus erythematosus and multiple system atrophy. Prolonged fever presents unique challenges in patients with rare diseases.

Multiple System Atrophy Showing Portomesenteric Venous Gas with Pneumatosis Intestinalis on Abdominal Computed Tomography Associated with a Cause of Death.

This manuscript describes the first known case of a patient with multiple system atrophy whose parasympathetic dominant disturbance might have been associated with the relative constriction of the superior mesenteric artery, leading to nonocclusive mesenteric ischemia and subsequent portomesenteric venous gas with pneumatosis intestinalis on abdominal computed tomography approaching death.

Multiple system atrophy mimicked by multi-organ pathology.

Both multiple system atrophy and Parkinson's disease may present with parkinsonism and autonomic dysfunction. We describe a patient who initially met the diagnostic criteria for multiple system atrophy and had atypical features for Parkinson's disease including blackouts and pyramidal signs. Ultimately, he was found to have three separate diagnoses rather than a single unifying one.

Speculating the timing of iron deposition in the putamen in multiple system atrophy.

BACKGROUND & OBJECTIVE: Although iron accumulation is thought to be associated with neurodegenerative processes, the timing of putaminal iron deposition during the disease course of multiple system atrophy (MSA) remains unclear. We sought to investigate the temporal pattern of iron deposition in the putamen of MSA patients by calculating the conditional probabilities (CPs) of multimodal MRI changes. METHODS: We simultaneously measured putaminal R2*, volume and MD values of 39 probable MSA patients and 22 control subjects. The presence of significant MRI changes was defined as higher R2* and MD values, or lower volumes than cut-off values derived from mean values in control putamen. The CPs of R2* changes without MD or volume changes were then compared with those of MD or volume changes without R2* changes. RESULTS: Regardless of the cut-off values, the CPs of R2* increments without MD or volume changes were significantly lower than those for MD or volume changes without R2* increments. The associations of R2* with volume and MD values appeared in non-linear exponential and quadratic patterns, respectively. CONCLUSIONS: Our findings suggest that putaminal iron accumulation would occur under volume atrophy or MD increments. Thus, iron deposition in the putamen of MSA patients is likely a secondary byproduct of neurodegeneration.

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

OBJECTIVES: 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. METHODS: 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 ± 8.0 years; initial recruitment period, 5 years; follow-up, 6.5 ± 4.0 years). RESULTS: 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 2.8 years (range 1-7 years). CONCLUSION: 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 2.8 years. It is clinically important to avoid unnecessary prostatic surgery when MSA patients see urologists before neurologists.

Deciphering the causes of sporadic late-onset cerebellar ataxias: a prospective study with implications for diagnostic work.

The management of sporadic late-onset cerebellar ataxias represents a very heterogeneous group of patients and remains a challenge for neurologist in clinical practice. We aimed at describing the different causes of sporadic late-onset cerebellar ataxias that were diagnosed following standardized, exhaustive investigations and the population characteristics according to the aetiologies as well as at evaluating the relevance of these investigations. All patients consecutively referred to our centre due to sporadic, progressive cerebellar ataxia occurring after 40 years of age were included in the prospective, observational study. 80 patients were included over a 2 year period. A diagnosis was established for 52 patients (65%) corresponding to 18 distinct causes, the most frequent being cerebellar variant of multiple system atrophy (n = 29). The second most frequent cause was inherited diseases (including spinocerebellar ataxias, late-onset Friedreich's disease, SLC20A2 mutations, FXTAS, MELAS, and other mitochondrial diseases) (n = 9), followed by immune-mediated or other acquired causes. The group of patient without diagnosis showed a slower worsening of ataxia (p < 0.05) than patients with multiple system atrophy. Patients with later age at onset experienced faster progression of ataxia (p = 0.001) and more frequently parkinsonism (p < 0.05) than patients with earlier onset. Brain MRI, DaT scan, genetic analysis and to some extent muscle biopsy, thoracic-abdominal-pelvic tomodensitometry, and cerebrospinal fluid analysis were the most relevant investigations to explore sporadic late-onset cerebellar ataxia. Sporadic late-onset cerebellar ataxias should be exhaustively investigated to identify the underlying causes that are numerous, including inherited causes, but dominated by multiple system atrophy.