Expert Review: How to better identify multi-system atrophy

Multiple system atrophy

Multiple system atrophy (MSA) is a rare, unexplained, progressive neurodegenerative disease
.
Oligodendrocyte inclusion body formation is a characteristic pathologic change of the disease, and the early clinical manifestations are multisystem involvement, especially the early onset of severe autonomic dysfunction including urinary and cardiovascular systems
.
Early clinical diagnosis of MSA is difficult and can be confused
with neurodegenerative diseases such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and other atypical PDs.
Because they have the same pathological changes, they all have synuclein (α-synuclein) deposition, and the clinical manifestations have many similarities
.
Recent studies have shown that autonomic dysfunction is a prominent clinical manifestation of the disease in the early stage, and accounts for a large proportion, so the diagnosis of MSA needs to emphasize the early recognition
of autonomic dysfunction.
Compared with PD and other atypical PDs, MSA also has more obvious clinical features
in disease progression, dopaminergic drug response, and dynamic imaging changes.
To allow clinicians to better identify MSAs, we provide a review
of progress in this area.

01 Epidemiology

The incidence of MSA is about 3.
4-4.
9 cases per 100,000 people, and rises to 7.
8 cases per 100,000 people over 40 years old, usually after the age of 60, with no obvious sex difference
.
The natural course from onset to death is about 6-10 years, which is shorter than the course of PD (about 13.
2 years), and very few patients can survive more than 15 years
.
The mean time from onset to need for assisted walking, wheelchair dependence, bedridden and death was 3, 5, 8 and 9 years
, respectively.
Sudden death and infection (pneumonia and urinary tract infections) are the most common causes of
death in patients with MSA.
Regarding the evolution of MSA understanding, several important milestones have been experienced: olive poncerebellar atrophy (OPCA) was first proposed in 1900; The concept of MSA was first proposed in 1969; The pathological features of the disease were first described in 1989; The MSA consensus standard was first published in 1998; In 2003, the European Multisystem Atrophy Study Group established a unified multisystem atrophy assessment scale; In 2015, it was proposed that the key feature of MSA is early onset and severe autonomic failure
.

02 Features of MSA autonomic dysfunction

Autonomic dysfunction occurs first in the onset of MSA and is more comprehensive and severe
than PD.
The main reasons are as follows: (1) PD autonomic nerve center and peripheral nerve are involved at the same time, mainly postganglionic fibropathies, while MSA belongs to central sympathetic preganglionic fibropathies, the severity is much greater than PD.

(2) The prominent feature of MSA pathology is the lesion of autonomic nuclei in different distribution areas of the brainstem, and compared with PD, the number and degree of nerves affected by MSA lesions are larger and more extensive, resulting in more serious
autonomic dysfunction.
For example, the loss of catecholaminergic neurons on the ventrolateral ventral side of the medulla oblongata in MSA patients is more severe than PD and pure autonomic insufficiency (PAF), resulting in more obvious
cardiovascular autonomic dysfunction.
The pathophysiological process of MSA autonomic dysfunction was elucidated by linking the classical MSA-related clinical symptoms with their corresponding lesion anatomy, as shown in Table 1
.
According to the different areas of MSA autonomic nucleus involvement, the common clinical symptoms and manifestations of MSA are highlighted:

1 Disorders of the urinary system

(1) Erectile dysfunction (ED): Almost all male patients have ED, and nearly 37%-48% can be the first symptom
.
Retrospective studies have reported that men with MSA have been present with ED for 5 to 10 years
before other symptoms develop.
Women showed reduced external genital sensitivity of 47%, compared with only 4%
of PD.

(2) Dysuria: manifested as urinary urgency, frequent urination, urinary incontinence and bladder emptying disorders, these symptoms are often not easy to be found or paid attention to by patients in the early stage, and it is often easy to consult a urologist
at the beginning.

2 Cardiovascular system

It occurs less frequently than genitourinary dysfunction and can be asymptomatic or mild.

Orthostatic hypotension (OH) can occur, nearly half of patients are also accompanied by postprandial hypotension (PPH) or nocturnal hypertension (NH), which needs to be recognized, and clinical manifestations include repeated syncope, dizziness, headache, etc.
, and sometimes neck and shoulder pain (also known as hanger-like pain).

In addition, it is also necessary to pay attention to exclude OH caused by other diseases, such as diabetic autonomic neuropathy, amyloidosis, drug properties and other factors
.
OH is defined using the 1999 Gilman criteria: OH is diagnosed
when subjects lie quietly on their backs for 5 minutes and then stand rapidly for 1 minute with a decrease in systolic blood pressure of > 30 mmHg and/or diastolic blood pressure of > 15 mmHg (1 mmHg to 0.
133 kPa).
It should be noted that if OH occurs after 3 minutes of standing, it is called late-onset OH.

Clinical attention should also be noted that a single measurement, the patient does not meet the OH diagnostic criteria, can not completely exclude the diagnosis of OH, need to repeated, multiple, different locations of the measurement to verify the diagnosis
of OH.

3 Other systems

Respiratory involvement often manifests as nocturnal stridor and obstructive sleep apnea, mainly suspected nuclear neuronal degeneration, resulting in laryngeal muscle innervation and laryngeal abductor paralysis, but can also be caused
by dystonia of the vocal cords.
REM sleep behavior disorder (RBD) is also one of the important clinical manifestations of MSA, sometimes appearing 10 to 15 years before the clinical diagnosis of MSA, and its occurrence is related to
pontineus lesions.
Regarding olfactory testing, studies have found that olfactory preservation or mild impairment may be associated with atypical Parkinson's disease (AP), particularly in 90% of patients with primary PD with decreased or lost
sense of smell.

The European MSA Association has conducted a summary analysis of clinical characteristics of 437 patients with MSA in 19 centers in ten countries, and the results are: 52.
8% male, 47.
2% female, mean age of onset 57.
8 years, average course of disease 5.
8 years, of which 59% are likely to diagnose MSA and 46% meet the criteria for
likely MSA.
Voiding dysfunction is more common than OH, and PD (87%) symptoms are more common
than cerebellar ataxia (64%).
99% of patients had autonomic dysfunction, urinary system symptoms accounted for 83%, including acute urinary incontinence 73%, incomplete bladder emptying 48%, ED84%; OH 75%, syncope 19%, chronic constipation 33%; Neuropsychiatric symptoms and sleep disorders, depression 41%, hallucinations 5.
5%, dementia 4.
5%, insomnia 19%, daytime sleepiness 17%, restless legs 10%.

In addition, pyramidal signs and tendon reflex activity are uncommon in MSA, with Pap sign positive in 28% and tendon reflex active in 43%.

These studies provide a basis for
understanding the diversity and complexity of the clinical features of MSA.

03Auxiliary inspection

1 Imaging features:

Early MSA cranial imaging societies have some characteristic findings such as cross sign and fissure sign.

The cruciform sign is due to the increased water content due to the fibrosis and glial hyperplasia of the transverse fibers of the pons and the mid-foot of the cerebellum, forming a T2-weighted cross-shaped hyperintense shadow
of the upper pons on MRI.
Deguchi et al.
showed that proton density-weighted images (PDWIs) on 3T MRI can show the "cross sign" more clearly than T2WI, and the gradient echo sequence (T2*WI) is more sensitive
than T2WI in finding MSA "cross sign".
Sometimes MSA is clinically suspected, but not supported by MRI of the head, and can be reviewed periodically every six months to 1 year
.
The fissure sign is characterized by high signal at the outer margin of the nucleus, which is associated
with low signal and atrophy of the nucleus, and increased iron deposition in substantia nigra.
Clinically, the "crucias" is sometimes not specific to MSA, but can also be seen in other neurological diseases, such as spinocerebellar ataxia (SCA), paraneoplastic syndrome, etc.
, which must be combined with clinical and imaging data for comprehensive analysis
.
In addition, it has been reported that measuring the midbrain/pont ratio can help distinguish MSA, PD, and progressive supranuclear palsy (PSP), see Figure 1-2
.
In recent years, 131I m-iodobenzylguanidine (131I-MIBG) test has been used more and more clinically, which is also helpful to distinguish PD from MSA, and its specificity is high
.
This is because 131I-MIBG can be taken up by cardiac postganglionic fibers, PD belongs to peripheral sympathetic postganglionic fibers damaged, and MSA belongs to central sympathetic preganglionic fibers
.
Therefore, the cardiac uptake rate of MSA patients is normal or slightly reduced, while the cardiac uptake rate of PD patients is significantly reduced
.

2 sphincter electromyography (EAS-EMG) features

The loss of neurons in MSA patients is manifested by prolonged time limit, increased percentage of polyphasic waves, and neurogenic damage such as autoelectric potential or satellite potential on EMG, which is mainly related to
Onuf nuclear neuron lesions.
However, it should be pointed out that in the early stage of MSA, the participation of Onuf nucleus does not seem to be prominent, and there are time-dependent characteristics, so the negative EMG result cannot completely rule out the diagnosis of MSA, and neurogenic damage can also see other diseases, such as PD, conus cauda equina lesions, etc
.
Tieson et al.
proposed that the average time limit of 13ms has good sensitivity and specificity
for distinguishing MSA and PD.
Vodusek proposes to distinguish MSA from PD on a 5-year time limit: if the EMG remains normal after 5 years of onset, MSA
can be excluded.

3 Evaluation of cognitive function

With the deepening of MSA research, it was found that MSA patients can have cognitive dysfunction, but all appear
in the middle and late stages of the disease.
Cognitive dysfunction is not included in the current early diagnostic criteria, and dementia is listed as not supported by diagnostic criteria
.
Stankovic et al.
emphasize that about 1/3 of MSA patients have cognitive impairment, especially frontal executive functions such as attention deficit and decreased
working memory.
The Simple Mental State Examination Scale (MMSE) and the Montreal Cognitive Assessment Scale (MoCA) scale should be preferred for initial screening for mild cognitive impairment or dementia
.
Tests of speech, visuospatial ability, and frontal executive function can also be performed by a neuropsychologist, as well as depression and anxiety assessment, which can help in the early diagnosis and treatment
of cognitive dysfunction in MSA patients.

04Diagnosis and differential diagnosis of MSA

In 2015, Fanciulli and Gregor proposed a new consensus on
diagnosis.
According to the clinical manifestations of Parkinson's disease symptoms and cerebellar ataxia, MSA is divided into MSA-P type and MSA-C type, that is, Parkinson's type and cerebellar type, but there is overlap and overlap
of clinical manifestations between each type.
The MSA-P type is pathologically degenerative of the substantia nigra of the striatum, and is clinically characterized by a rapidly progressive kinesia-rigidity syndrome characterized by reduced and slow movement, accompanied by muscle stiffness and passive motor resistance
.
The MSA-C type pathologically belongs to the degeneration of pontine cerebellar atrophy, and the clinical manifestations are progressive gait and limb ataxia, starting from the lower limbs, and the performance of the lower limbs is prominent
.
In practice, many patients exhibit mixed phenotypes
.
In the context of a diagnosis of Parkinson's symptoms or cerebellar symptoms that are insensitive to levodopa treatment, the severity of autonomic dysfunction is the most important distinguishing point
between possible and likely MSA diagnoses.
The presence of urinary incontinence (erectile dysfunction in men) or OH systolic blood pressure drop of ≥ 30 mmHg or diastolic blood pressure of ≥ 15 mmHg is called autonomic failure and supports a likely MSA diagnosis, whereas conversely, failure to meet criteria for autonomic failure is called possible MSA
.

For the differentiation of MSA and PD, in addition to the previous imaging and other aspects, clinical can also be distinguished by some non-motor symptoms as shown in Table 2
.
PD tends to be urinary frequency, urgency, and rarely urinary incontinence, while MSA is ED first, followed by dysuria, and finally OH.

Secondly, there are some differences between the two in terms of age of onset, course of disease and rate of progression: (1) MSA has an earlier age of onset; (2) MSA patients have a shorter duration of drug efficacy; (3) From the onset of motor symptoms to the occurrence of frequent falls, catheterization, dysarthria or dysphagia, wheelchair dependence and other series of events, MSA patients appear
at short intervals.
Due to the rapid progression of MSA, patients with early autonomic dysfunction have a poor prognosis, and poor response to dopaminergic drug therapy also help to distinguish between the two
.
Most clinicians think that MSA is not sensitive to levodopa response and abandons proper treatment, but studies have shown that more than 40% of MSA patients may be effective, and treatment should be trialed by gradually increasing the dose for > 3 months (if the patient can tolerate, the daily dose of levodopa can reach more than 1000mg/day), so early diagnosis and intervention are extremely important
.
In addition to the first-line drug levodopa, dopamine agonists are recommended as second-line drugs, but adverse reactions
such as hypotension, nausea, and edema should be paid attention to after medication.
Amantadine as a third-line drug can be gradually increased to 100 mg three times a day, but if symptoms do not resolve, it is recommended to stop it
as soon as possible.
Treatment of non-motor symptoms of MSA is of greater concern, such as routine screening for urinary tract infections in MSA patients with neurogenic bladder symptoms; Intermittent catheterization is the first-line therapy for patients with residual urine volume > 100 ml of urinary retention; For patients with severe depression and anxiety, serotonin reuptake inhibitors can be selected, and the adverse effects of OH and urinary retention are low
.

05Summary and prospect

In conclusion, the clinical diagnosis of MSA is easily confused with other types of neurodegenerative diseases, especially PD, and early recognition is difficult
.
The following key points should be noted: (1) The clinical manifestations of early autonomic dysfunction of MSA are the most prominent, especially the symptoms of urinary and cardiovascular systems, which account for a large proportion and are of great help to early identification; (2) The age of onset of MSA is earlier than that of PD and other atypical PDs; (3) Rapid progression of the disease, especially non-motor symptoms; (4) If the imaging is reviewed dynamically, it is more helpful
for the diagnosis of MSA.
However, due to the obvious clinical heterogeneity of MSA, especially the overlap between MSA and PD, it needs to be further clinically verified, and it is difficult to identify early and the course of the disease is very important, and it is recommended to follow up to observe the efficacy of the drug and monitor imaging dynamically to find supporting evidence
for clinical diagnosis.