Multiple system atrophy (MSA) is a sporadic neuro-degenerative disease with adult onset characterized by a combination of parkinsonism, cerebellar ataxia, py-ramidal signs, and autonomic deficiency symptoms ¹. MSA is one of the Parkinson plus syndromes included in the differential diagnosis of Parkinson's Disease (PD). Its incidence is 4.4/100000 ². There are no therapeutic options which cure the disease apart from symptomatic drugs ³. The second consensus state-ment on the diagnosis of MSA criteria are used for the diagnosis of MSA. According to these criteria, patients are diagnosed with definite, probable, or possible MSA ⁴.

In clinical practice, clinicians have to rely on diagnos-tic criteria for MSA. But, there are no reliable biologi-cal markers. Thus, clinicians can need to see brain imaging characteristics of MSA. However, the clinical diagnostic accuracy of MSA varies between 60% and 90% even in the late stage of the disease ^5,6. Espe-cially the early stage diagnostic accuracy of MSA is unknown ⁷. For this reason, there should be im-provements in clinical diagnosis criteria to increase diagnostic accuracy are of great importance.

The purpose of this study is to review diagnostic chal-lenges of MSA in view of the literature and assess clinical characteristics of patients diagnosed with prob-able MSA with regard to clinical subtypes of MSA-P and MSA-C.

Patients followed-up with MSA diagnosis at the Movement Disorders Polyclinic, Neurology Department, Erciyes University Faculty of Medicine Hospital between June 2014 and December 2016 were included in this study. The approval of the local ethics commit-tee was obtained and the consent of the patients was received. Eleven patients followed-up with probable MSA diagnosis according to the second consensus statement on the diagnosis of MSA criteria were in-cluded in the study ⁴. The patients were categorized for different types of MSA-P and MSA-C by a clini-cian with experience in movement disorders.

Patient files were reviewed retrospectively and the latest clinical examination characteristics were noted. Cranial magnetic resonance images (MRI) of all pa-tients were reviewed as well. Characteristics of peri-putaminal hyperintensity (rim sign), putaminal hy-pointensity, atrophy of the brainstem and middle cere-bellar peduncle, and the hot cross bun sign were deter-mined, if present. Additionally; initial symptoms, ini-tial diagnosis, treatment responses, the course of the disease in time, additional symptoms, previous cranial images (if available), disabling symptoms, and pre-dominant clinical characteristics of the patients were assessed with regard to their fit with respective sub-types of MSA. Global disability status was determined for each patient according to their Unified Multiple System Atrophy Rating Scale (UMSARS) scores in order to assess clinical progression of MSA ⁸.

Statistics
Demographical and clinical data obtained from the participants within the scope of the study were evaluat-ed with descriptive statistics. Mean ± SD and median 25 and 75 percentile values are presented. The results of the frequency analysis applied to certain data can be seen in Table 1 and 2. Statistical Package for the Social Sciences 15.0 (SPSS 15.0) was used for analysis.

The mean age of the patients was found 65.36. Six patients were female. The average disease time was 4 years. Ten patients were not diagnosed with MSA by the clinician when they applied with the onset of symp-toms. Only one patient was diagnosed with MSA cor-rectly. Seven out of ten patients were diagnosed with PD, whereas the other three patients were diagnosed with ataxia. Table 1 shows the demographic data about the patients.

Table 1: Demographic features of patients with MSA.

Clinical examination characteristics and observations of the patients were reviewed. Considering initial symptoms, five patients presented cerebellar findings, four patients presented parkinsonian findings, and two patients had cerebellar+parkinsonian findings (mixed). It was found that all patients had atrophy of the brain-stem and middle cerebellar peduncle and the hot cross bun sign. Neurogenic orthostatic hypotension symp-toms were observed in 10 patients. Seven patients were diagnosed with MSA-C and four patients were diag-nosed with probable MSA-P after assessment accord-ing to diagnostic criteria. All MSA-P patients and four MSA-C patients had received L-dopa treatment. How-ever, three MSA-C patients had been forced to give up the L-dopa treatment since it worsened neurogenic orthostatic hypotension symptoms. Clinical character-istics of the MSA patients can be seen in Table 2.

Table 2: The clinical features of patients with MSA.

Nine out of eleven patients had presented Rapid eye movement (REM) sleep behavior disorder (RBD) symptoms before the onset of symptoms. An assess-ment of the patients based on their latest examination findings showed that all patients required help with balance in everyday life activities according to the global disability scale. Four patients in particular had become wheelchair-bound due to cerebellar symptoms (stage 5). There is seen MRI image of a patient fol-lowed-up with MSA-C below (Figure 1).

Figure 1: The MRI scan of one patient with MSA-C. The hot cross bun sign of the pon and cerebellar atrophy is very common on course of the MSA.

In this study, we found that MSA patients are not accu-rately diagnosed especially in initial years where the symptoms start to manifest themselves. Only one in eleven patients followed-up had been accurately diag-nosed. This finding shows that there are diagnostic challenges throughout the clinical course of MSA, especially for patients who are followed-up in places other than centers specializing in movement disorders. The accurate diagnosis of MSA is significant for ap-propriate patient management, particularly in early stages of the disease where the symptoms are not yet fully manifested. However, as far as early diagnosis goes, it is obvious that the existing clinical diagnostic criteria have certain challenges. In this context, it should be mentioned that up-to-date laboratory and clinical findings may contribute to the accuracy of the diagnosis ⁹.

Today, an increasing number of publications highlight the challenges in MSA diagnosis ^9,10. Existing clin-ical diagnostic criteria used for MSA have various limitations. First of all, these criteria mostly focus on motor findings associated with the disease. Parkinson-ism and cerebellar ataxia non-responsive to L-dopa are not uncommon cases and may be observed in many disorders other than MSA ^11,12. Secondly, auto-nomic deficiency and genitourinary dysfunction in particular are not specific to MSA. These may be ob-served in other neurodegenerative diseases and even in healthy individuals between the ages of 50-60 ^13,14. Thirdly, orthostatic hypotension may be seen in many cases other than MSA. For example, it is reported in a study that 20% of PD patients present orthostatic hypo-tension ¹⁵. The fourth limitation is that both auto-nomic deficiency and motor symptoms are necessary for MSA diagnosis. However, autonomic deficiency and motor symptoms do not develop concurrently in many MSA patients. While some patients present auto-nomic deficiency from the onset of the disease, some do not show any symptoms even after 15 years ¹⁶. Indeed, one of our patients (Table 2, case 11) had the symptoms for four years, yet did not present orthostatic hypotension to this day.

A considerable number of patients are not correctly diagnosed with MSA during their lifetime due to diffi-culties in differentiating it from other diseases. (PD, pure autonomic failure, other rare movement disor-ders). MSA may be accompanied by Parkinsonian symptoms quite frequently. About 10% of patients diagnosed with Parkinson’s Disease are reported to have MSA at autopsy. About 29-33% of patients who present isolated late-onset cerebellar ataxia and 8-10% of patients with Parkinsonism develop MSA. For this reason, it is safe to assume a higher prevalence than estimations ¹⁷.

The EMSA registry study examined 437 patients diag-nosed with MSA. Sixty-eight percent of these patients were found to have symptoms that fit MSA-P and 32% were found to have symptoms that fit MSA-C. While 99% of the patients had autonomic deficiency symp-toms (urinary symptoms, orthostatic hypotension, and chronic constipation), 87% had Parkinsonism, 64% had ataxia, and 43% had pyramidal symptoms. Additional-ly, 41% of the patients showed signs of depression ¹⁰. As explained above, MSA may be manifested with different symptoms, and the clinical table may be heterogeneous, which causes diagnostic challenges for the clinician ¹⁸.

Imaging methods are frequently used for the clinically differential diagnosis of MSA. These methods include MRI, positron emission tomography (PET), and single photon emission computed tomography (SPECT). Issues related to nerve supply to heart may demonstrate an association with MSA or PD, which may be deter-mined using PET and SPECT scans. Also, it is not possible to exclude MSA due to normal dopamine transporter imaging. The hot cross bun sign is ob-served in 63% of MSA-P patients and 80% of MSA-C patients ¹⁷. This presentation may be observed in variant Creutzfeldt-Jakob disease, spinocerebellar atax-ia, cerebrotendinous xanthomatosis, and vasculitis-associated parkinsonism as well ^19-21. In addition, it has been shown in a considerable number of studies that lateral slit-like hyperintense putaminal rim and putaminal hypointensity are observed more frequently on conventional brain MRIs of MSA patients compared to controls and PD patients ^22,23.

It is recommended that clinicians pay attention to cer-tain characteristics to improve the accuracy of differen-tial MSA diagnosis ⁹. Table 3 shows these character-istics recommended for clinically differential diagnosis of MSA.

Table 3: Recent clinical and investigation findings based on clinical judgment to be considered in future.

The relatively low number of patients included in the study and lack of neuropathological examination of our MSA patients may be accepted as limitations of our study.

MSA is frequently diagnosed inaccurately by clinicians examining the patient for the first time, particularly in initial years of the disease. Therefore, clinicians should be careful and try their best to observe red flags while examining patients who may have differential symp-toms associated with MSA.