Multiple system atrophy (MSA) is a progressive neurodegenerative disease of the central nervous system characterized by parkinsonism, ataxia, and autonomic dysfunction.
Previously, multiple system atrophy was classified separately as olivopontocerebellar atrophy (predominantly cerebellar symptoms), striatonigral degeneration (predominantly parkinsonism), and Shy-Drager syndrome (predominantly autonomic symptoms). Currently, these are unified into two types: cerebellar type (MSA-C) and parkinsonian type (MSA-P).
The incidence in the United States is reported to be 0.6 to 3.0 per 100,000 people. The male-to-female ratio is approximately equal (some reports indicate 1.3:1), and the age of onset is most common in the early 50s, with a peak at 55 to 60 years. The average life expectancy after diagnosis is 6 to 10 years.
In MSA, ophthalmic signs occur in both the afferent (pupil) and efferent (eye movement) pathways. Diagnosis is often difficult; a retrospective study reported that it takes an average of 9.08 years from symptom onset to MSA diagnosis and an average of 2.89 years from deep brain stimulation (DBS) to MSA diagnosis. 4)
In MSA-C, nystagmus, vestibulo-ocular reflex impairment, and saccadic abnormalities due to cerebellar degeneration are prominent. In MSA-P, blepharospasm and pupillary abnormalities due to parkinsonism tend to be more common. However, findings overlap between the two types, so eye symptoms cannot be determined by type alone.
The most common signs of MSA are parkinsonism (87%) and cerebellar ataxia (54%). Ocular motor abnormalities have been reported in a study of 30 cases with the following frequencies.
MSA-C Key Findings
Square-wave jerks (SWJ): Excessive SWJ were observed in 21/30 cases (70%).
Gaze-evoked nystagmus: Observed in 12/30 cases (40%).
Positional downbeat nystagmus: Observed in 10/30 cases (33%).
Vestibulo-ocular reflex (VOR) impairment: Gaze shift disappears on head impulse test due to cerebellar degeneration.
MSA-P Major Findings
Saccadic hypometria: observed in 22/30 cases (73%).
Smooth pursuit eye movement impairment: more common in the horizontal direction, rare in the vertical direction.
Blepharospasm: occurs in association with parkinsonism.
Pupillary abnormalities: detected in about 1/4 of cases using infrared pupillometry. One of the earliest ocular symptoms. Usually bilateral and symmetric.
Cases with saccadic intrusions, intermittent macrosaccadic oscillations, and opsoclonus detected by VNG (videonystagmography) have also been reported. 1) For quantitative evaluation of eye movements, EOG (electrooculography) is used to record parameters such as visually guided saccades (latency, amplitude), pursuit (gain), VOR (gain), and fixation (nystagmus waveform, SWJ latency). Eventually, many patients develop gaze fixation.
Cerebellar degeneration impairs the vestibulo-ocular reflex, so the eyes do not properly compensate for head movements, causing the scenery to appear shaky. Among eye movement abnormalities, oscillopsia directly affects patients’ daily lives.
The direct cause of MSA is thought to be neuronal death resulting from the accumulation of misfolded α-synuclein within oligodendrocytes.
The consensus diagnostic criteria for MSA consist of four symptom domains: ① autonomic and urinary dysfunction, ② parkinsonism, ③ cerebellar ataxia, and ④ corticospinal tract dysfunction.
Based on the level of certainty, it is classified into the following three levels.
| Level of Certainty | Key Points of Criteria |
|---|---|
| Possible | At least one sign of autonomic failure + one other criterion |
| Probable | Autonomic failure + parkinsonism or cerebellar ataxia + poor levodopa response |
| Definite | Requires postmortem pathological confirmation |
Definition of autonomic failure in probable MSA: urinary incontinence (accompanied by erectile dysfunction in men) or a drop in blood pressure within 3 minutes of standing (systolic ≥30 mmHg or diastolic ≥15 mmHg). The MDS 2022 MSA diagnostic criteria (Wenning et al. 2022) introduced the concept of “clinically established MSA.” 2)
Ophthalmic “red flag” criteria suggestive of MSA include: excessive SWJ, moderate saccadic hypometria, VOR impairment, and nystagmus. VNG (video nystagmography) is useful for detecting early eye movement abnormalities in MSA. 1) In some MSA-P patients, eye movement abnormalities have been detected before MRI findings. 1)
Quantitative evaluation of eye movements using EOG records visually guided saccades (latency, amplitude), pursuit (gain), VOR (gain), and fixation (nystagmus waveform, SWJ latency).
In MSA, excessive SWJ, moderate saccadic hypometria, VOR impairment, and nystagmus are red flags for differentiation. If vertical gaze palsy is present, PSP should be considered first. In PD, oculomotor disturbances are often mild. Quantitative evaluation using VNG or EOG is useful for differentiation.
There is no established curative treatment for MSA, and symptomatic therapy is the mainstay.
DBS is not recommended for MSA patients. In a retrospective study of 12 patients, 9 showed temporary improvement but 7 experienced overall worsening. Adverse events such as cognitive impairment, gait difficulty, autonomic dysfunction, and dystonia occurred, requiring DBS cessation in 4 patients. 4)
Botulinum toxin injection is effective. If dry eye is also present, artificial tears and eyelid hygiene should be used together. Blepharospasm can occur during the course of MSA and significantly impacts daily life, so early consultation with an ophthalmologist is recommended.
Misfolded α-synuclein accumulates in oligodendrocytes to form GCI (glial cytoplasmic inclusions), impairing glial cell function and leading to neuronal death. The main sites of neuronal loss and gliosis are the external segment of the globus pallidus, caudate nucleus, putamen, substantia nigra, inferior olivary nucleus, pontine nuclei, cerebellar Purkinje cells, and the intermediolateral nucleus of the spinal cord (ICC).
The following three hypotheses have been proposed for the pathogenesis of opsoclonus. 2)
| Hypothesis | Proposed mechanism |
|---|---|
| Pontine theory | ON damage in the raphe interpositus of the pontine tegmentum → burst cell disinhibition |
| Brainstem theory | Changes in synaptic membrane properties between ON and burst cells → enhanced post-inhibitory rebound excitation |
| Cerebellar theory | Purkinje cell dysfunction → disinhibition of fastigial nucleus (FN) → FN strongly inhibits ON → burst cell hyperactivity |
The cerebellar theory is currently the most supported hypothesis, with fMRI confirming increased FN activation. 2)
Matsuoka et al. (2022) reported the world’s first first-in-human PET study using 18F-SPAL-T-06 to visualize α-synuclein lesions in MSA patients in vivo. 3) PET was performed in 2 MSA-P patients, 1 MSA-C patient, and 1 healthy control (72 years old). In MSA-P, increased SPAL-T-06 accumulation was observed in the putamen; in MSA-C, increased accumulation was also seen in the pons, cerebellar white matter, and cerebellar peduncles. The healthy control showed no significant accumulation in corresponding areas. The probe had a dissociation constant Kd = 2.49 nM (high affinity), and displacement by MAO-A/B inhibitors was minimal (minimal off-target effects). A topology consistent with the GCI distribution pattern was confirmed.
This study is foundational research with potential applications to Parkinson’s disease and dementia with Lewy bodies. It is expected to contribute to future diagnosis and disease understanding.
Cannilla et al. (2024) reported a systematic review of drug- and toxin-induced opsoclonus involving 30 articles and 158 cases, and described the first case of amantadine-induced opsoclonus in an MSA patient (Naranjo score 7). 2)
In a retrospective study by Badihian et al. (2022), 12 out of 1,496 MSA patients had undergone DBS, and 9 were diagnosed with PD at the time of surgery. 4) Red flags for atypical parkinsonism were present in all cases before surgery, suggesting the importance of preoperative autonomic function testing. The issue of MSA being misdiagnosed as PD and undergoing DBS remains a challenge.
As of 2022, the first-in-human study has been reported, but it is still at the research stage. Future applications to Parkinson’s disease and dementia with Lewy bodies are being considered. It is not available for general clinical use.
Wei Y, Chen J, Lu C, et al. Multiple system atrophy with oculomotor abnormalities as a prominent manifestation: A case series. Medicine. 2023;102(25):e34008.
Cannilla H, Messe M, Girardin F, et al. Drug- and Toxin-Induced Opsoclonus – a Systematized Review, including a Case Report on Amantadine-Induced Opsoclonus in Multiple System Atrophy. Tremor Other Hyperkinet Mov. 2024;14(1):23, 1-18.
Matsuoka K, Ono M, Takado Y, et al. High-Contrast Imaging of α-Synuclein Pathologies in Living Patients with Multiple System Atrophy. Mov Disord. 2022;37(10):2159-2161.
Badihian N, Jackson LM, Klassen BT, et al. The Effects of Deep Brain Stimulation in Patients with Multiple System Atrophy. J Parkinsons Dis. 2022;12(8):2595-2600.
Wang M, Wang Y, Yang Y, et al. A case report and literature review of possible multiple system atrophy–parkinsonian type with cholinergic deficiency. CNS Neurosci Ther. 2023;29:2384-2387.
