Neuro-ophthalmic Manifestations of Multiple System Atrophy

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Disease

Multiple systems atrophy (MSA) is a rare progressive neurodegenerative disorder of the central nervous system (CNS) characterized by parkinsonism, ataxia and autonomic dysfunction.[1] Previously, the disease was subcategorized based on the primary phenotype of the patient – olivopontocerebellar atrophy (cerebellar features), striatonigral degeneration (parkinsonism), and Shy-Drager syndrome (autonomic features). The classification is now streamlined into MSA cerebellar or parkinsonism predominant types (MSA-C and MSA-P). The clinical features of MSA are caused by degeneration of neurons in the brain, particularly the cerebellum (MSA-C) and basal ganglia (MSA-P).[2] Typical ophthalmologic manifestations of MSA may be both afferent (pupil) and efferent (eye movement).[1] Pathophysiology The pathophysiology of MSA involves neuronal loss and gliosis within the globus pallidus externus, caudate, putamen, substantia nigra, inferior olivary nuclei, pontine nuclei, cerebellar Purkinje cells, and spinal intermediate cell columns (ICC). An accumulation of a misfolded form of alpha-synuclein impairs function of glial cells leading to neuron death.[3] The hallmark histopathological sign is the finding of abnormal intracellular alpha-synuclein aggregates in glial cells known as Papp-Lantos bodies or glial cytoplasmic inclusions (GCI) in the hindbrain/basal ganglia. The most frequent locations of GCI’s are the cerebellum, pontine nuclei, inferior olivary nuclei or substantia nigra.[4] The exact cause of these inclusions has yet to be established. No nucleotide sequence changes have been noted in the alpha-synuclein gene in patients with multiple system atrophy.[5] On gross pathologic examination, the cerebral cortex in patients with MSA is degenerated particularly in the frontal lobes. The cerebellum and midbrain may also show gross atrophy. [6]

Epidemiology

The annual incidence of MSA is 3.0 per 100,000. It affects 1.3:1 males to females. The symptoms of MSA typically begin in the early fifth decade of life with a mean age of onset of 54 years and the median survival is 8.5 years.[7]

History

Patients with MSA may present with parkinsonism features (typically akinetic-rigid Parkinsons, or dystonias and dyskinesias), autonomic symptoms (including orthostatic hypotension and erectile dysfunction), dysphagia, and cerebellar signs (ataxia, nystagmus, dysarthria).[1] The presentation is typically subacute and slowly progressive, similar to other neurodegenerative disorders. Oscillopsia is a common neuro-ophthalmic symptom in MSA, although patients may be visually asymptomatic.[1]

Signs

The most common signs of SMA are parkinsonism (87% of patients) and cerebellar ataxia (54% of patients). Other signs include orthostatic hypotension, gastrointestinal dysmotility, enuresis, encopresis and dysphagia.[1] Ocular findings in MSA are less common but are less recognized. These include ophthalmoplegia, excessive square-wave jerks[7], blepharospasm, hypometria of saccades, impaired smooth pursuit movement, pupillary defects, nystagmus, and reduced vestibular-ocular reflex.[1] Visual acuity, color vision and visual fields are typically spared in MSA. Several ocular manifestation of MSA relate to autonomic dysfunction including blepharospasm, absence of blink reflex and dry eye – the dry eye is a result of motor dysfunction affecting blink rate in addition to autonomic dysfunction. As with other parkinsonian syndromes, reflexes (both acoustic blink reflex and acoustic startle reflex) and ocular motility (both spontaneous and voluntary movements) are impaired. Impaired ocular motility eventually leads to ocular fixation in a significant portion of SMA patients. Abnormal horizontal saccadic and smooth pursuit eye movements are seen in many SMA patients. In contrast, vertical smooth pursuit and saccadic movements are rarely impaired. In a study of oculomotor patient with SMA, 21 out of 30 patients demonstrated excessive square-wave jerks. 12/30 experienced a gaze evoked nystagmus and 10/30 experienced a positioning down-beat nystagmus.[8] Saccadic hypometria was evident in 22/30 patients.[8] The presence of a vertical gaze palsy with parkinsonism might prompt the clinician to consider another parkinsonism syndrome, such as progressive supranuclear palsy.[8] Due to cerebellar degeneration, the vestibular ocular reflex can be impaired, resulting in a lack of gaze change in the rapid head impulse test.[9] The impaired reflex can also lead to the sensation of oscillopsia.[9] Infrared pupillography has revealed that about one quarter of patients with MSA have abnormal pupillary reactivity. Pupillary dysfunction is one of the earliest ocular manifestations of SMA, and when seen is typically bilateral and symmetric.[10]

Diagnosis

The consensus criteria for MSA include four domains of symptoms: autonomic/urinary dysfunction, parkinsonism, cerebellar ataxia, and corticospinal dysfunction. A diagnosis of “possible” MSA requires at least one feature of dysautonomia and one other these criteria. “Probable” MSA require autonomic failure, presence of either parkinsonism or cerebellar ataxia and a poor response to levodopa. A diagnosis of definite MSA require pathological confirmation post-mortem.[11] The ocular manifestations of MSA may overlap with other parkinsonian syndromes including Parkinson’s disease, dementia from Lewy bodies, and progressive supranuclear palsy. Several authors have published ocular “red flag” criteria which are more suggestive of a diagnosis of MSA compared to other conditions – these include excessive square-wave jerks, moderate hypometria of saccades, impaired vestibular-ocular reflexes and nystagmus.[8] Patients will usually have magnetic resonance imaging (MRI) of their brain and possibly their spinal cord, depending on their presentation. Findings of disproportionate atrophy of the cerebellum, pons, or basal ganglia, may support the diagnosis of MSA. Workup for other causes of dysautonomia, cerebellar syndromes, and parkinsonism syndromes is also commonly performed due to the lack of a specific diagnostic test for MSA.

Management

There is no proven effective treatment for MSA, and management is typically symptomatic. Levodopa therapy can be trialed for parkinsonian rigidity but typically only one third respond.[1] Orthostatic hypotension can be managed with fludrocortisone, pyridostigmine or midodrine. Dry eyes and blepharitis can be treated with topical anti-inflammatory drops, topical tears/ointments, lid hygiene (lid scrubs) and oral medications (doxycycline). Blepharospasm can be treated with botulinum toxin injection.[1]

Prognosis

As with most neurodegenerative disorders, patients will usually progressively worsen, with median survival time of 8.5 years.

Summary

Patients with MSA may present with cerebellar or parkinsonism predominant phenotypes. Ocular symptoms include dry eye, saccadic abnormalities, and cerebellar nystagmus. There is no proven effective treatment for MSA and the prognosis is poor.

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Armstrong RA. Visual signs and symptoms of multiple system atrophy. Clin Exp Optom. 2014 Nov;97(6):483-91. doi: 10.1111/cxo.12206. Epub 2014 Sep 25. PMID: 25256122.
  2. Fanciulli A, Stankovic I, Krismer F, Seppi K, Levin J, Wenning GK. Multiple system atrophy. Int Rev Neurobiol. 2019;149:137-192. doi: 10.1016/bs.irn.2019.10.004. Epub 2019 Nov 21. PMID: 31779811.
  3. Lantos PL, Papp MI. Cellular pathology of multiple system atrophy: a review. J Neurol Neurosurg Psychiatry. 1994;57(2):129-133. doi:10.1136/jnnp.57.2.129
  4. Wenning GK, Tison F, Ben Shlomo Y, Daniel SE, Quinn NP. Multiple system atrophy: a review of 203 pathologically proven cases. Mov Disord. 1997 Mar;12(2):133-47. doi: 10.1002/mds.870120203. PMID: 9087971.
  5. Ozawa T, Takano H, Onodera O, et al. No mutation in the entire coding region of the alpha-synuclein gene in pathologically confirmed cases of multiple system atrophy. Neuroscience Letters. 1999 Jul;270(2):110-112. DOI: 10.1016/s0304-3940(99)00475-9.
  6. Horimoto Y, Aiba I, Yasuda T, Ohkawa Y, Katayama T, Yokokawa Y, Goto A, Ito Y. Cerebral atrophy in multiple system atrophy by MRI. J Neurol Sci. 2000 Feb 15;173(2):109-12. doi: 10.1016/s0022-510x(99)00308-1. PMID: 10675653.
  7. 7.0 7.1 Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Incidence of progressive supranuclear palsy and multiple system atrophy in Olmsted County, Minnesota, 1976 to 1990. Neurology. 1997 Nov;49(5):1284-8. doi: 10.1212/wnl.49.5.1284. PMID: 9371909.
  8. 8.0 8.1 8.2 8.3 Anderson T, Luxon L, Quinn N, Daniel S, David Marsden C, Bronstein A. Oculomotor function in multiple system atrophy: clinical and laboratory features in 30 patients. Mov Disord. 2008 May 15;23(7):977-984. doi: 10.1002/mds.21999. PMID: 18383533.
  9. 9.0 9.1 Rascol O, Sabatini U, Fabre N, Senard JM, Simonetta-Moreau M, Montastruc JL, Clanet M, Rascol A. Abnormal vestibuloocular reflex cancellation in multiple system atrophy and progressive supranuclear palsy but not in Parkinson's disease. Mov Disord. 1995 Mar;10(2):163-70. doi: 10.1002/mds.870100206. PMID: 7753058.
  10. Bremner F, Smith S. Pupil findings in a consecutive series of 150 patients with generalised autonomic neuropathy. J Neurol Neurosurg Psychiatry. 2006;77(10):1163-1168. doi:10.1136/jnnp.2006.092833
  11. Gilman S, Low PA, Quinn N, Albanese A, Ben-Shlomo Y, Fowler CJ, Kaufmann H, Klockgether T, Lang AE, Lantos PL, Litvan I, Mathias CJ, Oliver E, Robertson D, Schatz I, Wenning GK. Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci. 1999 Feb 1;163(1):94-8. doi: 10.1016/s0022-510x(98)00304-9. PMID: 10223419.