Coexistence of Multiple Sclerosis and Spinocerebellar Ataxia Type-8

Abstract

Cerebellar dysfunction is likely to cause severe and treatment-resistant disability in multiple sclerosis (MS). Certain spinocerebellar ataxia (SCA)-related alleles can increase MS susceptibility, and channel polymorphisms can impact disability measures. Following an index patient with the coexistence of MS and SCA Type-8 (SCA8) in the MS clinic, an institutional engine search for MS and hereditary ataxia coexistence was conducted but did not reveal any other cases. This extremely rare coexistence of MS and SCA8 in our index patient may be incidental; however, a yet-to-be-identified contribution of coexistent hereditary ataxia(s) to the susceptibility of a prominent progressive ataxia MS phenotype cannot be ruled out.

Introduction

Cerebellar dysfunction causes severe and treatment-resistant disability in multiple sclerosis (MS).[1] In addition to neuroinflammation and neurodegeneration, alternative mechanisms like channelopathies may impact cerebellar dysfunction in MS.[1] Acquired channelopathies and hereditary channel polymorphisms are also associated with cerebellar symptom pathophysiology in MS.[2] Furthermore, spinocerebellar ataxia (SCA) alleles may be associated with increased MS susceptibility.[3]

Based on an index case with MS and SCA Type-8 (SCA8), we evaluated the potential coexistence of MS and hereditary ataxia(s) (HA) in our institution, considering the possible increase in MS susceptibility and worse MS disease outcomes with such coexistence.

Methods

Following an index patient identified with MS and SCA8 in the clinic, a keyword search was completed in our institutional search engine to identify cases with MS-HA coexistence between 1990 and 2022. Diagnostic codes for “hereditary ataxia, familial ataxia, Friedrich’s ataxia, spinocerebellar ataxia, episodic ataxia, ataxia telangiectasia, cerebellar ataxia” were searched among MS patients. Patient records were then reviewed for MS-HA coexistence. Patients who consented to medical record utilization for research were included.

Results

The search yielded 325 patients, but after further assessment, only our index patient was confirmed as having MS-HA coexistence.

Our index patient was a 30-year-old man who presented with slowing speech and declining sports performance starting at 19 years of age. He has had balance problems since he was 25 and cognitive problems and numbness in his fingers since he was 26. All his symptoms were slowly progressive.

His family originated from Western Europe with no family history of neurological diseases except for a paternal cousin with cerebellar ataxia. On examination, his speech was ataxic dysarthric but fluent. He had ataxic gait and dysmetria, increased patellar reflexes, clonus, and decreased vibration/proprioception in lower extremities. Cranial nerve and motor examination were unremarkable.

Brain magnetic resonance imaging (MRI) showed lesions typical for MS (Figure 1(a)-(e)) and prominent cerebellar atrophy (Figure 1(i)-(k)). Cervical and thoracic spinal cord MRIs demonstrated lesions consistent with MS (Figure 1(f)-(h)). Based on his progressive neurological symptoms, typical MS lesions in the brain and spinal cord, and oligoclonal band (OCB) positivity in the cerebrospinal fluid (CSF), he was diagnosed with MS.

Figure 1.

Brain and spinal cord MRIs of a patient with MS and SCA8 coexistence demonstrating MS lesions and cerebellar atrophy. (a–e) Brain MRI showed multiple subcortical, juxtacortical, and periventricular lesions typical for MS with the involvement of corpus callosum, cerebellar peduncles, and cerebellum. Brain axial: (a–c) T2, (d–e) T2 FLAIR. (f–h) Cervical and thoracic spinal cord MRIs demonstrated multiple short-segment T2 hyperintense lesions consistent with MS. (f) Cervical axial T2. (g) Cervical sagittal T2. (h) Thoracic sagittal T2. (i–k) Significant cerebellar atrophy was present in the absence of cerebral, brainstem, or cervical spinal cord atrophy and without high lesion burden in the cerebellum. Brain T1 MPRAGE: (i) coronal, (j) axial, and (k) sagittal.

As the brain MRI revealed diffuse profound cerebellar atrophy that could not only be explained by MS, further diagnostic workup, including blood work and genetic testing, was completed. Neurocognitive evaluation was not typical for MS and revealed difficulty in visuomotor coordination. Electromyography (EMG) was unremarkable. Nutritional, infectious, inflammatory etiologies and paraneoplastic syndromes were excluded. The genetic repeat expansion panel showed >150 CTG/CAG repeats in the ATXN8OS/ATXN8 genes (>70 repeats are positive), confirming a molecular diagnostic result for SCA8.

The case was diagnosed as primary progressive multiple sclerosis (PPMS) and SCA8 coexistence. The treatment plan included ocrelizumab and physical, occupational, and speech therapies.

Discussion

The index patient was diagnosed with PPMS and SCA8. SCA8 is an autosomal dominant HA due to (CTA·TAG)_n(CTG·CAG)_n repeat expansion in the ATXN8/ATXN8OS genes.[4, 5] Despite its incomplete penetrance, >70 repeats are associated with higher penetrance, referred to as pathogenic expansion and important for SCA8 diagnosis.[4, 5] Our index patient’s presentation was consistent with SCA8 because he had pathogenic expansion (>150 repeats) with progressive cerebellar symptoms and diffuse cerebellar atrophy with low cerebellar lesion burden that cannot be explained by MS alone. Visuomotor coordination difficulty was also attributed to SCA8. There was no family history of HA except for a paternal cousin, but although SCA8 is an autosomal dominant condition, individuals with a pathologic expansion may appear asymptomatic due to incomplete penetrance.

Distinguishing SCA from MS can be challenging as they may both present with ataxia. HA often manifests with slowly progressive ataxia of speech, limbs, and gait.[5] MS can also manifest with worsening ataxia, but this may be more rapid due to relapses or slowly progressive in the progressive phase. MS diagnosis in this patient was supported by multiple typical MS lesions in the brain and spinal cord and by CSF OCB positivity in the setting of slowly progressive ataxia and sensory symptoms with a normal EMG. Also, although there were SCA8 cases demonstrating cerebral white matter hyperintensities,[6] spinal cord lesions are not associated with SCA8, and OCB positivity has not been reported in SCAs. The patient was diagnosed with PPMS because of the progressive nature of the sensory symptoms, which is uncommon in SCA8. However, radiologically isolated syndrome diagnosis instead of PPMS is also possible, as isolated sensory progression in MS is not as well described compared to motor/cerebellar progression.

Literature review revealed only four other cases with dual diagnoses of MS-HA.[7-10] Additionally, a nationwide genetic study revealed two MS patients with SCA8 expansions.[4] However, considering the incomplete penetrance,[5] the contribution of expansions to the phenotype remained unknown, with no clinical/radiological data available.[4] Expectedly, cerebellar symptoms were prominent and progressive in cases with such coexistence. Thus, it is important to consider MS and HA coexistence if a patient with MS presents with an uncommonly prominent progressive ataxia. These reports do not indicate causation but support a potential genetic association between HA and MS and suggest the likely impact of HA on MS susceptibility as previously described for certain SCA2 alleles and ATXN1 gene.[3, 11]

Potential connection between SCA8 or its protein product ataxin-8 and MS has not been studied, but several findings might be relevant to our case. Ataxin-1 has immunomodulatory properties, and ataxin-1 deficiency can increase neuroinflammation and disease severity in experimental autoimmune encephalomyelitis (EAE).[11] The effect of mutant forms of ataxin on neuroinflammation is not fully understood, but EAE disease course of mice with increased CAG repeats was found similar to those with partial ATXN1 knockout,[11] suggesting that mutant forms can potentially have an attenuated immunomodulatory effect and can increase MS susceptibility and disease severity.

Furthermore, cerebellar channelopathies, whether hereditary or acquired, are likely to contribute to cerebellar symptoms and disability in MS.[1, 2] Polymorphisms in the gene encoding Nav1.8 sodium channel (SCN10A) were associated with a worse disability and decreased cerebellar functional connectivity in MS, suggesting an impact of hereditary channelopathies on prominent cerebellar dysfunction in MS.[2] SCA8 is not typically considered a channelopathy, but inhibition of KLHL1 expression, which potentially partakes in SCA8 pathophysiology, can lead to P/Q type calcium channel dysfunction.[12] Although the role of KLHL1 and the changes in its expression in SCA8 are unclear, the possible effect of channelopathy on the SCA8 pathophysiology is nevertheless intriguing. Additionally, dalfampridine, a voltage-gated potassium channel blocker that can be used in MS to treat gait disturbances and ataxia symptomatically, was used experimentally in HA.[13] Due to this potential commonality in the pathophysiology of MS and HA, especially those with channelopathies, we also investigated the coexistence of MS with other subtypes of HA.

Our engine search yielded 325 patients, but a review of patient records confirmed the MS-HA coexistence only in our index patient. This might be related to the following: (1) Based on the diagnostic codes (HA, common HA types, cerebellar ataxia), we might have missed cases if these diagnoses were not entered into the records. (2) Since the keyword “cerebellar ataxia” is commonly used in MS, it might have overestimated the number of potential cases in the first place. (3) As both MS and HA have overlapping symptoms, atypical/severe symptoms might have been attributed only to MS or HA instead of further investigating a potential coexistence. (4) Even if a potential coexistence was investigated in certain MS cases, a limited/inadequate genetic evaluation might not have revealed HA diagnosis.

Dual diagnosis of MS-SCA8 in our index patient may be incidental because our search did not reveal any other confirmed case with such coexistence. However, the contribution of yet-to-be-defined coexistent HA in MS susceptibility and prominent progressive ataxia phenotype in MS cannot be ruled out without systematic and extensive genotype-phenotype studies.