Dear Editor,

Alexander dsease (AxD) is a progressive astrocytic leukodystrophy primarily attributed to autosomal dominant or de novo mutations in the GFAP gene [1]. AxD presents differently across age groups and is classified into infantile, juvenile, and adult subtypes, each with its own set of symptoms and prognoses. Adultonset AxD is characterized by bulbar symptoms, ataxia, autonomic dysfunction, and gait disturbance, while juvenile- and infantile-onset AxD are characterized by cognitive impairment, developmental delay, seizures, and encephalopathy [1,2]. Radiological findings in patients with a younger age of onset have revealed extensive frontal dominant white matter changes on magnetic resonance imaging (MRI), while late-onset patients exhibited a predominance of posterior fossa white matter abnormalities and atrophy of the brainstem, cerebellum and cervical cord [1,2]. Ocular motor disturbances, such as nystagmus, saccadic impairment, and oculopalatal myoclonus, associated with medullary, cerebellar, and upper cervical cord lesions have been reported in patients with adult-onset AxD [1,3]. However, vestibulopathy in a patient with adult-onset AxD has not been previously reported. Here, we report a case of combined vestibulopathy presenting late after the course of motor symptoms in a patient with adultonset AxD.

A 51-year-old man presented with abnormalities on cervical spine MRI after a minor car accident. He did not have any neurological symptoms, but on neurological examination, hyperreflexia in the bilateral deep tendon reflex of the knees was observed. His older brother had exhibited mental retardation and gait disturbance since childhood and committed suicide at the age of 52. His younger brother also exhibited mental retardation. However, his parents and three sisters exhibited no similar symptoms (Supplementary Figure 1 in the online-only Data Supplement). Cervical spine MRI revealed a lateral medullary cleft and marked cervicomedullary atrophy with intramedullary signal changes (Figure 1A). Brain MRI revealed tadpole-like brainstem atrophy (Figure 1B) and eyespot signs in the corticospinal tract of the medulla (Figure 1C and D) but no areas of hyperintensity in the cerebral cortex. Next-generation sequencing revealed a pathogenic heterozygous missense mutation of the GFAP gene, p.Arg376Pro (c.1127G>C), which was previously reported as a pathologic variant in AxD [4].

After two months, the patient began to complain of mild gait disturbance. His gait was spastic, and the spasticity was slowly progressive. At the age of 55, he started experiencing tinnitus, which was louder in the left ear. Two weeks after onset, he fell in a paddy field and was unconscious for several minutes. He had a small abrasion on the top of his head, but there was no other intracranial hemorrhage. Two months later, his gait worsened, and he experienced dysarthria and dizziness. Neurological examination revealed Medical Research Council (MRC) grade IV + weakness in the right upper and lower extremities. He exhibited mild impairment in his independent gait and tandem gait. The results of the Berg balance test were within the normal range (52/56). Neurotological examination revealed subtle spontaneous left-beating nystagmus without visual fixation and no gazeevoked nystagmus. After horizontal head shaking, a downbeat with counterclockwise (from the patient’s view) nystagmus was observed. He exhibited macrosaccadic oscillations during the positional maneuver. A catch-up saccade was observed during the rightward bedside head impulse test. There was no interval change in brain or cervical MRI. He was diagnosed with right vestibulopathy and treated with betahistine. After one month, the patient’s dizziness improved, and video-oculography (SLVNG; SLMED, Seoul, Korea) of eye motion revealed spontaneous macrosaccadic oscillations with fixation, which increased after the head shaking and positioning maneuvers. The following intermittent saccadic abnormalities were observed: increased latency, mild slowing, and mild dysmetria. The gain of smooth pursuit decreased bilaterally. The video-head impulse test (vHIT) demonstrated a mildly decreased gain in the horizontal canal and preserved gain in the vertical canals (Figure 1E). The bithermal caloric test (Figure 1F) and vestibular evoked myogenic potential were normal. Pure tone audiometry revealed a pattern of age-related high-tone hearing loss. After two months of vestibular rehabilitation, the patient’s dizziness improved, but his right-sided weakness and spastic gait persisted without further deterioration. The vHIT performed 10 months later showed improvement.

A variety of ocular motor findings are observed in patients with AxD, but this case is the first report of coexisting vestibulopathy. Ocular motor abnormalities are common features of adult-onset AxD, with nystagmus, particularly pendular nystagmus and gaze-evoked nystagmus, being prevalent, as well as saccadic dysfunction and oculopalatal myoclonus [3,5]. Ocular motor dysfunction typically emerges after disease onset and affects approximately 60% of patients [3]. The development of ocular motor dysfunction in AxD patients may be associated with structures involved in gaze holing or stabilization, including the flocculus and medullary areas, such as the medial vestibular nuclei and nuclei prepositus hypoglossi. Our findings regarding the vestibulo-ocular reflex (VOR) in this patient differ from those of previous reports. Our patient showed a decreased gain in the head impulse test and a preserved caloric response test. Previous reports have proposed that a positive head impulse test with a preserved caloric response is most likely caused by cerebellar flocculus dysfunction, considering the findings related to the high-frequency VOR [6-9]. This ocular motor finding is meaningful because it expands the neurotological spectrum of AxD. While no structural lesions were identified in the flocculus on brain MRI, cervicomedullary atrophy with intramedullary signal changes suggested broader implications for functional integration within the medulla and cerebellum. The primary areas affected by pathological changes in late-onset AxD are the brainstem and cerebellum [10]. Functional MRI of patients with bulbospinal type AxD revealed greater neuronal activity in the cerebellar vermis, cerebellopontine angle, and posterior parietal cortex, and voxel-based morphometry indicated overlapping white matter atrophy in these regions, as well as the medulla [11]. Notably, brain MRI did not reveal significant white matter lesions, suggesting a potential overload and collapse of the brain network with compensatory mechanisms involving the cerebellum, medulla and surrounding structures [11].

In addition, it is crucial to consider the possibility of late-onset vestibular symptoms in AxD patients, as previous reports have linked symptom exacerbation to minor head trauma [12-14]. Commonly reported symptoms following this type of trauma include deteriorating gait disturbance, dysarthria, and dysphagia, with no observable changes on brain or cervical MRI in most patients. However, one patient exhibited significant alterations on diffusion tensor imaging (DTI), with increased fractional anisotropy and decreased mean diffusivity in the corticospinal tracts, despite the absence of macrostructural changes on brain MRI [12]. These DTI changes are indicative of extracellular space reduction, posttraumatic astrocytic swelling, and reactive gliosis [13]. As AxD is an astrocytic leukodystrophy, it is believed to be associated with symptom aggravation due to the critical role of astrocytes in the aftermath of trauma. However, the exacerbation of motor symptoms has been confirmed only in the context of corticospinal tract degeneration. In our patient, both motor symptoms and vestibulopathy exacerbation occurred after mild head trauma, suggesting that this trauma might have triggered astrocyte damage within not only the corticospinal tract but also the peripheral and central vestibular system. Given that this patient had adult-onset AxD, which is typically less severe than juvenile- or infantile-onset AxD, these findings suggest that this patient had preserved astrocyte function [1,2]. The evolution of symptoms in our patient is particularly notable. While his gait aggravation persisted, his dizziness improved, and his vHIT notably normalized at follow-up 10 months after symptom onset. A recent study revealed that the compensatory mechanism for vestibulopathy involves microglia-associated neuroinflammation [15]. Additionally, a mouse model study revealed that microglia exhibit astrocyte dysfunction in AxD, inducing alterations in morphology and Ca2+ signaling, which can regulate the expression of various AxD pathologies [16]. Based on these findings, we conclude that the involvement of the vestibular system, including the flocculus, following minor head trauma resulted in the observed neurotological findings in the patient and that the recovery of vestibular dysfunction may be attributed to microglial regulation of AxD pathology and compensatory mechanisms [15,16].

In this report, we present the first case of adult-onset AxD with late-presenting vestibulopathy. Although motor symptoms such as ataxia and spastic paraparesis are common in patients with adult-onset AxD, it is important to consider associated ocular motor findings, particularly in cases involving the cervicomedullary regions. This case highlights the importance of performing a comprehensive assessment of the clinical spectrum and radiologic findings in adult-onset AxD patients.

Supplementary Materials

Notes

Ethics Statement

This study was conducted retrospectively, and informed consent was waived.

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

None

Author Contributions

Conceptualization: all authors. Data curation: all authors. Formal analysis: all authors. Funding acquisition: Eungseok Oh. Investigation: all authors. Methodology: all authors. Project administration: Seong-Hae Jeong, Eungseok Oh. Resources: Seong-Hae Jeong, Eungseok Oh. Supervision: Seong-Hae Jeong, Eungseok Oh. Validation: all authors. Visualization: Hee Jin Chang. Writing—original draft: Hee Jin Chang. Writing—review & editing: all authors.

Acknowledgments

The brain research resource (blood) was provided by Korea Brain Bank Network (Chungnam National University Brain Bank) operated through National Brain Bank Project and Korean Brain Central Bank promotion project funded by the Ministry of Science and ICT. We would like to express our sincerest gratitude to Korean Brain Central Bank for providing human brain research resources.

Figure 1.

Cervical MRI (A) and brain MRI (B-D) at initial presentation. Sagittal T2-weighted image revealing a lateral medullary cleft and marked cervicomedullary atrophy with intramedullary signal changes (A). Sagittal T1-weighted image revealing tadpole-like brainstem atrophy (B), and axial T2-weighted images revealing eyespot signs in the corticospinal tract of the medulla (C and D). Neurotologic evaluations after head trauma (E and F). The video head impulse test revealed decreased vestibulo-ocular reflex gain and covert saccades in the horizontal canals (normal gain = 0.88–1.27) but preserved gains in the anterior (normal gain = 0.75–1.29) and posterior (normal gain = 0.77–1.13) semicircular canals (E). The bithermal caloric test indicated normal responses (F). MRI, magnetic resonance imaging.

REFERENCES

• 1. Prust M, Wang J, Morizono H, Messing A, Brenner M, Gordon E, et al. GFAP mutations, age at onset, and clinical subtypes in Alexander disease. Neurology 2011;77:1287–1294.ArticlePubMedPMC
• 2. Pareyson D, Fancellu R, Mariotti C, Romano S, Salmaggi A, Carella F, et al. Adult-onset Alexander disease: a series of eleven unrelated cases with review of the literature. Brain 2008;131(Pt 9):2321–2331.ArticlePubMed
• 3. Pfeffer G, Abegg M, Vertinsky AT, Ceccherini I, Caroli F, Barton JJ. The ocular motor features of adult-onset Alexander disease: a case and review of the literature. J Neuroophthalmol 2011;31:155–159.ArticlePubMed
• 4. Heshmatzad K, Naderi N, Masoumi T, Pouraliakbar H, Kalayinia S. Identification of a novel de novo pathogenic variant in GFAP in an Iranian family with Alexander disease by whole-exome sequencing. Eur J Med Res 2022;27:174.ArticlePubMedPMCPDF
• 5. Martidis A, Yee RD, Azzarelli B, Biller J. Neuro-ophthalmic, radiographic, and pathologic manifestations of adult-onset Alexander disease. Arch Ophthalmol 1999;117:265–267.ArticlePubMed
• 6. Kirchner H, Kremmyda O, Hüfner K, Stephan T, Zingler V, Brandt T, et al. Clinical, electrophysiological, and MRI findings in patients with cerebellar ataxia and a bilaterally pathological head-impulse test. Ann N Y Acad Sci 2011;1233:127–138.ArticlePubMed
• 7. Kremmyda O, Kirchner H, Glasauer S, Brandt T, Jahn K, Strupp M. Falsepositive head-impulse test in cerebellar ataxia. Front Neurol 2012;3:162.ArticlePubMedPMC
• 8. Park HK, Kim JS, Strupp M, Zee DS. Isolated floccular infarction: impaired vestibular responses to horizontal head impulse. J Neurol 2013;260:1576–1582.ArticlePubMedPDF
• 9. Jeong SH, Kim JS, Baek IC, Shin JW, Jo H, Lee AY, et al. Perverted head impulse test in cerebellar ataxia. Cerebellum 2013;12:773–775.ArticlePubMedPDF
• 10. Sosunov A, Olabarria M, Goldman JE. Alexander disease: an astrocytopathy that produces a leukodystrophy. Brain Pathol 2018;28:388–398.ArticlePubMedPMCPDF
• 11. Song X, Jiang J, Tian W, Zhan F, Zhu Z, Li B, et al. A report of two cases of bulbospinal form Alexander disease and preliminary exploration of the disease. Mol Med Rep 2021;24:572.ArticlePubMedPMC
• 12. Namekawa M, Takiyama Y, Aoki Y, Takayashiki N, Sakoe K, Shimazaki H, et al. Identification of GFAP gene mutation in hereditary adult-onset Alexander’s disease. Ann Neurol 2002;52:779–785.ArticlePubMed
• 13. Benzoni C, Aquino D, Di Bella D, Sarto E, Moscatelli M, Pareyson D, et al. Severe worsening of adult-onset Alexander disease after minor head trauma: report of two patients and review of the literature. J Clin Neurosci 2020;75:221–223.ArticlePubMed
• 14. Kang YR, Nam TS, Kim JM, Kang KW, Lee SH, Choi SM, et al. Older adult-onset Alexander disease with atypical clinicoradiological features: a case report. Front Neurol 2023;14:1139047.ArticlePubMedPMC
• 15. El Mahmoudi N, Marouane E, Rastoldo G, Pericat D, Watabe I, Lapotre A, et al. Microglial dynamics modulate vestibular compensation in a rodent model of vestibulopathy and condition the expression of plasticity mechanisms in the deafferented vestibular nuclei. Cells 2022;11:2693.ArticlePubMedPMC
• 16. Saito K, Shigetomi E, Shinozaki Y, Kobayashi K, Parajuli B, Kubota Y, et al. Microglia sense astrocyte dysfunction and prevent disease progression in an Alexander disease model. Brain 2024;147:698–716.ArticlePubMedPDF

Figure & Data

References

Citations

Citations to this article as recorded by  

Comments on this article