The clinical spectrum of late-onset Alexander disease: a systematic literature review

Balbi, Pietro; Salvini, S; Fundarò, Cira; Frazzitta, Giuseppe; Maestri, Roberto; Mosah, Dibo; Uggetti, Carla; Sechi, GianPietro

doi:10.1007/s00415-010-5706-1

Cited by 60 publications

(57 citation statements)

References 38 publications

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“…The available literature data indicate that in patients with adult-onset AxD, the clinical course is usually that of a progressive neurodegenerative disease without spontaneous remission (Schwankhaus et al 1995;Balbi et al 2010), as also shown by the evaluation of our patient during the first 2 years of observation without therapy. Thus, it seems very unlikely that the progressive improvement of the patient over a 4-year period, after ceftriaxone therapy, may be due to the natural course of the disease.…”

Section: Discussionsupporting

confidence: 79%

Ceftriaxone for Alexander’s Disease: A Four-Year Follow-Up

et al. 2012

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In 2010, we reported the successful clinical outcome related to a 20-month course of intravenous, cyclical ceftriaxone, in a patient with adult-onset Alexander's disease. We now provide evidence that the progression of the patient's signs/symptoms was halted and reversed with a 4-year-long extension of the trial.The patient's clinical signs/symptoms were evaluated before the start and every 6 months for 6 years. For the early 2 years, without therapy, and for the following 4 years, after intravenous ceftriaxone 2 g daily, for 3 weeks monthly during the initial 4 months, then for 15 days monthly.Gait ataxia and dysarthria were assessed clinically on a 0 to 4 scale. Palatal myoclonus and nystagmus/oscillopsia were monitored by videotape and a self-evaluation scale. The degree of disability, measured by a modified Rankin scale, and the brain MRI were periodically evaluated.Before ceftriaxone therapy, in a 2-year period, gait ataxia and dysarthria worsened from mild to marked, palatal myoclonus spread from the soft palate to lower facial muscles, and the patient complained of oscillopsia. After 4 years of ceftriaxone therapy, gait ataxia and dysarthria improved, from marked to mild at clinical rating scales. The palatal myoclonus was undetectable; the patient did not complained of oscillopsia and declared a progressively better quality of life. Ceftriaxone was safe.This case report provides Class IVevidence that intravenous cycles of ceftriaxone may halt and/or reverse the progression of neurodegeneration in patients with adult-onset Alexander's disease and may significantly improve their quality of life.

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Section: Discussionsupporting

confidence: 79%

Ceftriaxone for Alexander’s Disease: A Four-Year Follow-Up

et al. 2012

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“…A systematic review of known cases of AxD supports the imaging and clinical presentation of "juvenile AxD" as intermediate form with features of both infantile-and adult-onset disease. 17 One case would have been categorized as juvenile and the other as adult based on prior criteria. The consistent observation of an intermediate form of AxD led one group to propose a classification system consisting of 3 groups: cerebral AxD (type I), bulbospinal AxD (type II), and intermediate form (type III).…”

Section: Resultsmentioning

confidence: 99%

Neuroimaging and clinical features in type II (late-onset) Alexander disease

et al. 2014

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Objective: To describe the imaging and clinical features in type II (late-onset) Alexander disease (AxD). Methods:We retrospectively identified all cases of type II AxD evaluated at Mayo Clinic, Rochester from January 1996 to February 2012. Clinical and neuroimaging data abstracted from the record included age at onset of symptoms, age at diagnosis, first symptom, neurologic symptoms, physical/neurologic findings on examination, genetic testing and/or biopsy (if performed), and MRI findings.Results: Thirteen patients with type II AxD were identified. Median age at onset was 38 years (range: 12-63). Five patients were female. Eleven of 13 patients had atrophy of the medulla while all 13 had medullary T2 hyperintensity. In 7 patients, these brainstem regions showed patchy enhancement. Five subjects had T2 signal change in the middle cerebellar peduncle, with associated contrast enhancement in 4 subjects. Eleven of 12 patients with T2 fluid-attenuated inversion recovery (FLAIR) imaging had pial FLAIR signal change in the medulla. Nine of 12 patients with spinal cord imaging had cord atrophy, and 3 of 9 of these evaluated with contrast had cervical cord enhancement.Conclusions: Our study confirms prior reports of atrophy and signal change of the medulla and spinal cord in late-onset AxD. We expand on previous imaging studies by identifying middle cerebellar peduncle and pial FLAIR signal changes as important diagnostic clues. Variable patchy enhancement may occur in regions of T2 hyperintensity, leading to diagnostic uncertainty. In addition, we demonstrate that previously emphasized clinical features such as palatal tremor may not be common. We affirm that age at onset predicts clinical phenotype and imaging findings. Alexander disease (AxD) 1 is a leukodystrophy that is pathologically characterized by the presence of Rosenthal fibers. Mutations in the glial fibrillary acidic protein (GFAP) gene cause AxD. Traditionally, AxD has been categorized into infantile, juvenile, and adult forms according to the age at onset.3 MRI criteria for the infantile variant consist of frontal white matter changes; a periventricular rim with high T1 and low T2 signal; T2 hyperintensity (herein referred to as signal abnormality) involving the basal ganglia, thalamus, and brainstem; and contrast enhancement of particular gray and white matter structures (ventricular lining, periventricular rim of tissue, white matter of the frontal lobes, optic chiasm, fornix, basal ganglia, thalamus, dentate nucleus, and brainstem). 4 Imaging and clinical features of late-onset AxD have been less frequently described. Available studies suggest that the clinical and radiologic presentation differs significantly from infantile-onset cases.5-11 Adult-onset cases appear to have less cerebral white matter involvement. Medullary and spinal cord atrophy occurs in most, but often with a mixture of additional findings that may present diagnostic challenges. 5,12 In a review of more than 215 cases of AxD, AxD was divided into 2 groups: type I was char...

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“…The repeat expansion results in an increased PPP2R2B expression (27), similar to what was observed in the cerebellum of the S218L KI mice. Gain-of-function mutations in glial fibrillary acidic protein (GFAP) are associated with infantile and juvenile Alexander disease, a rare leukodystrophy of the cerebellum (14), with gait ataxia as a clinical feature in many patients with adult-onset Alexander disease (28). Transgenic mice in which wild-type human GFAP was overexpressed were presented as a mouse model for Alexander disease (29).…”

Section: à3mentioning

confidence: 99%

RNA expression profiling in brains of familial hemiplegic migraine type 1 knock-in mice

et al. 2013

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Background: Various CACNA1A missense mutations cause familial hemiplegic migraine type 1 (FHM1), a rare monogenic subtype of migraine with aura. FHM1 mutation R192Q is associated with pure hemiplegic migraine, whereas the S218L mutation causes hemiplegic migraine, cerebellar ataxia, seizures, and mild head trauma-induced brain edema. Transgenic knock-in (KI) migraine mouse models were generated that carried either the FHM1 R192Q or the S218L mutation and were shown to exhibit increased Ca V 2.1 channel activity. Here we investigated their cerebellar and caudal cortical transcriptome. Methods: Caudal cortical and cerebellar RNA expression profiles from mutant and wild-type mice were studied using microarrays. Respective brain regions were selected based on their relevance to migraine aura and ataxia. Relevant expression changes were further investigated at RNA and protein level by quantitative polymerase chain reaction (qPCR) and/or immunohistochemistry, respectively. Results: Expression differences in the cerebellum were most pronounced in S218L mice. Particularly, tyrosine hydroxylase, a marker of delayed cerebellar maturation, appeared strongly upregulated in S218L cerebella. In contrast, only minimal expression differences were observed in the caudal cortex of either mutant mice strain. Conclusion: Despite pronounced consequences of migraine gene mutations at the neurobiological level, changes in cortical RNA expression in FHM1 migraine mice compared to wild-type are modest. In contrast, pronounced RNA expression changes are seen in the cerebellum of S218L mice and may explain their cerebellar ataxia phenotype.

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The clinical spectrum of late-onset Alexander disease: a systematic literature review

Cited by 60 publications

References 38 publications

Ceftriaxone for Alexander’s Disease: A Four-Year Follow-Up

Ceftriaxone for Alexander’s Disease: A Four-Year Follow-Up

Neuroimaging and clinical features in type II (late-onset) Alexander disease

RNA expression profiling in brains of familial hemiplegic migraine type 1 knock-in mice

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