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

Abstract

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.

GFAP at 50

“…However, whether these findings can be translated into clinical application is an open question. Pharmacologic approaches have targeted other pathways downstream of mutant GFAP, such as use of ceftriaxone to increase expression of glutamate transporters (Bachetti et al., 2010; Sechi et al., 2013). Based on the evidence described earlier that Alexander disease is associated with reduced expression of Glt-1, increasing its levels could be beneficial.…”

Alexander Disease Modeling in Zebrafish: An In Vivo System Suitable to Perform Drug Screening

“…Lysosomes were also identified in untreated embryos expressing p.R239C, a presence that may be linked to the activation of cellular autophagy, a known cellular response to proteasome overloading caused by mutant GFAP [ 33 ]. These results not only provided further validation of the zebrafish model by reproducing the effects of the drugs observed in cell cultures and in a patient [ 10 , 28 ], but also confirmed that ceftriaxone is worthy of further investigation as therapy.…”

“…To further validate the zebrafish model of AxD, we investigated whether the antibiotic ceftriaxone (CEF), previously shown to decrease mutant GFAP aggregation in vitro [ 10 ] and to improve the clinical severity in an AxD patient [ 28 ], could also exert beneficial effects in our in vivo model.…”

Tau Spreading Mechanisms; Implications for Dysfunctional Tauopathies

“…It is worth mentioning that some compounds used in clinical practice for decades have been demonstrated to pass freely through the BBB and to be effective in the treatment of some neurodegenerative disorders. This is the case for ceftriaxone, a β-lactam antibiotic used for halting or reversing neurodegeneration in some disorders such as Alexander’s Disease and Parkinson's Disease, thanks to its chaperon-like effect on some of the misfolded proteins involved in these pathologies (GFAP and α-synuclein, respectively) [ 125 , 126 , 127 ].…”