Episodic Ataxias: Primary and Secondary Etiologies, Treatment, and Classification Approaches

Abstract

Background: Episodic ataxia (EA), characterized by recurrent attacks of cerebellar dysfunc tion, is the manifestation of a group of rare autosomal dominant inherited disorders. EA1 and EA2 are most frequently encountered, caused by mutations in KCNA1 and CACNA1A. EA3-8 are reported in rare families. Advances in genetic testing have broadened the KCNA1 and CACNA1A phenotypes, and detected EA as an unusual presentation of several other genetic disorders. Additionally, there are various secondary causes of EA and mimicking disorders. Together, these can pose diagnostic challenges for neurologists.Methods: A systematic literature review was performed in October 2022 for 'episodic ataxia' and 'paroxysmal ataxia', restricted to publications in the last 10 years to focus on recent clinical advances. Clinical, genetic, and treatment characteristics were summarized.Results: EA1 and EA2 phenotypes have further broadened. In particular, EA2 may be accom panied by other paroxysmal disorders of childhood with chronic neuropsychiatric features. New treatments for EA2 include dalfampridine and fampridine, in addition to 4aminopyridine and acetazolamide. There are recent proposals for EA9-10. EA may also be caused by gene mutations associated with chronic ataxias (SCA-14, SCA-27, SCA-42, AOA2, CAPOS), epilepsy syndromes (KCNA2, SCN2A, PRRT2), GLUT1, mitochondrial disorders (PDHA1, PDHX, ACO2), metabolic disorders (Maple syrup urine disease, Hartnup disease, type I citrullinemia, thiamine and biotin metabolism defects), and others. Secondary causes of EA are more commonly encountered than primary EA (vascular, inflammatory, toxicmetabolic). EA can be misdiagnosed as migraine, peripheral vestibular disorders, anxiety, and functional symptoms. Primary and secondary EA are frequently treatable which should prompt a search for the cause.Discussion: EA may be overlooked or misdiagnosed for a variety of reasons, including phenotypegenotype variability and clinical overlap between primary and secondary causes. EA is highly treatable, so it is important to consider in the differential diagnosis of paroxysmal disorders. Classical EA1 and EA2 phenotypes prompt single gene test and treatment pathways. For atypical phenotypes, next generation genetic testing can aid diagnosis and guide treatment. Updated classification systems for EA are discussed which may assist diagnosis and management.

Spinocerebellar ataxia 27B: A novel, frequent and potentially treatable ataxia

“…84 Acetazolamide and 4-aminopyridine (4-AP) have both been shown in randomised placebo-controlled trials to similarly reduce the frequency of attacks in EA2. 76,85 In comparison, initial observations in patients with SCA27B suggested that 4-AP, but not acetazolamide, may reduce the severity and frequency of ataxic symptoms. 21 These initial findings were largely confirmed in subsequent open-label series.…”

“…71,72,75 Acetazolamide also appears to be more effective in EA2 than in SCA27B to decrease the frequency and severity of episodes of ataxia. 51,76…”

“…Inter‐ictal progressive cerebellar ataxia and cerebellar atrophy on MRI may eventually develop in some patients with EA2 71,72,75 . Acetazolamide also appears to be more effective in EA2 than in SCA27B to decrease the frequency and severity of episodes of ataxia 51,76 …”

Acute Myopic Shift after a Single Dose of Acetazolamide: A Case Report and Review of the Literature

“…Behandlungsoptionen umfassen systematisches Absetzen des Medikaments in Verbindung mit Zykloplegie, antiglaukomatösen Medikamenten und/oder Kortikosteroiden. Eine vollständige Auflösung tritt in etwa 5 Tagen ein (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Aufgrund der weit verbreiteten Anwendung von Acetazolamid ist das Wissen über diese idiosynkratische Reaktion entscheidend, um Komplikationen eines Winkelblockglaukoms zu vermeiden.…”

“…Treatment options include systematic drug withdrawal associated with cycloplegia, anti-glaucomatous agents, and/or corticosteroids. Full recovery is achieved within about 5 days (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Given the widespread use of acetazolamide, awareness of this idiosyncratic reaction is crucial to avoid complications of acute angle-closure glaucoma.…”