By Marcello Cherchi, MD PhD
For patients
Episodic ataxias (EA) are a set of inherited disorders that cause episodes of disequilibrium, clumsiness and sometimes other symptoms, lasting minutes to hours, sometimes triggered by stress, by physical exertion or by dietary factors. Episodes often begin in childhood, and may occur a few times per year or multiple times per day. Patients feel normal (or mostly normal) in between episodes. Some patients improve with the oral medication acetazolamide. If acetazolamide fails, then your doctor may consider referring you to a specialist in ataxia, or to a genetics counselor.
For clinicians
Overview
Episodic ataxias (EA), and more broadly the so-called acetazolamide-responsive ataxias, are due to genetic defects in ion channels. Most of these diseases are familial, inherited in an autosomal dominant fashion. Symptoms often, though not always, begin in childhood. EAs are rare, but among them, EA1 and EA2 were the first described, and are the most common. EA3-6 are much rarer. In many cases episodes are triggered by “stress” (emotional duress), physical exertion or dietary factors (e.g., caffeine). The frequency of the episodes is extremely variable. The duration is also variable, though generally, the episodes in EA1 last minutes, while those in EA2 last hours. Typical symptoms include disequilibrium, ataxia/incoordination and dysarthria; less common symptoms include visual symptoms, weakness, tremor, headache and nausea. EA1 and EA2 have been connected to a broad range (dozens each) of genetic mutations, though the mechanism by which these mutations provoke neurological dysfunction is unclear. During an episode patients with EA1 and EA2 may exhibit a variety of eye movement abnormalities. Inter-ictally some patients exhibit subtle eye movement abnormalities as well. Most of these eye movement abnormalities broadly localize to the cerebellum, but none is specific or sensitive for these disorders. For most of these disorders, many patients will exhibit some improvement with acetazolamide; EA2 patients tend to be most responsive. Several other medications have been tried in the treatment of episodic ataxias, though none has been studied as well as acetazolamide.
In a patient complaining of episodes disequilibrium and incoordination lasting minutes to hours, sometimes triggered by stress, by exertion or by dietary factors, who feels normal (or nearly so) inter-ictally, whose examination is unremarkable, and who has a family history of similar symptoms, EA is a reasonable consideration. Because EAs are rare, the clinician should keep a broader differential diagnosis that includes much more common entities, such as migraine associated vertigo. Imaging (usually an MRI of the brain) is reasonable to exclude structural lesions. A trial of acetazolamide (absent any contraindications) is reasonable. If that is unsuccessful, then referral to a specialist in ataxia, or a genetics counselor, is reasonable.
Introduction
Some sources (Bain, O’Brien et al. 1992, Klaas, Burkholder et al. 2013) credit Harry Lee Parker (1894 – 1959) with the original description of a cohort of patients with what eventually became known as familial episodic ataxia (Parker 1946).
Familial episodic ataxias (EA) are channelopathies manifesting with episodic ataxia and disequilibrium (Baloh and Jen 2002). Episodic ataxia type 1 (EA1) is caused by missense mutations in the potassium channel gene KCNA1 on chromosome 12p13. Episodic ataxia type 2 (EA2) is caused by missense and nonsense mutations in the calcium channel gene CACNA1A on chromosome 19p.
Episodic ataxias type 1 and 2 are quite rare but have been relatively well described. More recently reported episodic ataxias (types 3, 4, 5 and 6) are even more rare, and are still being studied and debated.
These diseases are often grouped together because they share some features, yet there is probably no single feature that unifies them all. They are probably all due to genetic mutations, though for some variants the culprit gene has not yet been identified. They are mostly hereditary, although EA6 has only been identified in a single individual (perhaps as a de novo mutation), so the term “familial” is probably inappropriate. Patients experience episodic symptoms, but inter-ictally may experience milder chronic symptoms at baseline. Most patients exhibit ataxia, but not all. Most types have at least some patients whose symptoms improve with acetazolamide, but not all (such as EA4).
Episodic ataxia type 1
Introduction
In 1975 VanDyke and colleagues described a kindred in which 11 people over 3 generations exhibited episodic ataxia and continuous myokymia (VanDyke, Griggs et al. 1975). Subsequent reports (Hanson, Martinez et al. 1977) identified similar findings in other families. In 1994 linkage analysis identified mutations at a locus on chromosome 12p13 (Litt, Kramer et al. 1994) that was identified as a gene that encodes the KCNA1 potassium channel (Browne, Gancher et al. 1994). This eventually led to this being designated as a familial episodic ataxia, and it was ultimately called “episodic ataxia type 1,” when other types were discovered.
Episodic ataxia type 1, various genetic mutations
EA1 is inherited in an autosomal dominant fashion.
A broad range of genetic mutations has been described in EA1 (Bretschneider, Wrisch et al. 1999, Eunson, Rea et al. 2000, Knight, Storey et al. 2000, Klein, Boltshauser et al. 2004, Imbrici, Gualandi et al. 2008, Shook, Mamsa et al. 2008, D’Adamo, Gallenmuller et al. 2014, Lassche, Lainez et al. 2014, Petitjean, Kalstrup et al. 2015, Chen, Fu et al. 2016, Mestre, Manole et al. 2016, Karalok, Megaro et al. 2018, Yuan, Yuan et al. 2020, Lee, Kim et al. 2021).
For each mutation there have been various proposals for the mechanism by which is causes neurological dysfunction (D’Adamo, Liu et al. 1998, D’Adamo, Imbrici et al. 1999, Manganas, Akhtar et al. 2001, Maylie, Bissonnette et al. 2002, Klein, Boltshauser et al. 2004, Imbrici, D’Adamo et al. 2006, Heeroma, Henneberger et al. 2009, Tomlinson, Tan et al. 2010, Imbrici, D’Adamo et al. 2011, Peters, Werry et al. 2011, Zhu, Alsaber et al. 2012, Ferrick-Kiddie, Rosenthal et al. 2017, Zhao, Petitjean et al. 2020).
Episodic ataxia type 1, clinical presentation
Episodes of EA1 can begin in early childhood or adolescence (Kotagal 2012).
Some episodes of EA1 have no apparent trigger. In some patients the triggers are relatively consistent. Graves and colleagues studied 39 patients (51% male), age 15 – 65 years (median 37 years), with genetically confirmed EA1, and reported the triggers listed in the Table below from Graves and colleagues (Graves, Cha et al. 2014).
EA1 attacks usually last minutes (Baloh and Jen 2002, Dressler and Benecke 2005), less commonly hours (Graves, Cha et al. 2014). In some patients the episodes can occur with impressive frequency, up to dozens of times per day (Kotagal 2012). Symptoms usually include midline cerebellar dysfunction (truncal ataxia), limb ataxia, dysarthria, dystonia (Dressler and Benecke 2005), and sometimes visual symptoms such as oscillopsia and visual blurring (Rajakulendran, Schorge et al. 2007). The Table below lists the symptoms reported by the patients studied in the series by Graves and colleagues (Graves, Cha et al. 2014).
Although the disease is genetically mediated, it appears that non-genetic factors also influence the clinical manifestations (Graves, Rajakulendran et al. 2010, Gilbert, Graves et al. 2011).
Episodic ataxia type 1, ocular motor manifestations
Some of these patients exhibit down beat nystagmus (Jorge, Melancia et al. 2022).
Episodic ataxia type 1, inter-ictal symptoms
In between episodes, patients with EA1 often exhibit myokymia, but may also experience other symptoms, such as headache or pseudodystonia (Bhattacharjee, Deenadayalu et al. 2022).
Episodic ataxia type 1, treatments
Acetazolamide was fortuitously found to have some effect on symptoms of EA1 (Griggs, Moxley et al. 1978), and subsequently it was reported that approximately 50% of patients improve with acetazolamide (Baloh and Jen 2002).
There are a few reports of EA1 responding to phenytoin (Dressler and Benecke 2005).
Episodic ataxia type 2
Episodic ataxia type 2, epidemiology
The prevalence of EA2 has been estimated at 1 in 100,000 (Kotagal 2012). One report of several generations of a Korean family found decreasing age of onset with increasing number of trinucleotide repeats, suggesting anticipation (Choi, Yook et al. 2013).
Episodic ataxia type 2, clinical presentation
Episodes of EA2 usually begin in infancy or childhood. Some mutations appear to have much later onset; Cuenca-Leon and colleagues reported a patient in whom symptom onset was in the 6th decade (Cuenca-Leon, Banchs et al. 2009).
Episodes of EA2 can be triggered by stress, exercise and caffeine (Baloh and Jen 2002). The mechanism for these triggers is unclear, but animal models suggest that emotional and physiologic duress activate the locus coeruleus and trigger release of norepinephrine in the cerebellum, which has downstream effects of interfering with Purkinje cell function. This postulated mechanism is illustrated in the Figure below from Benarroch (Benarroch 2023).
The frequency of the episodes in EA2 is extremely variable, ranging from a few per year to a few per week; they can last for hours (Kotagal 2012).
Ictal symptoms of EA2 include a sensation of vertigo, dysarthria and truncal ataxia (Kotagal 2012), and may be accompanied by headache (Dressler and Benecke 2005). Jen and colleagues (Jen, Kim et al. 2004) state that the most common neurologic symptoms are ataxia, vertigo and fluctuating weakness. Additional features are listed in the Table below.
Some patients describe experiencing vertigo without ataxia (Ling, Zhao et al. 2019).
The clinical presentation cannot be predicted from the specific mutation (discussed below) (Jen, Kim et al. 2004). Multiple patients in the same family with the same genetic mutation can have different clinical manifestations (Jung, Testard et al. 2010).
Episodic ataxia type 2, genetics
EA2 is inherited in an autosomal dominant fashion.
Linkage analysis identified a locus on chromosome 19p (Kramer, Yue et al. 1995, von Brederlow, Hahn et al. 1995) that was found to encode the CACNA1A calcium channel gene (Ophoff, Terwindt et al. 1996). Most of the CACNA1A mutations in EA2 are nonsense mutations leading to a truncated protein with loss of function (Kotagal 2012). However, over 30 mutations in this gene have been found to manifest as EA2, and these mutations are of various types, including nonsense mutations, missense mutations, deletions, an insertion and a donor splice site mutation (Jen, Kim et al. 2004).
A large number of mutations has been described in patients diagnosed with EA2 (Kramer, Yue et al. 1995, von Brederlow, Hahn et al. 1995, Ophoff, Terwindt et al. 1996, Denier, Ducros et al. 1999, Jen, Yue et al. 1999, Denier, Ducros et al. 2001, Guida, Trettel et al. 2001, Jen, Wan et al. 2001, Scoggan, Chandra et al. 2001, van den Maagdenberg, Kors et al. 2002, Hirose, Arayama et al. 2003, Subramony, Schott et al. 2003, Jen, Kim et al. 2004, Kaunisto, Harno et al. 2004, Spacey, Hildebrand et al. 2004, Eunson, Graves et al. 2005, Imbrici, Eunson et al. 2005, Spacey, Materek et al. 2005, Wan, Carr et al. 2005, Jeng, Chen et al. 2006, Kim, Kim et al. 2006, Graves, Imbrici et al. 2008, Jeng, Sun et al. 2008, Kaja, Van De Ven et al. 2008, Riant, Mourtada et al. 2008, Cuenca-Leon, Banchs et al. 2009, Labrum, Rajakulendran et al. 2009, Robbins, Lipton et al. 2009, Zafeiriou, Lehmann-Horn et al. 2009, Jung, Testard et al. 2010, Mantuano, Romano et al. 2010, Riant, Lescoat et al. 2010, Nikaido, Tachi et al. 2011, Wan, Mamsa et al. 2011, Hu, Jiang et al. 2013, Nachbauer, Nocker et al. 2014, Kinder, Ossig et al. 2015, Dahimene, Page et al. 2016, Maksemous, Roy et al. 2016, Pradotto, Mencarelli et al. 2016, Tomlinson, Tan et al. 2016, Dorgans, Salvi et al. 2017, Isaacs, Bradshaw et al. 2017, Petrovicova, Brozman et al. 2017, Sintas, Carreno et al. 2017, Sivak, Kurca et al. 2017, Balck, Tunc et al. 2018, Lance, Mossman et al. 2018, Maksemous, Smith et al. 2018, Ahuja, Rozen et al. 2019, Algahtani, Shirah et al. 2019, Nardello, Plicato et al. 2020, Verriello, Carrera et al. 2021, Verriello, Pauletto et al. 2021, Hommersom, van Prooije et al. 2022, Lipman, Fan et al. 2022, Nielsen, Asbjornsdottir et al. 2022, Xu, Wang et al. 2022).
The CACNA1A-encoded calcium channels are heavily expressed in Purkinje and granule cells in the cerebellum.
Other mutations in the CACNA1A gene manifest as other neurological disorders: familial hemiplegic migraine type 1, and spinocerebellar ataxia type 6 (Denier, Ducros et al. 1999, Jen 1999, Kotagal 2012, Pradotto, Mencarelli et al. 2016).
Episodic ataxia type 2, pathophysiology
The exact mechanism by which EA2 mutations provoke dysfunction of calcium channels is unclear. Possibilities include “reduced current density, increased rate of inactivation, and a shift in the voltage dependence of activation to more positive values” (Spacey, Hildebrand et al. 2004).
MR spectroscopy on patients with EA2 reported abnormal pH (alkalosis) in the cerebellum (Bain, O’Brien et al. 1992, Sappey-Marinier, Vighetto et al. 1999). Harno and colleagues (Harno, Heikkinen et al. 2005) speculate that acetazolamide may “stabilize the dysfunctioning P/Q‑type calcium channels, which express highly in the cerebellum.” Identification of abnormal metabolism in the cerebellar cortex seems logical given the clinical manifestations of EA2.
However, there is also some evidence of abnormalities in cerebral cortical function. Helmich and colleagues (Helmich, Siebner et al. 2010) studied six EA2 patients and 13 healthy controls with transcranial magnetic stimulation and reported that, “patients with episodic ataxia type 2 have an excessive increase in motor cortex excitability following a strong facilitatory input.” Indelicato and colleagues (Indelicato, Unterberger et al. 2021) studied 19 genetically confirmed EA2 patients with electroencephalography and found 12 (63%) were abnormal at baseline (outside of any attack), usually showing “lateralized intermittent slowly, mainly affecting the temporal region,” and 7 (37%) showed “interictal epileptic discharges.”
There is also some evidence of peripheral nerve dysfunction in EA2. Krishnan and colleagues (Krishnan, Bostock et al. 2008) reported on 3 members of a family with EA2 and found that, “Nerve excitability testing demonstrated significant abnormalities, with all patients outside the normal 95 % confidence limits in having a high rheobase and reduced early hyperpolarizing threshold electrotonus. On average there were also significant reductions in refractoriness, late sub excitability and early depolarizing threshold electrotonus.” Tomlinson and colleagues (Tomlinson, Tan et al. 2016) studied 8 patients from 2 families with EA2 and reported that, “All patients had similar excitability abnormalities, including a high electrical threshold and increased responses to hyperpolarizing and depolarizing currents in threshold electrotonus,” and 2 patients, showed “increased jitter in single-fibre EMG studies indicated unstable neuromuscular transmission.”
Episodic ataxia type 2, physical examination
If an EA2 patient is examined during an attack one may identify spontaneous nystagmus. Early in the disease the patient’s examination may be normal inter-ictally, but later there may be spontaneous down beat nystagmus even between attacks (Kotagal 2012) and gaze-evoked nystagmus (Bertholon, Chabrier et al. 2009).
Kim and colleagues (Kim, Kim et al. 2014) reported the case of an EA2 patient with rebound up beat nystagmus after lateral gaze holding — in effect, perverted rebound nystagmus.
Shervin Badv and Niksirat (Shervin Badv and Niksirat 2013) reported downward gaze palsy during attacks of a patient with EA2.
Episodic ataxia type 2, vestibular testing
Harno and colleagues (Harno, Hirvonen et al. 2004) studied three patients with genetically confirmed EA2 with nystagmography while the patients were off, and then back on, treatment with acetazolamide. The first patient while off treatment exhibited hypermetric saccades; this improved on treatment. The second patient, while off treatment, exhibited spontaneous left beat nystagmus of 5 deg/sec that increased with head turns; the nystagmus improved (but did not cease) on treatment. The third patient while off treatment exhibited spontaneous up beat nystagmus of 3 deg/sec and horizontal rebound nystagmus of 2 deg/sec.
The Figure below, from Harno and colleagues (Harno, Hirvonen et al. 2004), shows the spontaneous left beat nystagmus while off acetazolamide (panel A) and while on acetazolamide (panel B).
Figure : Nystagmographic tracings from a patient with genetically confirmed episodic ataxia type 2. Panel A shows spontaneous left beat nystagmus of 5 deg/sec while the patient was off treatment. Panel B shows reduction of the spontaneous left beat nystagmus to 2 deg/sec while the patient was on treatment with acetazolamide. From Harno et al. (2004).
Harno and colleagues (Harno, Hirvonen et al. 2004) also studied computerized dynamic posturography on the second patient, and reported that, “the sway velocities in posturography were pathologically increased without medication.”
Choi and colleagues (Harno, Hirvonen et al. 2004) studied 16 patients with EA2 inter-ictally and reported that more than half of the patients exhibited abnormalities in at least one of each vestibular test of video head impulse testing (vHIT), subjective visual vertical (SVV), ocular vestibular evoked myogenic potentials (oVEMP) or cervical vestibular evoked myogenic potentials (cVEMP). Specifically, “Patients with EA2 commonly showed abnormal VOR [vestibulo-ocular reflex] responses at least for one SCC [semicircular canal] with high-acceleration, high-frequency head impulses (14/16, 88%), and impaired visual-vestibular interaction (7/12, 58%). In response to low acceleration and frequency stimuli, the VOR gains were generally normal. The majority of EA2 patients had impairments in at least one of the otolith function tests (13/16, 81%): SVV [subjective visual vertical] tilt or variability (7/14, 50%), oVEMP [ocular vestibular evoked myogenic potentials] (8/15, 53%), and cVEMP [cervical vestibular evoked myogenic potentials] (4/16, 25%). Vestibular impairments are common in EA2 even during the interictal periods.” (Choi, Oh et al. 2022).
Another report of 4 patients observed, “deficits in tracking behavior with common features. Ocular tracking tended to result in hypermetric saccades at longer than normal latencies. Smooth pursuit tracking was absent in 1 patient and had lower than normal gain in the others” (Engel, Anderson et al. 2004).
Gordon and colleagues (Gordon, Caspi et al. 2008) studied four EA2 patients using scleral search coils. They reported that 2 (50%) exhibited “abnormal VOR” (vestibulo-ocular reflex) and “showed essentially no SP” (smooth pursuit).
Kipfer and colleagues (Kipfer, Jung et al. 2013) reported on a family of three EA2 patients who demonstrated slow horizontal saccades.
Kim and colleagues (Kim, Kim et al. 2022) reported the case of an EA2 patient with slow vertical saccades (both upward and downward).
Rucker and colleagues (Rucker, Jen et al. 2005) reported on two patients with EA2 who exhibited slowing of adducting saccades. Shimmura and colleagues (Shimmura, Uehara et al. 2017) described slow adducting movements during smooth pursuit in a patient with EA2.
Some investigators point out that there are some similarities in eye movement abnormalities between EA2 and spinocerebellar ataxia type 6 (Ying, Jen et al. 2001).
Episodic ataxia type 2, imaging
MR spectroscopy on patients with EA2 reported abnormal pH (alkalosis) in the cerebellum (Bain, O’Brien et al. 1992, Sappey-Marinier, Vighetto et al. 1999). Harno and colleagues (Harno, Heikkinen et al. 2005) speculate that acetazolamide may “stabilize the dysfunctioning P/Q‑type calcium channels, which express highly in the cerebellum.”
Episodic ataxia type 2, treatments
Acetazolamide remains the best studied treatment for EA2, with response rates ranging from 70% (Strupp, Zwergal et al. 2007) to 90% (Baloh and Jen 2002). This remains the best studied treatment.
One report described symptomatic improvement in EA2 through a combination of acetazolamide and valproate (Scoggan, Friedman et al. 2006).
There is also some literature regarding 4‑AP (4‑aminopyridine, also called dalfampridine) (Strupp, Kalla et al. 2004, Lohle, Schrempf et al. 2008, Strupp, Kalla et al. 2008, Alvina and Khodakhah 2010, Strupp, Kalla et al. 2011, Claassen, Teufel et al. 2013, Strupp, Teufel et al. 2017, Malamud and Otallah 2022). An extended release of 4‑AP called fampridine has also been studied (Muth, Teufel et al. 2021).
One report advocated the combination of 4‑AP plus topiramate in patients unresponsive to acetazolamide (Gonzalez-Mingot, Lopez-Ortega et al. 2022).
Other proposed treatments have included chlorzoxazone (Alvina and Khodakhah 2010), levetiracetam (Lee, Jang et al. 2017, Na and Kim 2021) and flunarizine (Yuan, Zheng et al. 2022).
Episodic ataxia type 3
In 2001 Steckley and colleagues (Steckley, Ebers et al. 2001) reported on a large Canadian family of Mennonite ancestry. In this kindred there was a broad age range of symptom onset (1 – 42 years). Episodes were sometimes provoked by movement (kinesiogenic), involved symptoms of vertigo, nausea and tinnitus, and tended to last minutes, rarely hours, and responded to acetazolamide (Steckley, Ebers et al. 2001). Linkage analysis identified a locus on chromosome 1q42 (Cader, Steckley et al. 2005), but the specific gene has not yet been identified.
Episodic ataxia type 4
Episodic ataxia type 4, also called periodic vestibulocerebellar ataxia, is another autosomal dominant ataxia originally described in two families from North Carolina (Damji, Allingham et al. 1996). Its symptoms are similar to those of EA2 (Kotagal 2012), though the age of onset is later (3rd – 6th decade) and the attacks do not respond to acetazolamide.
Episodic ataxia type 5
Episodic ataxia type 5 was described by Escayg and colleagues (Escayg, De Waard et al. 2000) who reported on a French Canadian kindred whose members suffered from attacks very similar to EA2, although the age of onset was somewhat later (3rd – 4th decade); symptoms included vertigo, ataxia and dysarthria, lasting hours at a time, improved with acetazolamide (Kotagal 2012). The disorder is linked to a mutation in a gene for a different calcium channel (CACNB4).
Episodic ataxia type 6
Episodic ataxia type 6 was described in a single child in a report by Jen and colleagues (Jen, Wan et al. 2005). Aside from symptoms of ataxia, the episodes are different in that they involve hemiplegia and seizures. The disease has been attributed to a mutation in an astrocyte glutamate transporter (Kotagal 2012).
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