Timothy C. Hain, MD • Page last modified: July 25, 2020
There are two common variants of episodic ataxia syndrome, called EA1 and EA2, as well as a number of other miscellaneous conditions that have episodic ataxia as a common feature. Many of these syndromes also have other associated neurologic symptoms such as movement disorders, muscular problems, or headache. More information about inherited ataxia is found here.
The episodic ataxias are very rare. In our clinic database of mainly adult dizzy patients, containing roughly 12,000 distinct patients with dizziness, we have only 23 patients diagnosed as "episodic ataxia".
Salman et al (2017), reviewed episodic ataxia in pediatric neurology, excluding brain tumors and vestibular system disorders. The "crude period prevalence rate for the 18-year study period was 7.44/100,000. Eight patients had episodic ataxia and seven had inflammatory and metabolic disorders. In the rest the etiology was unknown." They further commented that "neuroimaging is essential".
In 1946, Parker described a familial ataxia characterized by attacks of generalized cerebellar ataxia beginning in the 3rd and 4th decade. Vertigo is infrequent and both the trunk and extremities are ataxic. Diplopia and slurring of speech can occur. Acetazolamide was found to prevent episodic ataxia by Griggs et al in one family, and this medication has also subsequently been found to be useful in both variants (see following as well as this link)
In a second description, Farmer and Mustian (1963) described a family with recurrent vertigo/imbalance beginning in the 2-4th decade, followed by a slowly progressive truncal ataxia. This vestibulocerebellar syndrome is dominantly inherited. It is characterized by episodic ataxia (of course), rebound nystagmus, saccadic overshoot dysmetria, abnormal pursuit and optokinetic nystagmus, and normal semicircular canal responses. About 50% of patients report migraine symptoms. A subtle aspect of otolith related responses, the bias component of OVAR, is reduced in these patients (Furman et al, 1997). This disorder is linked to chromosome 19p. The abnormal gene apparently encodes a subunit of the calcium channel, and these patients have a decrease in their calcium channel density. A mutation in this gene is also associated with familial hemiplegic migraine, as well as in SCA-6 (see following), but is not involved in the familial variant of benign recurrent vertigo. This episodic ataxia syndrome responds to acetazolamide like the first variant. Another family with a mutation in the calcium channel gene 19p with progressive ataxia was described by Yue et al (1997).
Brandt and Strupp (1997) discuss a nomenclature of EA-1 and EA-2. EA-1 is without vertigo, while EA-2 has vertigo.
EA-1 is due to mutations in a potassium channel gene KCNA1 on 12p13. EA1 may begin in early childhood with attacks of ataxia lasting minutes and with interictal myokymia.
EA-2 is caused by mutations of a calcium channel gene CACNL1A4 on chromosome 19p, which is highly expressed in the cerebellum. EA2 may be particularly important because of it's link to migraine associated vertigo (see following), which is common and can have overlapping symptomatology. According to Baloh and others (1997), EA2 is characterized by a progressive ataxia with interictal rebound nystagmus evoked by gaze, as well as downbeating nystagmus. At least 21 distinct CACNA1A mutations have been identified in EA2. (Subramony et al, 2003). Some variants have abnormal ocular fixation and heat sensitivity, resembling that of multiple sclerosis. Other triggers may include ethanol, caffeine or sudden movements. In our practice at CDH, we have suspected EA2 in many patients, but rarely have we gotten back genetic data that confirms our suspicion. This is perhaps due to the lack of percieved benefit to patients in doing this somewhat expensive genetic testing, when treatment options are so limited. However, we do have a number of patients who have done well with the treatment (acetazolamide or 4AP).
Altogether, these disorders resemble the phenotype of migraine associated vertigo, and perhaps there is an overlap between these two conditions. Baloh also reported 4 cases of EA2, with classic migraine, linked to chromosome 19p (Baloh et al, 1997). Familial hemiplegic migraine has also been linked to mutations in the calcium channel gene (Ophoff et al, 1996). Strupp et al (2004) have recently reported that EA2 can be treated with the potassium channel blocker 4-aminopyridine (4-AP)
Yet another related syndrome is caused by a mutation in CACNA1A. It is characterized by episodic ataxia and weakness or hemiplegia. (Jen et al, 1999) Some kindreds have myotonia in addition (Zasorin et al, 1983). Another calcium channelopathy is hypokalemic periodic paralysis which is coded by mutations in CACNA1S. Patients with calcium channelopathies including SCA-6 and EA2 have deficient ocular responses to otolith input. These disorders also can present with positional symptoms closely resembling a common ear condition -- benign paroxysmal positional vertigo (BPPV) (Jen et al, 1998).
Baloh also reported 4 cases of EA2, with classic migraine, linked to chromosome 19p (Baloh et al, 1997).
Familial hemiplegic migraine, is somewhat similar but adds a headache and hemiplegia to the picture. Again dominantly inherited, onset is in childhood or adolescence. Hemiplegia is typically transient but not necessarily. Nystagmus, ataxia and cerebellar atrophy may occur. Impaired P/Q-type calcium channel function is the etiology, and the mutation is again on CACNL1A(Ophoff et al, 1996).
One of the numerous to count spinocerebellar ataxias, SCA6, is due to a tri-nucleotide repeat on this gene.
Another variant, found largely in North Carolina is "periodic vestibulocerebellar ataxia", another autosomal dominant ataxia with defective smooth pursuit. This disorder is genetically distinct from SCA 1,2,3,4,5 as well as episodic ataxia with myokymia (12p), nystagmus (19p), acetazolamide responsive (19p), and DRPLA (12p), according to Damji et al (1996). The acronym "EA3" has been suggested for this syndrome (Steckley et al, 2001). This syndrome does not respond to acetazolamide, has no interictal myokymia, and also have abnormal eye movements.
A fourth variant distinct from EA1 and EA2 has been proposed to be EA4. This disorder includes episodic vestibular ataxia, vertigo, tinnitus, and interictal myokymia. Thus this disorder has symptoms closely resembling Meniere's disease. It is also acetazolamide responsive (Steckley et al, 2001). It was described in a large Canadian kindred of Mennonite heritage. Twelve of 26 individuals had myokymia.
The episodic ataxia's are sometimes called "French Canadian Episodic Ataxia". This is not the best name - as it is not found in French Canadians solely -but it is useful to clinicians in North America as it reminds one of the large kindreds that have been studied in Quebec with this condition. Because French Canadians are a small group that intermarry, they have a much higher prevalence of certain genetic conditions (Musselman et al, 2014). A Canadian physician, Dr. Adrian Barbeau, lead an immense effort concerning another autosomal ataxia -- Friedreichs ataxia, and also had some comments to make about the episodic ataxias. (e.g. Barbeau and Roy, 1984). The French Canadian ataxias are largely autosomal recessive, unlike the situation with EA2 (dominant). This means that neither parent may be a carrier.
Six other kindreds, representing three distinct syndromes, were described by Gancher and Nutt (1986). One kindred included paroxysmal choreoathetosis.
Several variants of migraine and episodic vertigo have been reported by Baloh. There has recently been a report of a familial vestibulopathy consisting of episodic vertigo and migraine headache. Vestibular testing documents profound bilateral vestibular loss. This syndrome responds to acetazolamide (Baloh et al, 1994). Also reported by Baloh and associates, a form exists with episodic vertigo and essential tremor. This form is also responsive to acetazolamide. (Baloh et al, 1996).
At present (2014), the main options for treatment of the episodic ataxias are acetazolamide and 4-AP.
Yue et al have speculated that the mechanism for acetazolamide's effect is to decrease pH which inhibits ion permeation through open calcium channels. Acetazolamide might stabilized channels that fail to properly inactivate. Acetazolamide might not work in all cases if the mutation distorted the pore region of the channel, altering the stabilizing effect of H+ ions (Yue et al, 1997).
See the 4-AP page for more information about this drug. It is more difficult to prescribe and is generally used when acetazolamide is not possible or helpful. 4-AP is a potassium channel blocker. It is puzzling that it should work in EA variants that do not affect the potassium channel.
Although there is no literature that we know of concerning off-label use of verapamil and clonazepam, we will often try these medications in patients with EA as well.
Image of downbeating nystagmus in EA above contributed by Dr. Dario Yacovino