We present the case of a 20-year-old man presented because of increasingly frequent spells of gait instability, dizziness, and dysarthria. The patient's identity may not be ascertained from this report.
These attacks began at age 10 and typically lasted 3-6 hours. He was having 2-4 episodes per month, mostly evoked by physical exertion (typically after amateur five-a-side football matches). He was empirically treated with valproic acid and subsequently levetiracetam with no improvement. Family history was unremarkable.
Interictal neurological examination was normal except for a congenital gaze-evoked downbeat nystagmus, impaired smooth pursuit, and for very mild axial ataxia only noticeable during tandem gait.
Brain MRI was normal (Figure 1). Diffuse slow waves with no epileptic spikes were observed on electroencephalogram. Laboratory assays, neurosonologic examination, and complete cardiologic screening were normal. The cognitive profile was normal.
Given his history, highly suggestive of EA2, he was started on acetazolamide 250 mg/day with an excellent response. Our patient did not experience further EA spells in the 3 years following the introduction of acetazolamide, which was optimally tolerated. The very mild ataxia was no longer appreciable, whereas the nystagmus persisted.
Genetic testing showed a novel heterozygous variant in exon 6 of the CACNA1A gene, c.889G>A (p.G297R). The amino acid modified in our patient (glycine) is well conserved through the species, and in silico analysis (PolyPhen) showed that this missense variant is probably damaging, with the highest possible score of 1.00; the same results were obtained with other bioinformatic tools (Panther, Mutation Tester). This mutation was absent in both parents, who were examined and did not show any features of EA nor other neurological signs. This genetic finding confirmed the diagnosis of EA2 in our patient, who had a highly suggestive clinical picture. The excellent responsiveness to acetazolamide further supported the diagnosis of EA2 (see later).
The mainstays of treatment of degenerative cerebellar ataxia (including EA patients with stabilized ataxia) are currently physiotherapy, occupational therapy, and speech therapy. Specific pharmacological therapies are available for EA1 and especially EA2.
Several drugs could improve symptoms in some EA1 patients but, so far, no medication has been proven effective. Furthermore, the responses are variable. Responsiveness to acetazolamide treatment is only occasional in EA1 patients. The antiepileptic drug, phenytoin, is a modulator of voltage-gated Na+ channels that is also capable of decreasing ataxia and myokymia in EA1 patients. However, phenytoin can cause permanent cerebellar dysfunction and atrophy and should be used with extreme caution in these patients. Carbamazepine stabilizes the inactivated state of voltage-gated sodium channels, making fewer of these channels available to subsequent opening. It could significantly reduce the frequency of attacks in members of several large families. Even if in some cases the initial response was not sustained, carbamazepine is currently the treatment of choice for EA1.
Acetazolamide is the pharmacological treatment of choice for EA2; a dosage between 250 and 1000 mg/day is usually effective. Acetazolamide 250 mg/day could fully suppress EA episodes in our EA2 patient. Alternatively, 4-aminopyridine can be used. Other drugs, including dalfampridine, have been proposed as potential treatment options, but further studies are still needed.
As previously seen, EA2 is a dominant genetic disease caused by mutations in the CACNA1A gene encoding the CaV2.1 subunit of the PQ-type calcium channel, highly expressed in Purkinje cells. The loss in the precision of Purkinje cell pacemaking likely contributes to EA2 symptoms. In a mouse model, Purkinje cells exhibit high-frequency burst firing during attacks. The changes induced by the mutation, resulting in a reduced calcium current, are considered to decrease the inhibitory effect of Purkinje cells. This may result in disinhibition of the deep cerebellar nuclei and therefore ataxia, and also in disinhibition of vestibular nuclei neurons receiving anterior semicircular canal pathways. As aminopyridines (potassium channel blockers) improve nystagmus, their effects on the frequency of attacks in EA2 were evaluated. Specifically, 4-aminopyridine was reported to reduce the frequency of attacks and improve the quality of life in EA2, likely restoring the diminished precision of pacemaking in Purkinje cells, by increasing the action potential after hyperpolarization and prolonging the action potential.
A recent systematic review has concluded that for patients with EA2, 4-aminopyridine 15 mg/day probably reduces ataxia attack frequency over 3 months, based on one randomized, double-blind, placebo-controlled, crossover, class 1 study performed on 10 patients. This study showed that EA2 subjects receiving placebo had a median monthly attack frequency of 6.5, whereas patients taking this drug had a frequency of 1.65 (significant difference, p<0.03). Considering that further controlled trials on 4-aminopyridine are still strongly needed, the same review acknowledged that 'historical treatment approaches, such as the use of acetazolamide for the treatment of EA2, can have clinical value even in the absence of clinical trial evidence'. Potential side effects of long-term acetazolamide use include kidney stones; therefore, ultrasound monitoring is warranted. Acetazolamide can be safely administered to patients with a history of antibiotic allergic reactions.
Recently, an EA2 patient with poor response to acetazolamide has been reported to significantly improve with a combination of acetazolamide 750 mg/day and levetiracetam 750 mg/day. Levetiracetam could be effective by inactivating calcium channels, but further studies are needed.
Furthermore, the muscle relaxant agent, chlorzoxazone, has been proposed as a new potentially effective treatment of EA2. In a mouse model of EA2, chlorzoxazone could restore the precision of Purkinje cell pacemaking in a dose-dependent manner. Oral administration of chlorzoxazone could improve interictal motor performance and reduce the duration, severity, and frequency of spells of motor imbalance in this mouse model, with no adverse effects. Studies in human patients are still needed.