Interictal Nystagmus Research Articles

Episodic ataxia type 2 (EA2) with interictal myokymia and focal dystonia.

Episodic ataxia type 1 and 2 (EA1 and EA2) are the most well-described of the episodic ataxias. They are autosomal dominantly inherited early-onset diseases characterized by attacks of cerebellar dysfunction. EA1 is clinically characterized by short episodes of ataxia with interictal myokymia, whereas EA2 is characterized by longer-lasting recurrent ataxia, slurred speech, and interictal nystagmus. We report on a patient with EA2 with interictal focal dystonia and also interictal myokymia, which is hitherto not reported as an interictal feature associated to EA2. The patient carries a previously described heterozygous pathogenic de novo frameshift variant in the CACNA1A gene, establishing the diagnosis of EA2. She had symptom onset at age 13 and from age 48 she developed interictal myokymia and focal dystonia as illustrated in Supplemental Movie S1. We conclude that interictal myokymia and focal dystonia may be interictal features associated to EA2 caused by the cerebellar pathophysiology of EA2. Episodes of ataxia were successfully treated with acetazolamide in low dose, whereas the interictal features were unresponsive to acetazolamide.

Clinical, oculographic, and vestibular test characteristics of vestibular migraine.

We characterise the history, vestibular tests, ictal and interictal nystagmus in vestibular migraine. We present our observations on 101 adult-patients presenting to an outpatient facility with recurrent spontaneous and/or positional vertigo whose final diagnosis was vestibular migraine (n = 27) or probable vestibular migraine (n = 74). Ictal and interictal video-oculography, caloric and video head impulse tests, vestibular-evoked myogenic potentials and audiometry were performed. Common presenting symptoms were headache (81.2%), spinning vertigo (72.3%), Mal de Débarquement (58.4%), and motion sensitivity (30.7%). With fixation denied, ictal and interictal spontaneous nystagmus was observed in 71.3 and 14.9%, and purely positional nystagmus in 25.8 and 55.4%. Spontaneous ictal nystagmus was horizontal in 49.5%, and vertical in 21.8%. Ictal spontaneous and positional nystagmus velocities were 5.3 ± 9.0°/s (range 0.0-57.4), and 10.4 ± 5.8°/s (0.0-99.9). Interictal spontaneous and positional nystagmus velocities were <3°/s in 91.8 and 23.3%. Nystagmus velocities were significantly higher when ictal (p < 0.001/confidence interval: 2.908‒6.733, p < 0.001/confidence interval: 5.308‒10.085). Normal lateral video head impulse test gains were found in 97.8% (mean gain 0.95 ± 0.12) and symmetric caloric results in 84.2% (mean canal paresis 7.0 ± 23.3%). Air- and bone-conducted cervical-vestibular-evoked myogenic potential amplitudes were symmetric in 88.4 and 93.4% (mean corrected amplitude 1.6 ± 0.7, 1.6 ± 0.8) with mean asymmetry ratios of 13.0 and 9.0%. Air- and bone-conducted ocular-vestibular-evoked myogenic potentials were symmetric in 67.7 and 97.2% (mean amplitude 9.2 ± 6.4 and 20.3 ± 12.8 µV) with mean asymmetry ratios of 15.7 and 9.9%. Audiometry was age consistent and symmetric in 85.5%. Vestibular migraine is characterised by low velocity ictal spontaneous nystagmus, which can be horizontal, vertical, or torsional, and normal audiovestibular test results.

Nystagmus characteristics of healthy controls.

BACKGROUND:Healthy controls exhibit spontaneous and positional nystagmus which needs to be distinguished from pathological nystagmus.OBJECTIVE:Define nystagmus characteristics of healthy controls using portable video-oculography.METHODS:One-hundred and one asymptomatic community-dwelling adults were prospectively recruited. Participants answered questions regarding their audio-vestibular and headache history and were sub-categorized into migraine/non-migraine groups. Portable video-oculography was conducted in the upright, supine, left- and right-lateral positions, using miniature take-home video glasses.RESULTS:Upright position spontaneous nystagmus was found in 30.7% of subjects (slow-phase velocity (SPV)), mean 1.1±2.2 degrees per second (°/s) (range 0.0 – 9.3). Upright position spontaneous nystagmus was horizontal, up-beating or down-beating in 16.7, 7.9 and 5.9% of subjects. Nystagmus in at least one lying position was found in 70.3% of subjects with 56.4% showing nystagmus while supine, and 63.4% in at least one lateral position. While supine, 20.8% of subjects showed up-beating nystagmus, 8.9% showed down-beating, and 26.7% had horizontal nystagmus. In the lateral positions combined, 37.1% displayed horizontal nystagmus on at least one side, while 6.4% showed up-beating, 6.4% showed down-beating. Mean nystagmus SPVs in the supine, right and left lateral positions were 2.2±2.8, 2.7±3.4, and 2.1±3.2°/s. No significant difference was found between migraine and non-migraine groups for nystagmus SPVs, prevalence, vertical vs horizontal fast-phase, or low- vs high-velocity nystagmus (<5 vs > 5°/s).CONCLUSIONS:Healthy controls without a history of spontaneous vertigo show low velocity spontaneous and positional nystagmus, highlighting the importance of interictal nystagmus measures when assessing the acutely symptomatic patient.

Therapy of episodic ataxias: case report and review of the literature.

Episodic ataxias (EAs) are characterized by recurrent, discrete episodes of vertigo and ataxia. EA1 and EA2 are the two most common forms. In the interictal interval, myokymia is typically present in EA1, whereas EA2 patients present with interictal nystagmus. Specific pharmacological therapies are available for EA1 and especially EA2. We briefly discuss the case of an Italian young man with EA2, with a novel de novo CACNA1A mutation, who in our opinion is particularly illustrative for introducing the therapeutic approach. Acetazolamide could fully suppress EA episodes in our patient. We also provide a perspective review of the topic. 4-Aminopyridine is another valid treatment option. For EA1 (and for rarer EAs), the therapeutic possibilities are more limited. Carbamazepine is probably the treatment of choice for EA1, but the optimal treatment plan is unknown. A better understanding of the molecular processes involved in the mediation of EAs will lead to more specific and efficacious therapies for this still elusive group of disorders.

Recurrent spontaneous vertigo with interictal headshaking nystagmus.

To define a disorder characterized by recurrent spontaneous vertigo (RSV) of unknown etiology and interictal headshaking nystagmus (HSN). We characterized HSN in 35 patients with RSV-HSN compared to that recorded in randomly selected patients with compensated vestibular neuritis (VN), vestibular migraine (VM), and Ménière disease (MD). The estimated time constant (TC) of the primary phase of HSN was 12 seconds (95% confidence interval [CI] 12-13) in patients with RSV-HSN, which was larger than those in patients with VN (5 seconds, 95% CI 4-5), VM (5 seconds, 95% CI 5-6), or MD (6 seconds, 95% CI 5-6). TCs of the horizontal vestibulo-ocular reflex were also larger during the rotatory chair test in patients with RSV-HSN. Among the 35 patients with RSV-HSN, 7 showed vigorous long-lasting HSN with a peak slow-phase velocity >50.0°/s. In 5 patients (5 of 7, 71%) with vigorous HSN, HSN could have been induced even with headshaking for only 2 to 5 seconds. Long-term prognosis was favorable, with a resolution or improvement of the symptoms in more than half of the patients during the median follow-up of 12 (range 2-58) years from symptom onset. None developed VM, MD, or cerebellar dysfunction during the follow-up. The clinical features and characteristics of HSN in our patients indicate a hyperactive and asymmetric velocity-storage mechanism that gives rise to intermittent attacks of spontaneous vertigo probably when marginal compensation of underlying pathology is disrupted by endogenous or exogenous factors.

Late-onset episodic ataxia associated with SLC1A3 mutation.

Episodic ataxia type 6 (EA6) is caused by mutations in SLC1A3 that encodes excitatory amino acid transporter 1 (EAAT1), a glial glutamate transporter. EAAT1 regulates the extent and durations of glutamate-mediated signal by the clearance of glutamate after synaptic release. In addition, EAAT1 also has an anion channel activity that prevents additional glutamate release. We identified a missense mutation in SLC1A3 in a family with EA. The proband exhibited typical EA2-like symptoms such as recurrent ataxia, slurred speech with a duration of several hours, interictal nystagmus and response to acetazolamide, but had late-onset age of sixth decade. Whole-exome sequencing detected a heterozygous c.1177G>A mutation in SLC1A3. This mutation predicted a substitution of isoleucine for a highly conserved valine residue in the seventh transmembrane domain of EAAT1. The mutation was not present in 100 controls, a large panel of in-house genome data and various mutation databases. Most functional prediction scores revealed to be deleterious. Same heterozygous mutation was identified in one clinically affected family member and two asymptomatic members. Our data expand the mutation spectrum of SLC1A3 and the clinical phenotype of EA6.

The Clinical Spectrum of Autosomal-Dominant Episodic Ataxias.

Autosomal-dominant episodic ataxias (EAs) represent a clinically and genetically heterogeneous group of disorders characterized by recurrent episodes of cerebellar ataxia (CA). Ataxia episodes are usually of short duration and often triggered by specific stimuli. There are currently seven classified subtypes of EA. EA types 1 and 2 have the highest prevalence and are therefore the clinically most relevant. Between attacks, EA 1 is associated with myokymia. In EA 2, often an interictal downbeat nystagmus with other cerebellar ocular dysfunctions is present; patients with EA 2 may display slowly progessive ataxia and vermian atrophy. EA 1 and 2 are both channelopathies, affecting the potassium channel gene, KCNA1, in EA 1 and the PQ calcium channel-encoding gene, CACNA1A, in EA 2. The types EA 3 to 7 are very rare and have to be further elucidated. Here, we review the historical, clinical, and genetic aspects of autosomal-dominant EAs and their current treatment, focusing on EA 1 and 2.

Possible anticipation associated with a novel splice site mutation in episodic ataxia type 2

Anticipation is a phenomenon characterized by decreasing age at onset and increasing severity of symptoms of a disease in successive generations within a pedigree. Anticipation mostly occurs in neurodegenerative diseases with expansion of unstable trinucleotide repeats. However, it has not been previously pointed out in episodic ataxia type 2 (EA2). Clinical and genetic analyses were performed in nine members from three consecutive generations of a Korean family with EA2. We performed a polymerase chain reaction (PCR)-based direct sequence analysis of all coding regions of CACNA1A using genomic DNA. The clinically affected family members showed recurrent vertigo, interictal nystagmus, and childhood epilepsy. There is a decrease in the age onset (possible genetic anticipation) in three succeeding generations of the family. Genetic analysis identified a splice site mutation (p.Val1465Glyfs13X) and normal trinucleotide repeats in CACNA1A in all clinically affected and one unaffected members. Recognizing anticipation would aid in genetic counseling in EA2.

Large genomic deletions in CACNA1A cause episodic ataxia type 2

Episodic ataxia (EA) syndromes are heritable diseases characterized by dramatic episodes of imbalance and incoordination. EA type 2 (EA2), the most common and the best characterized subtype, is caused by mostly nonsense, splice site, small indel, and sometimes missense mutations in CACNA1A. Direct sequencing of CACNA1A fails to identify mutations in some patients with EA2-like features, possibly due to incomplete interrogation of CACNA1A or defects in other EA genes not yet defined. Previous reports described genomic deletions between 4 and 40 kb in EA2. In 47 subjects with EA (26 with EA2-like features) who tested negative for mutations in the known EA genes, we used multiplex ligation-dependent probe amplification to analyze CACNA1A for exonic copy number variations. Breakpoints were further defined by long-range PCR. We identified distinct multi-exonic deletions in three probands with classic EA2-like features: episodes of prolonged vertigo and ataxia triggered by stress and fatigue, interictal nystagmus, with onset during infancy or early childhood. The breakpoints in all three probands are located in Alu sequences, indicating errors in homologous recombination of Alu sequences as the underlying mechanism. The smallest deletion spanned exons 39 and 40, while the largest deletion spanned 200 kb, missing all but the first three exons. One deletion involving exons 39 through 47 arose spontaneously. The search for mutations in CACNA1A appears most fruitful in EA patients with interictal nystagmus and onset early in life. The finding of large heterozygous deletions suggests haploinsufficiency as a possible pathomechanism of EA2.

Identification of novel and recurrent CACNA1A gene mutations in fifteen patients with episodic ataxia type 2

Episodic ataxia type 2 is a rare autosomal dominant disease characterized by recurrent attacks of vertigo and cerebellar ataxia. The disease was caused by mutations in the CACNA1A gene, on chromosome 19p. We perform a mutational screening in a group of 43 unrelated patients. Forty-two patients presented episodes of disequilibrium and ataxia, and one child was studied because of the occurrence of episodic torticollis. The genetic analysis showed 15 mutated patients (35%). In 13 cases we found novel CACNA1A gene mutations, including missense, protein truncating, and aberrant splicing mutations. Two truncating mutations lead to the uppermost premature stop so far reported, challenging recent hypotheses on dominant negative effect. In patients without CACNA1A mutations, molecular testing for CACNB4 gene mutations excluded this genetic subtype. Clinical features of mutated subjects mostly confirmed previous sign and symptoms associated with EA2, including paroxysmal torticollis and mental retardation. CACNA1A mutated patients have an earlier age at onset, interictal nystagmus, and abnormalities of ocular movements. A review of all CACNA1A mutations so far reported showed that they are mainly located downstream exon 18. Our data substantially increase the number of the described CACNA1A mutations, and propose clinical and molecular criteria for a more focused genetic screening.

Episodic Ataxia Associated With EAAT1 Mutation C186S Affecting Glutamate Reuptake

Episodic ataxia (EA) is variably associated with additional neurologic symptoms. At least 4 genes have been implicated. Recently, a mutation in the SLC1A3 gene encoding the glutamate transporter EAAT1 was identified in a patient with severe episodic and progressive ataxia, seizures, alternating hemiplegia, and migraine headache. The mutant EAAT1 showed severely reduced uptake of glutamate. The syndrome was designated EA6 and shares overlapping clinical features with EA2, which is caused by mutations in CACNA1A. To test the role of the SLC1A3 gene in EA. Genetic and functional studies. We analyzed the coding region of the SLC1A3 gene by direct sequencing. Academic research. DNA samples from 20 patients with EA (with or without interictal nystagmus) negative for CACNA1A mutations were analyzed. We identified 1 novel EAAT1 mutation in a family with EA and studied the functional consequences of this mutation using glutamate uptake assay. We identified a missense C186S mutation that segregated with EA in 3 family members. The mutant EAAT1 showed a modest but significant reduction of glutamate uptake. We broadened the clinical spectrum associated with SLC1A3 mutations to include milder manifestations of EA without seizures or alternating hemiplegia. The severity of EA6 symptoms appears to be correlated with the extent of glutamate transporter dysfunction.

Large CACNA1A Deletion in a Family With Episodic Ataxia Type 2

Episodic ataxia (EA) is an ion channel disorder that manifests as paroxysmal attacks of imbalance and incoordination. Episodic ataxia type 2 (EA2) is characterized by prolonged episodes of ataxia with interictal nystagmus and is caused by mutations in CACNA1A. All mutations identified thus far (to our knowledge) are nonsense or missense point mutations. To describe a family with EA2 having a novel mutation deleting several exons of CACNA1A. Clinical and molecular study of a family manifesting EA2 attacks. Academic research. DNA was extracted from blood samples of 3 family members. Microsatellite genotyping of CACNA1A, quantitative multiplex polymerase chain reaction of short fluorescent fragments (QMPSF), and sequencing were performed. Genotyping of CACNA1A showed nonmendelian inheritance of a CAG repeat located at the 3' end of the gene in a mother and daughter, suggesting a deletion event, which was subsequently confirmed by QMPSF analysis and sequencing. This 39.5-kilobase deletion removes the last 16 coding exons of the gene. Deletion of several exons of CACNA1A may cause EA2 and should be assessed in patients having EA2 without a CACNA1A point mutation.

Episodic vertical oscillopsia with progressive gait ataxia: clinical description of a new episodic syndrome and evidence of linkage to chromosome 13q

We describe four families with late onset episodic vertical oscillopsia and progressive gait ataxia. Probands presented between the ages of 40 and 64 years with initial symptoms of episodic vertical...

CACNA1A Mutation in a EA-2 Patient Responsive to Acetazolamide and Valproic Acid

Episodic ataxia type-2 (EA-2) is an autosomal dominant neurological disorder that has been shown to result from mutations in the CACNA1A gene encoding the P/Q-type calcium channel. Affected individuals experience episodes of cerebellar ataxia usually associated with migraine symptoms, interictal nystagmus, mild residual and in some cases a progressive cerebellar incoordination and respond to acetazolamide treatment. We identified a patient with a positive family history for episodic ataxia, who was originally diagnosed with epilepsy and treated with valproic acid. Subsequent examination revealed that the symptoms were consistent with a diagnosis of EA-2. The patient responded positively to a combination of acetazolamide and valproic acid. Molecular genetic analysis of the CACNA1A gene was performed in order to confirm a diagnosis of EA-2. The CACNA1A gene was evaluated for mutations using single strand conformational polymorphism analysis and direct DNA sequencing. Allele specific oligo hybridization was used to confirm that the mutation was segregating with only affected family members and was not present in the control group. In this study we identified a new missense mutation in exon 12 of the CACNA1A gene from a patient with EA-2 whose symptoms could be controlled with a combination of acetazolamide and valproic acid. This G to A transition changes a highly conserved glutamic acid residue to a lysine residue in domain II S2 of the P/Q-type calcium channel alpha1A subunit. The use of valproic acid in treating patients with EA-2 is not well documented. Here we describe a patient with a novel mutation in the CACNA1A gene who responded positively to a combination of acetazolamide and valproic acid.

Episodic Ataxia Type 2 due to a Deletion Mutation in the CACNA1A Gene in a Korean Family

Episodic ataxia type 2 (EA-2) is an inherited disorder that is characterized by intermittent vertigo, ataxia, and interictal gaze-evoked nystagmus. Although abnormalities associated with this disorder have been found in the CACNA1A gene encoding the alpha1A (Cav2.1) subunit of the P/Q-type calcium channel, there are few reports of genetically confirmed EA-2 in Korea. In 1998, a Korean family with acetazolamide-responsive hereditary paroxysmal ataxia was reported, but the genetic background was not defined at that time. In the present study we performed direct sequencing of the entire exons and their flanking intronic sequences of the CACNA1A gene and found a deletion mutation (c.2042_2043delAG).

A novel insertion mutation of acetazolamide-responsive episodic ataxia in a Japanese family

We report a Japanese family with acetazolamide-responsive episodic ataxia. The proband was a 41-year-old woman with interictal nystagmus. She experienced recurrent attacks of loss of equilibrium and loss of coordination of the extremities accompanied by dysarthria and nausea beginning at about 10 years old. These episodes usually lasted for several hours two or three times a week. Direct sequence of CACNA1A demonstrated a novel insertion mutation in the patient and her father. This mutation is estimated to cause early stop of the gene transcription, producing a truncated protein. This is the first report of episodic ataxia type 2 of which the mutation was identified in a Japanese family.

Episodic ataxia type 2

Episodic ataxia type 2 is an autosomal dominant paroxysmal cerebellar ataxia characterized by acetazolamide-responsive recurrent attacks with interictal nystagmus. This disease is caused by mutations (mainly truncating mutation) within the alpha1(A) subunit of P/Q type voltage-dependent calcium channel gene, CACNA1A. Further researches would establish the genotype/phenotype correlation and clarify the mechanism of this disorder.

Familial Episodic Ataxias and Related Ion Channel Disorders.

Familial episodic ataxias are unusual hereditary disorders of early onset characterized by recurrent episodes of ataxia. Most patients recover fully between attacks, but some may develop progressive ataxia with cerebellar atrophy. There are two subtypes of episodic ataxia: type 1 (EA1), with interictal myokymia, and type 2 (EA2), with interictal nystagmus. Stress and fatigue can trigger ataxic spells, which can be responsive to acetazolamide. These clinical features are reminiscent of other channelopathies or paroxysmal neurologic disorders with progressive features caused by ion channel mutations. Familial episodic ataxias indeed are channelopathies. EA1 is caused by mutations in a potassium channel-encoding gene, whereas EA2 is caused by mutations in a calcium channel-encoding gene, which is also the disease-causing gene in spinocerebellar ataxia type 6 and several kindreds with familial hemiplegic migraine. Treatment with acetazolamide can be effective in decreasing the frequency of attacks and is generally well tolerated. Understanding the mechanism of action of acetazolamide and the functional consequences of these mutations will help one to develop a rational pharmacologic treatment for these disorders, which may share similar mechanisms with benign recurrent vertigo and more common forms of migraine.

Episodic ataxia and channelopathies

Clinical details are given of different types of episodic ataxia: type 1, with myokymia, and attacks which usually last a few minutes, and may occur several times a day, and treatment with acetazolamide can reduce the number of attacks; type 2, with interictal nystagmus, and attacks which last for several hours to a day or more, and treatment with acetazolamide is very effective; paroxysmal choreoathetosis with episodic ataxia, with attacks lasting for about 20 min and occurring at varying intervals; and familial hemiplegic migraine, with transient hemiplegia presenting during the aura of a migraine headache, the symptoms improving on treatment with acetazolamide. Their inheritance is of dominant type; and the gene for type 1 is mapped to chromosome 12p near to a cluster of potassium channel genes, and that for type 2 and for familial hemiplegic migraine to chromosome l9p near to calcium channel genes. The differential diagnosis from other conditions with a periodic symptomatology is discussed, especially from a number of metabolic disorders. Treatment is effective for many of these, and the treatment of the episodic ataxias with acetazolamide can sometimes have a dramatic effect. The possible role of the channelopathies in the causation of some periodic neurological disorders is considered; with the expectation that further research will improve the identification of specific diseases, and lead to more effective treatment.

Familial episodic ataxia: clinical heterogeneity in four families linked to chromosome 19p.

We describe the clinical and oculographic findings in 4 families with episodic ataxia and interictal nystagmus (EA-2) linked to chromosome 19p. Episodes varied from pure ataxia to combinations of symptoms suggesting involvement of the cerebellum, brainstem, and cortex. Some affected individuals exhibited a progressive ataxia syndrome phenotypically indistinguishable from the dominantly inherited spinocerebellar ataxia (SCA) syndromes. About one-half of the affected individuals had migraine headaches and several had episodes typical of basilar migraine. Oculographic findings were localizing to the vestibulocerebellum and posterior vermis. Additional genetic and environmental factors must account for the marked clinical heterogeneity in these families with an abnormal gene on chromosome 19p.