Abstract
An association between hemiplegic migraine (HM) and episodic ataxia type 2 (EA2) has been described; both disorders are linked to mutations in the CACNA1A gene. Although confusion occurs in 21% of patients with HM, we found only one case in the literature of confusional episodes associated with ataxia without hemiplegia. These findings raise the possibility of confusional episodes being part of both the HM and EA2 phenotype. However, a patient with episodic ataxia, confusional spells and CACNA1A gene mutations has not been identified. We describe four individuals, spanning three generations of a family, with episodic ataxia without hemiplegia and confusion, in association with a CACNA1A mutation. We follow with a description of the relationship between the CACNA1A mutations and the three syndromes, suggesting a potential need for a new classification in which the conditions can be subsumed.
Introduction
An association between hemiplegic migraine (HM) and episodic ataxia type 2 (EA2) exists; both disorders are linked to mutations in the CACNA1A gene. Although episodic confusional states occur in 21% of patients with HM, we found only one case in the literature of confusional episodes associated with ataxia without hemiplegia (1). These findings raise the possibility of confusional episodes being part of both the HM and EA2 phenotype. However, a patient with episodic ataxia, confusional spells and CACNA1A gene mutations has not been identified.
We describe four individuals, spanning three generations of a family, with episodic ataxia without hemiplegia and confusion, in association with a CACNA1A mutation. We follow with a description of the relationship between the CACNA1A mutations and the three syndromes, suggesting a potential need for a new classification in which the conditions can be subsumed.
Family pedigree; affected members of the family highlighted in black. Magnetic resonance image of sibling A, 14 years old: T1 sagittal view, illustrating cerebellar and vermian atrophy. Sibling B, 15 years old; sagittal magnetic resonance image, T1 sequences, illustrating vermian and cerebellar atrophy.
History
Proband siblings A and B were evaluated for paroxysmal events that first developed at 14 and 15 years of age, respectively.
Sibling A first developed symptoms at 14 years of age. He developed blurred vision and numbness and tingling on either side, followed by contralateral headache, nausea, vomiting and fever lasting 12 h. During the episodes, the patient became encephalopathic, and unable to answer questions properly with incorrect word choice (e.g. ‘He has said he is going to bed and goes into the bath-tub’) and slurred speech (with normal grammar). The gait was ataxic. He had some memory loss of events. The patient was aware something was wrong and reported being frustrated at that time. There was no weakness associated with the spells.
The episodes lasted 12–24 h and occurred every 4 months. Emotional stress seemed to trigger the spells. The medical history was unremarkable except for depression, for which he took sertraline.
Sibling B developed symptoms at the age of 15 years. Events were characterized by bilateral visual blurriness and tingling and numbness on either side, followed by headache, nausea, vomiting and fever. During the attacks, he became encephalopathic, unable to answer questions properly with slurred speech and incorrect word choice followed by loss of memory of some of the events. Some of the events were triggered by mild head trauma.
The family history was of significance. The patients' father and paternal grandfather reported similar symptoms that started at the age of 35 years. The father and grandfather both recalled episodes of confusion associated with headache, and the grandfather had been tentatively clinically diagnosed with spinocerebellar ataxia type 6 (SCA-6). Their mother also had a history of migraine headaches. Figure 1 illustrates the family pedigree.
In between attacks, neurological examination of the siblings revealed mild postural tremor and dysmetria. Their gait was slightly clumsy, they were unable to perform tandem gait, and had a positive Romberg.
Magnetic resonance imaging (MRI) showed vermian atrophy in both patients (Figs 2 and 3). An EEG during a spell showed left-sided slowing; repeat EEG when asymptomatic was normal in the eldest sibling. He also had a lumbar puncture during an event that was normal.
CACNA1A sequencing in patient A showed a sequence variation in exon 13, designated as arginine (CAG) 583 glutamine (CAA). This variation has been associated with both EA2 and familial hemiplegic migraine (FHM). Although further genetic testing was offered for the other affected members of the family, they chose not to pursue this.
Treatment was started with verapamil for patient A, which resulted in no further confusional episodes after 12 months' treatment.
Discussion
The CACNA1A gene, located on chromosome 19p, encodes the pore-forming α-subunit of a neuronal calcium voltage gated channel designated Cav2.1, also known as the P/Q-type Ca2+ channel. Cav2.1 channels are located throughout the central nervous system, including the cerebellum where they are present in high concentrations. They also occur in structures implicated in the pathophysiology of migraine such as the cerebral cortex, the brainstem nuclei and trigeminal ganglia. These calcium channels play a major role in excitatory neurotransmitter release, such as glutamate (2). In experimental animal studies, mutations have been associated with severe cerebellar ataxia, dystonia and absence seizures. Loss of function of the channels may be associated with a reduced response to inflammatory and neuropathic pain, thereby contributing to central sensitization (3).
The clinical spectrum of CACNA1A mutations is broad. Several autosomal dominant disorders in humans have been described in association with these mutations, including FHM type 1 (FHM1) with and without cerebellar symptoms, EA2, SCA-6 and absence epilepsy.
The link between cerebellar pathology, severe aura and calcium channelopathies was explored by Sandor et al. (4), who found subclinical dysmetria in migraine with aura patients, and suggested that since calcium channels occur densely in the Purkinje cells, this dysmetria is a manifestation of cerebellar dysfunction due to calcium channelopathy.
A mild degree of confusion or somnolence is seen in 21% of patients with HM (see discussion below on Ducros et al. (1)) and death secondary to massive cerebral oedema following minor head trauma in a patient with S218L missense CACNA1A gene mutation has also been reported (5). It is possible that given the underlying lower threshold for cortical spreading depression in these patients secondary to channel dysfunction, an apparently trivial trigger such as minor head injury or emotional stress results in changes at the cellular level, with significant cellular damage and disruption of the blood–brain barrier.
EA2 is another paroxysmal disorder characterized by brief attacks of ataxia, imbalance, and vertigo lasting for several hours that may be precipitated by emotional stress and physical exertion (6). Although considered a paroxysmal disorder, patients may exhibit only progressive ataxia without episodic exacerbations (7) and > 90% of patients with EA2 may exhibit oculomotor disturbances such as gaze-holding deficits, saccadic smooth pursuit, and nystagmus (8), and slowly progressive limb ataxia and postural imbalance. This phenotype is consistent with the clinical findings of the patients presented in this report, where they not only exhibited ataxia during the acute events, but also had interictal manifestations of cerebellar dysfunction as described in the neurological examination. Common findings on MRI in patients with EA2 include cerebellar atrophy, especially over the anterior vermis (9). When one considers the young age of our patients, 14 and 15 years at the time of presentation, the cerebellar and vermian atrophy seen in imaging studies is more than expected for an otherwise healthy adolescent.
Episodic confusional states and varying degrees of changes in mental status as part of the migraine complex have been described since the 1800s, especially in patients with basilar-type migraine. In the paediatric population, episodic acute confusional states have been recognized by some neurologists as a manifestation of childhood migraine unique to young patients, and is referred to by some as ‘migraine variant’.
The term acute confusional migraine (CM) was first suggested in 1970 by Gascon and Barlow, who described four cases of migraine in childhood presenting as an acute confusional state (10). In addition to episodic confusion, aphasia can accompany an agitated state. These symptoms can last 2–24 h, followed by migraine headache, and CM is a diagnosis of exclusion (11). Mild head trauma is a common trigger for CM as it is for HM attacks (12).
Information regarding confusional migraine is, for the most part, limited to case reports in the medical literature. A retrospective study conducted by Strain et al. (13) described the clinical characteristics of 22 patients and reviewed those published in the literature. Fifty-six of these patients were male, with mean age of onset of symptoms of 12 years. The most common symptoms included headache, disorientation, agitated state and impaired speech. The average duration of the attack was 5 h, although some patients exhibited symptoms for up to 2 days. Of note, mild head trauma preceded the attacks in 30% of the patients. As mentioned above, fatal cases of cerebral oedema following minor head trauma have been reported in patients carrying CACNA1A mutations; similarly, a relationship between this entity and trauma triggered migraine, which may also manifest with an agitated state, needs to be considered and genetic testing for CACNA1A mutations should be considered (14).
The diagnosis of CM must be considered only with caution; an acute confusional state may be the result of multiple disease processes, some of which can be life-threatening, including meningitis, toxic ingestions, and post-ictal states. Therefore, appropriate investigations including toxicology screen, EEG and, in certain cases, neuroimaging and cerebrospinal fluid analysis need to be carried out before this diagnosis is made. Special consideration must be given to EEG interpretation, since abnormal findings such as transient slowing during the acute confusional state have been described in these patients, which could lead to a misdiagnosis of seizures. Once other diagnostic possibilities have been excluded, a diagnosis of CM can be made.
Significant clinical overlap exists between the three syndromes, FHM, CM and EA2. Migraine with and without aura have been described in more than half of patients with EA2; patients with EA2 may also experience hemiplegia during the ataxic episodes, and patients with HM often experience cerebellar symptoms such as ataxia and nystagmus both during and in between spells.
In 1999, Battistini et al. (15) reported two sisters who experienced severe attacks characterized by fever, confusion and hemiparesis, associated with progressive cerebellar ataxia and evidence of cerebellar atrophy on MRI studies. Mutation analysis in the two sisters showed the same R583Q mutation that was identified in our family, which happens to be one of the most common mutations reported in patients with FHM as well as in cases of EA2.
Further studies by Ducros et al. (1) described the phenotype–genotype correlations in patients with FHM and CACNA1A mutations. Of 104 patients identified, 21% reported some degree of confusion or somnolence during the hemiplegic attacks. Sixty-six atypical attacks were reported in these patients, characterized by severe diffuse encephalopathy, hemiplegia and fever, with symptoms lasting up to 6 weeks followed by full recovery; most of these attacks occurring in young patients (mean age 21 ± 16 years). Furthermore, 13 subjects with CACNA1A mutations did not have a history of hemiplegic attacks. One of these patients presented with episodes of headache and loss of consciousness. Cerebellar symptoms were prominent in this group. As mentioned above, although transient alterations in mental status have been reported in the presence of hemiplegic attacks, to our knowledge our proband patients represent the first reported cases of an expanded phenotype of CACNA1A mutations, manifested by episodic confusional states in association with cerebellar symptoms in the absence of hemiplegic attacks.
Consideration should be given to genetic testing for these mutations in patients with acute confusional states regarded as migraine variants (once other causes have been excluded), especially in the presence of cerebellar findings or symptoms, even in the absence of hemiplegic attacks and signs of cerebellar disease, when isolated confusion seems to be the predominant manifestation. Accurate diagnosis in these patients will help guide appropriate treatment, and more specific therapies such as acetazolamide or calcium channel blockers should be considered. Further, as the syndromes associated with calcium channelopathies expand (16), consideration should be given to genotypic rather than phenotypic classification.