Combined early treatment in hemiplegic attacks related to CACNA1A encephalopathy with brain oedema: Blocking the cascade?

Abstract

Introduction

Variants in the CACNA1A gene on chromosome 19p13 result in a spectrum of neurological phenotypes ranging from familial or sporadic hemiplegic migraine to congenital or progressive encephalopathies. Patients with CACNA1A variants often show acute attacks with ataxia or hemiplegia till coma, sometimes related to unilateral brain oedema. No guidelines for the medical management of these attacks are available since treatment is empiric, and many cases do not respond to common antimigraine drugs.

Case description

We report on the emergency personalized treatment protocol used in an 11 year-old girl with CACNA1A-related encephalopathy for the management of acute attacks of headache, hemiconvulsions and hemiplegia with coma.

Discussion

Combined corticosteroid pulses and hypertonic solution led to a reduction in severity and duration of acute attacks when administered in the early stages, characterized by migraine, seizure, fever, vomiting and impairment of consciousness associated to hemispheric slowing on the EEG.

Introduction

The CACNA1A gene encodes the alfa-1 subunit of the voltage-dependent calcium channel Ca_v2.1, which regulates neurotransmitters release in central synapses. Functional studies have revealed essential changes in the gating properties leading to a channel gain of function in patients with CACNA1A variants (1).

The clinical phenotype related to CACNA1A mutation is heterogeneous, ranging from familial or sporadic hemiplegic migraine type 1 (FHM/SHM) to episodic ataxia type 2, to other forms of congenital or progressive ataxia (1). The clinical presentation of FHM/SHM varies from pure hemiplegic migraine to severe early-onset forms with permanent cerebellar ataxia and, rarely, epilepsy, elicited repetitive transient blindness or intellectual disability (2–5). Reversible cerebral oedema and coma are described in attacks of hemiplegic migraine in otherwise normal subjects, as well as in children with encephalopathy (4,5). These acute episodes are frequently triggered by exogenous factors such as minor head trauma, fever or other stress (6) and can be extremely severe, lasting weeks to months and requiring ICU admission (7–9).

The pathogenesis of migraine attacks and cerebral oedema is not well understood and their management is still empiric; patients often undergo prophylactic treatment with antimigraine drugs, most commonly acetazolamide and flunarizine, with partial efficacy (10).

We describe a child with encephalopathy, cerebellar atrophy and severe episodes of hemiplegic migraine with coma related to unilateral brain oedema. An individualized treatment protocol resulted in the reduction of the severity and length of the attacks.

Case report

The patient, an 11-year-old girl born after an uneventful pregnancy, presented developmental delay that ended in a stable intellectual and motor disability with hypotonia, ataxia and pyramidal signs at the lower limbs. The first brain MRI performed when she was one year old was normal (Figure 1a, b).

Figure 1.

Brain MRI findings. Figure 1a, b, c: One year old. Coronal Fluid Attenuated Inversion Recovery (FLAIR) and axial T2- and T1-weighted images do not reveal definite brain abnormality. Figure 1d, e, f: Three years old. Coronal FLAIR, axial and coronal T2-weighted images demonstrate volume loss of both cerebellar hemispheres with local hyperintensity of the cerebellar cortex (arrows, d). There is concomitant ex-vacuo enlargement of the fourth ventricle and infratentorial subarachnoid spaces. Figure 1g, h: Six years old. Axial FLAIR image shows hyperintensity and mild swelling of the left striatum (arrows, g); corresponding ADC map demonstrates increased diffusivity (arrows, h) in keeping with vasogenic oedema. Figure 1i: Six years old. Follow-up MRI performed six months later shows complete resolution of the striatal lesion. Figure 1j, k: Nine years old. Axial FLAIR and coronal T2-weighted images show mild hyperintensity and swelling of the left hemispheric cerebral cortex (arrows) with mild shift of midline structures. ADC maps (not shown) demonstrated facilitated diffusion. Post-contrast imaging did not reveal areas of pathologic enhancement (not shown). Figure 1l: 10 years old. Axial FLAIR image shows complete normalization of the picture.

When three years old, she experienced a two-hour episode of unconsciousness, followed by vomiting, fever and left hemiconvulsions. Midazolam was effective on the convulsive status, but left hemiparesis persisted for the following three weeks. Blood and cerebrospinal fluid examination excluded metabolic and infectious causes, while the MRI revealed cerebellar atrophy along with local hyperintensity of the cerebellar cortex (Figure 1c, d, e).

A muscle biopsy with oxidative chain and Coenzyme Q10 dosage, molecular analysis for MELAS, mitochondrial tRNA, MTATP6/MTATP8, CGH array, methylation test, UBE3A, SPG35, and PLA2G6 were negative.

After this episode, a focal epilepsy appeared with brief daily episodes after awakening (grimace and loss of tone with backward fall), drug-resistant to phenobarbital, carbamazepine, topiramate, lamotrigine, levetiracetam and clobazam. Moreover, nystagmus became evident and episodes of apnoea appeared while awake.

When six years old, she presented a second attack characterized by impaired consciousness, right hemiconvulsions then hemiplegia, lasting two weeks.

Brain MRI showed mild swelling and oedema involving the left striatum (Figure 1g, h) and progression of cerebellar atrophy. A subsequent brain MRI performed six months later showed complete resolution of the striatal lesion without evidence of sequelae (Figure 1i).

When nine years old, she was admitted to ICU because of a third attack with impaired consciousness, right hemiconvulsions and hemiplegia. The EEG showed diffuse slowing over the left hemisphere. The brain MRI demonstrated small patchy areas of restricted diffusion in the left frontal, temporal and parietal cortex. Cerebrospinal fluid examination was normal. After one week, an empiric therapy with dexamethasone (0.6 mg/Kg/day in three pulses) was tried for persisting drowsiness and hemiparesis, producing gradual improvement. A control MRI, performed two weeks later, showed swelling and oedema of the left hemispheric cerebral cortex (Figure 1j, k). In the hypothesis of a CACNA1A-related encephalopathy, acetazolamide was added and steroids were reduced, with a sudden worsening of consciousness. Therefore, steroids were raised and hypertonic solution was added for five days with subsequent rapid improvement (hemiparesis resolved completely in four months). A follow-up MRI performed one year later showed complete regression of brain oedema (Figure 1l).

The patient’s DNA was extracted from blood leukocytes using the Maxwell Extractor (Promega), according to the standard protocol. The coding region and flanking intron sequences of the CACNA1A gene were analysed by direct Sanger sequencing. The analysis identified a nucleotide substitution in exon 25 (c.4046G>A) leading to the missense variant p.Arg1349Gln in the putative protein. The variant was not present in the parents.

Flunarizine, acetazolamide and further valproate did not change the sudden increase in the frequency of the episodes (to five to six per year), characterized by hemiconvulsion, then headache, vomiting, fever, and drowsiness till coma with hemiparesis. Only two attacks occurred after minor head trauma. The EEG performed at the beginning of the attacks always showed an asymmetric slowing in one hemisphere, in concordance with the lateralization of clinical signs, sometimes with a paroxysmal activity interposed with the hemispheric delta activity (Figure 2a).

Figure 2.

2a: EEG performed during a hemiplegic attack involving the left side of the body. Wake EEG, SI 10-20, Sens 10 uV/mm, HF 15 Hz, LF 0.10 sec. Continuous slow delta high-amplitude activity on the right hemisphere with superimposed paroxysmal abnormalities predominant on the right frontal regions. On the left hemisphere, a background diffuse activity is evident. 2b: EEG after 10 days. Wake EEG, SI 10-20, Sens 10 uV/mm, HF 15 Hz, LF 0.10 sec. Return to a symmetrical activity with diffuse background rhythms and persistence of rare bilateral paroxysmal abnormalities.

In the first episodes after genetic diagnosis, we started steroid therapy immediately (0.5 mg/kg/day of dexamethasone IV in three pulses/day for three days, followed by gradual oral tapering), with improvement of consciousness, hemiplegia and EEG within the following week (Figure 2b). Surprisingly, during steroid treatment the drug-resistant daily seizures disappeared. During the third relapse we added a two-day treatment with hypertonic solution (saline hypertonic solution at 3%, 1.5 ml/kg/h, with adjustments to maintain sodium levels at between 145 and 155 mEq/L) with further reduction in the duration of the episode (to within three to five days). The efficacy of the combined treatment was confirmed during the following episodes, in which admission to ICU was no longer necessary.

Lamotrigine seemed to be effective in reducing the frequency of the attacks, but the patient was moved to Topiramate after five months because of a skin rash. Under topiramate, no new episodes have occurred for three months.

Discussion

We describe the clinical history and therapeutic approach in a young patient with SHM, intellectual disability and cerebellar atrophy, with acute episodes of hemiplegic migraine, seizures and coma associated with unilateral brain oedema.

The patient bears the R1349Q CACN1A mutation already described in a girl with developmental delay and ataxia who experienced a hemiplegic migraine-like attack with coma and fever associated with unilateral brain oedema (7), supporting a more severe phenotype in patients bearing this variant. No data on treatment efficacy was reported for this case.

We established an emergency protocol of combined corticosteroids and administration of hypertonic solution to be started in the early stage of the attack, characterized by migraine, seizures, vomiting and unexplained fever together with hemispheric slowing on the EEG. This approach reduced the severity of hemiconvulsions occurring during the acute phase and the length of the following hemiplegia and coma, permitting a quicker recovery and early discharge.

Two others patients bearing a different CACNA1A pathogenic variant showed a shortening of the acute stage after methylprednisolone pulses (8,11) and the same was observed in an FHM patient with coma after minor head trauma (12).

Steroids may indirectly inhibit the activity of voltage-dependent calcium channels, reducing the gain of function of the mutated channel, and may mitigate cortical spreading depression, accelerating recovery from brain oedema and reducing the pain (11,13). No data on the use of hypertonic solution has been reported for patients with CACNA1A mutations to the best of our knowledge.

In conclusion, combined corticosteroid pulses and hypertonic solution seem to be an effective treatment for acute episodes in our patient. Despite this, our experience is unique and we cannot demonstrate the efficacy of the treatment for all patients with severe hemiplegic migraine related to brain oedema bearing a CACNA1A mutation.

Further studies are needed to confirm this therapeutic strategy, which should anyway be considered in patients with CACNA1A pathogenic variants and recurrence of episodic brain oedema.