Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental condition with onset before 18 months of age, characterized by recurrent attacks of hemiplegia involving one or both sides of the body that typically resolve on sleep, and other paroxysmal disturbances including epilepsy, paroxysmal dystonic attacks, oculomotor abnormalities, and autonomic phenomena. Subsequently, non-paroxysmal neurological signs appear, such as cognitive impairment and movement disorders including choreoathetosis, dystonia, or ataxia. Mutations in the ATP1A3 gene, encoding the α3 isoform of the Na+/K+ ATPase pump, are reported in ~85% of individuals.1, 2 Mutations in the same gene are also associated with other clinical syndromes.3-7

Disease course and progression in AHC is now a matter of debate. A non-progressive course has been described in the past,8 whereas in a more recent case series, seven patients, aged 12 years and below, were reported to have experienced abrupt and irreversible regression along with significant acquired cortical and cerebellar atrophy.9 Slow and mild progression of non-paroxysmal disability were recently observed in a multicentric cohort of 94 children and young adults.10

The only case of regression in adulthood described so far happened in concomitance with frequent episodes of status epilepticus, but few details regarding neurological function are given and the time course is unprecise.11

We report seven adult patients with AHC with detailed clinical history and long-term follow-up, adding data on the natural history of the disease and its phenotypic variability. Three of them presented acute regression, which we characterize with respect to clinical features, precipitating factors, genotype, and treatment.

Methods

All patients and/or their parents/legal guardians gave informed consent/assent, including for video-recordings. This study was approved by the local Ethics Committee. Clinical records of patients attending University College London Hospitals (UCLH), with a clinical diagnosis of AHC according to the Aicardi criteria,12 were reviewed. Video-recordings of the neurological examination were acquired between May and September 2019.

Sequencing of the ATP1A3 gene was performed in all individuals with the identification of a pathogenic ATP1A3 mutation in six out of seven. One patient had whole-exome sequencing, which did not identify any ATP1A3 or other gene pathogenic variants.

Results

We describe seven adult patients (six female, one male; age range, 25–42 years), diagnosed with AHC and followed-up at our center for a median of 16 years (range, 7–24 years). The disease course for each individual is detailed in Table 1 and Video 1. During follow-up, 3 of 7 patients experienced an episode of abrupt neurological deterioration in adulthood (age range at onset of deterioration, 19–34 years), following a febrile illness that triggered an extremely prolonged quadriplegic episode (n = 1), status epilepticus (SE) (n = 1), or both (n = 1). These adults went from being able to walk independently to being wheelchair-bound, and they went from being mildly dysarthric to almost full loss of language function. One of them developed severe spastic tetraparesis with joint contractures and severe axial hypotonia with impaired head control (Video 1, patient 2). All three patients required percutaneous endoscopic gastrostomy (PEG) insertion because of severe dysphagia. One of the three died at age 29 years likely because of pneumonia (as stated on the death certificate), 10 years after the episode of acute neurological deterioration: she had had a cough and fever and post mortem computed tomography (CT) findings showed bilateral pulmonary consolidation. These patients with a history of severe regression carried three different mutations, S137F, S811P, and E815K. They were all on flunarizine as part of their regular treatment and had had no recent interruption in its use.

TABLE 1. Clinical features, diagnostic findings and treatment Patient N Age, gender ATP1A3 mutation Age of onset (mo) Symptoms at onset Paroxysmal features Non- paroxysmal features Psychiatric features Other Baselinea GMFCS score23 Last GMFCS score23 Intellectual disability History of epilepsy and SE History of acute regression Treatment EEG (age in yr) MRI (age in yr) 1 42, F c.2839G > A; p.G947R 3 Paroxysmal nystagmus and hemiplegic episodes, hypotonia Hemiplegic episodes, paroxysmal dystonic attacks, myoclonus, headaches Ataxia, hypotonia, chorea, dystonia, mild spastic paraparesis, dysarthria Visual and auditory hallucinations, onset in her 30s Scoliosis 2 2 Mildb No No BAC EEG (2, 18, 23, 30, 32) VT (34) some irregular theta activity -Normal (18) -Mild cortical and vermis atrophy (34) 2 34, F c.2431 T > C; p.S811P 1 Paroxysmal eye fluttering, hypotonia Hemiplegic and quadriplegic episodes, headaches, painful muscle spasms Hypotonia, spastic tetraparesis, dysarthria Depression 2 5 Moderate–severeb Yes, last GTC sz age 25 yr Yes (23 yr) after prolonged quadriplegic episode triggered by febrile illness PHT, TPM, FLN, BAC EEG (1) VT (26, 31) abnormal bursts of sharpened slow -Normal (23, 23.5, 24) -Cerebellar atrophy, vermis and superior hemispheres predominant (25) 3 27, M c.2214A > C; p.S772R 12 Paroxysmal nystagmus and quadriplegic episodes, hypotonia Hemiplegic episodes, paroxysmal dystonic attacks, headaches Ataxia, dysarthria No Fatigue 1 1 Mildb Yes, SE age 15 yr No TPM, FLN, PZT EEG (11, 16) normal Normal (19) 4 25, F c.2839G > A; p.G947R 3 Dystonic attacks, hypotonia Hemiplegic episodes, paroxysmal dystonic attacks, headaches Ataxia, mild dysarthria No Fatigue 1 1 Mildb No No No EEG (1) normal Normal (1) 5 37, F None 4 Hemiplegic episodes, hypotonia Hemiplegic and quadriplegic episodes, painful muscle spasms Mild ataxia, ligamentous laxity Depression, episodes of persecutory delusions with aggression Fatigue 1 1 Mild No No ZNS, FLN, PZT EEG (9, 10, 11, 21, 24) VT (25) non specific theta abnormalities Cerebellar atrophy (19, 24) 6 29, F (deceased) c.2443G > A; p.E815K 2 Dystonic attacks, hypotonia Hemiplegic episodes, paroxysmal dystonic attacks, myoclonus, headaches Dystonia, choreoathetosis No 4 5 Moderate–severeb Yes, focal sz recorded during sleep age 24 yr Yes (19 yr) after febrile illness LCS, FLN, CLB EEG (2, 3) normal VT (24) Focal spikes Normal (10) 7 34, F c.410C > T; p.S137F 1 Paroxysmal eye fluttering, hypotonia Hemiplegic episodes, paroxysmal dystonic attacks, headaches, autonomic spells Ataxia, dystonia No Fatigue 1 3 Moderateb Yes, SE age 34 Yes (34 yr) after febrile illness and SE LEV, FLN, PZT, CBZ VT (23) diffuse slowing of background and generalized spike and slow waves (frontal dominant) Left hippocampal sclerosis (5, 23) Abbreviations: GMFCS, gross motor function classification system; SE, status epilepticus; VT, video-telemetry; GTC sz, generalized tonic–clonic seizure; BAC, baclofen; PHT, phenytoin; TPM, topiramate; FLN, flunarizine; PZT, pizotifen; ZNS, zonisamide; LCS, lacosamide; CBZ, carbamazepine; CLB, clobazam.; LEV, levetiracetam; yr, yearrs.

Patient 1. At rest, she shows mild dystonic features, more prominent on the right side and a few generalised jerky movements. Her speech is mildly dysarthric. With arms outstretched, dystonia of upper limbs becomes more evident. At the finger-to-nose test, there is some dysmetria on the right. Fine movements are impaired, more on the right, with great asymmetry. There is no true bradykinesia but some clumsiness bilaterally. Handwriting is legible but clearly dystonic. When walking, there is in-turning of the feet, mainly on the right and abnormal posturing of both arms, flexed and with hands in a clenched fist. Posture is impaired, with mild antecollis. Patient 2. She is wheelchair-bound with permanent right-sided hemiplegia. She has also bilateral foot in-turning with reduced articular mobility. When repeatedly stimulated, she can keep eye contact. Reaching movements are possible with the left arm. Head control is impaired, with limited ability to follow an object and sudden head drops. She has striatal toes and extension at the plantar reflex. Patient 3. When seated, he has mild truncal deviation towards the left. With arms outstretched, mild dystonia of the upper limbs becomes more prominent. There is some clumsiness during prono-supination of the arms, along with mobile dystonia. A slight bilateral dysmetria is seen at the finger-to-nose test. At finger tapping there is no true bradykinesia, but the fluidity of the movement is bilaterally reduced due to the dystonia. In this segment of the video it is also possible to notice a reduced blink rate and a mild antecollis. Handwriting is barely intelligible, and severe dystonic posturing of the right hand while holding the pen is shown. While walking, hands are both held in clenched fist, with some involuntary proximal jerky movement of the arms. There is mild antecollis. He complains about fatigue, however he can walk independently for few meters. Patient 4. She is examined at the end of a prolonged right hemiplegic episode which evolved into paroxysmal dystonic attack. The right arm is still flexed, held in front of the body with the hand raised upwards. The rest of the examination is typical of her interictal condition. Her speech is clearly dysarthric. When asked to outstretch her arms and pronate/supinate the hands, she shows a bilateral, distal mobile dystonia with overflow phenomenon. No clear dysmetria at the finger-to-nose test, while fine hands movements are severely impaired on the right, due to the dystonia. However, handwriting is clear. Gait is independent with mild antecollis and some jerky movements of the left upper limb.

The remaining four patients developed other new symptoms in adulthood: fatigue (n = 4), psychiatric symptoms (n = 2), painful muscle spasms (n = 2), and scoliosis (n = 1). In particular, one individual showed significant deterioration of a pre-existing movement disorder, with new onset of myoclonus (Video 1, segment 5); four individuals started to show signs of fatigue, becoming dependent on a wheelchair for short/medium distances, and two individuals started to complain of painful muscle spasms, which partially responded to baclofen. With respect to psychiatric issues, one patient experienced recurrent hallucinatory symptoms with aggression and the other had recurrent episodes of persecutory delusions on a background of low mood. To date, these symptoms have been relatively stable without the need for psychiatric treatment. One patient is awaiting psychiatric assessment.

Discussion

Our cohort suggests that individuals with AHC may experience either abrupt or slowly progressive worsening of their neurological function and for most adults the hemiplegic episodes may no longer be the main clinical issue.

A previous longitudinal characterization of large AHC cohorts suggested a generally non-progressive course of AHC,8 but adult patients represented a small proportion of the group (14/157). Review of the data in that report shows that 5 of 14 adults developed fine motor abnormalities after infancy (three in childhood, one in adolescence, and one in adulthood), 3 of 14 developed chorea and/or dystonia after infancy (two in late childhood, one in adulthood) and 2 of 14 developed new-onset hypotonia and gross motor abnormalities after the age of 24 years. More recently, Uchitel et al10 described a large cohort of 94 children and young adults that they studied retrospectively and partly prospectively with a linear mixed effects model and observed a mild decline in non-paroxysmal disability. Their methodological approach allowed to detect subtle degrees of progression and their cohort included 7 of 42 adults (age range, 20–43 years; mean follow-up, 3.4 years) prospectively evaluated, and 23 of 52 adults in the retrospective analysis (19–39 years, mean follow up 9.9 years). In this cohort, a “catastrophic” regression is described in one subject, who did not have an ATP1A3 mutation.

Other authors have already noted that movement disorders and spasticity can appear at a later stage,13 but, to the best of our knowledge, this is the first report of fatigue and muscle spasms in adults with AHC. Although muscle spasms could be interpreted as painful paroxysmal dystonic attacks, their predominance at night and their response to baclofen suggest they may be associated with chronic spasticity (as in multiple sclerosis).14 The same parallel with multiple sclerosis can be proposed for fatigue, the most common disorder where this symptom presents along with chronic spasticity. Fatigue could be also associated with the fear of exercise-induced paroxysmal events.

In terms of psychiatric features, in a recent publication, 20/25 individuals with AHC had a neuropsychiatric diagnosis including attention deficit/hyperactivity disorder (ADHD), disruptive behavior, and mood disorders,15 but only three individuals were adults. Additionally, two individuals with a severe AHC phenotype and childhood-onset schizophrenia have been reported.16 Milder adult-onset psychiatric features have been described in two adult individuals with difficulties in social integration.17 It is not clear whether these psychiatric manifestations are independent comorbidities or if they are a new feature directly linked to the genetic mutation. We cannot exclude that psychiatric disorders in adults with AHC might be under-reported.

Of our seven patients, three experienced an abrupt neurological regression in adulthood, following a febrile illness that triggered either or both an extremely prolonged quadriplegic episode and status epilepticus. There are at least 17 reports of abrupt neurological regression,11, 18, 19 although these were not always fully characterized (Table 2). Median age at regression was 6.5 years and only one patient was an adult.11 Of the 10 patients with available genetic data, six had the E815K mutation, which was proposed as a risk factor for acute regression. It was also observed that only one patient was on flunarizine, whereas the others had either recently discontinued it or never used it. In all these reported patients, catastrophic events were preceded by status or very frequent seizures. In our cohort, one of the three adult patients who experienced an acute regression had the E815K variant, whereas the others did not, and all were on flunarizine; regression was triggered by prolonged quadriplegia and fever and not only by seizure activity. Notably, none of the 13 patients (10 previously reported and three from our series) with a history of acute regression had the most common (D801N) recurrent mutation.

TABLE 2. Clinical and genetic features of patients with acute clinical regression ID Mutation Age at regression (y) Language regression Motor function impairment Precipitating events Flunarizine treatment with respect to onset of clinical regression References Sasaki-1 p.E815K 5 Words → absent Stand → bed SE, fevera Discontinued 2 years before 17 Sasaki-2 p.E815K 10 Absent Bed SE Discontinued same year 17 Sasaki-3 p.E815K 6 Sentence → words Sit → bed SE, fevera Discontinued 1 year before 17 Sasaki-4 p.E815K 7 Words Stand → bed SE Discontinued 1 year before 17 Sasaki-5 p.E815K 4 Words → absent Stand → bed SE Discontinued 1 year before 17 Sasaki-6 p.G755S 12 Words → absent Stand → bed SE Ongoing treatment 17 Sasaki-7 p.815 K 3 Words → absent Sit → bed SE Never used 17 Uchitel-21 Not identified 8 Sentence Residual hemiparesis SE Never used 19 Uchitel-32 p.V589F 2 – Walk → bed SE Never used 19 Ito p.G755S 38 – Walk → bed SE Discontinued 13 years before 20 #2 p.S811P 23 Sentence → words Walk → bed Fever followed by quadriplegia Ongoing treatment Current study #6 p.E815K 19 Words → absent Crawl → bed Fever followed by SE/quadriplegiab Ongoing treatment Current study #7 p.S137F 34 Sentence → words Walk → sit Fever followed by SE/quadriplegia Ongoing treatment Current study Abbreviations: Bed, bedridden; sit, sit without support; stand, stand with support; walk, walk unassisted; SE, status epilepticus. For the seven patients reported in Panagiotakaki et al17 the only information provided is that the regression was typically triggered by a “stressful event”.

In addition, there are 11 reports8, 20 of sudden unexpected death, an outcome that has recently been grouped together with regression as “catastrophic events in AHC.”20 The cause of these events and in particular the role of paroxysmal events and fever remain elusive. In 8 of 11 patients with sudden death, there were preceding prolonged paroxysmal episodes, either seizures or quadriplegic episodes.8, 20 Conversely, in a large clinical cohort, the previous degree of fixed disability emerged as the only significant risk factor for mortality, whereas the severity of paroxysmal events was not associated with early death.8 Episodes of abrupt onset or worsening of neurological signs triggered by fever or other stressors have been reported in other ATP1A3-related conditions such as rapid-onset dystonia parkinsonism21 and relapsing encephalopathy with cerebellar ataxia,22 where paroxysmal events are not a feature. This suggests that paroxysmal events and catastrophic events may be provoked by the same trigger, but are not causally linked.

Compared with the existing literature,8,12,13 we add here further characterization of the AHC course in adulthood and new information on genotype–phenotype correlation: we did not find an association between acute regression and mutation type or lack of flunarizine treatment as previously reported,10,18,19 although we acknowledge the small sample size of our cohort. In conclusion, our case series of patients with long follow-up in adulthood provides useful insights on the natural history of AHC. In the long term, most patients have reduced frequency of paroxysmal events. However, adult patients may present with new onset of fatigue, muscle spasms, psychotic symptoms, and aggravation of movement disorders, all of which have a detrimental impact in their quality of life and level of independence. Finally, a sudden and irreversible deterioration of their condition, mainly with pyramidal and bulbar signs, may occur not only after status epilepticus, but also after prolonged non-epileptic spells, which should, therefore, be promptly treated. Our report expands the spectrum of clinical and genetic factors associated with neurological regression in AHC. Understanding the evolution of disease in adulthood and its associated pathophysiology will help to design targeted interventions.

Acknowledgments

We thank the patients and their families for participation in our research.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.

M.P.: 1A, 1B, 1C, 3A

J.P.: 1C, 3B

G.D.L.: 1C, 3B

S.D.A.: 1B, 3B

K.S.: 1B, 3B

S.Z.: 1B, 3B

D.J.J: 1B, 3B

D.B.: 1A, 3B

S.M.S.: 1A, 3B

S.B.: 1A, 3B

Disclosures Ethical Compliance Statement

We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. This study was approved by the UCLH Ethics Committee. Patients have signed consent for video acquisition and publication.

Funding Sources and Conflicts of Interest

The authors report no sources of funding and no conflicts of interest.

Financial Disclosures for the Previous 12 Months

J.P., S.D., S.B., and S.M.S. are supported by the Epilepsy Society. S.B. is supported by the Muir Maxwell Trust. Part of this work was undertaken at University College London Hospitals, which received a proportion of funding from the National Institute for Health Research (NIHR) Biomedical Research Centres funding scheme. K.S. is supported by a Wellcome Trust Strategic Award (WT104033AIA).